Critical Connections Among Embedding of Childhood Adversity and Adult Chronic Gastrointestinal and Genitourinary Disorders: A Review of the Literature

The origins of gastrointestinal (GI) diagnostic categories, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), as well as genitourinary (GU) diagnostic categories such as endometriosis, pelvic floor disorders, and interstitial cystitis in adults have long stymied clinicians. Meanwhile, the impact of adverse childhood experiences (ACEs) on health and well-being across the lifespan has been definitively demonstrated,¹ with ACEs having a dose–response relationship with the leading causes of death in adulthood as well as associations with population-attributable risks such as substance abuse, job loss, depression, and high-risk sex behaviors.² A gap in the literature exists examining associations between ACEs as potential a priori contributing factors to GI/GU disorders. The purpose of this narrative review of the literature was to explore critical connections between ACEs and GI/GU disorders with a working hypothesis of a dose–responsive relationship existing between them. The background section discusses aspects of biologic plausibility for the associations among ACEs and GI and GU disorders (Figure 1).

ACEs. The dose–response relationship between ACEs and adverse adult health outcomes, both physical and mental, has been definitively demonstrated,^1,3,4 with ACEs being defined as “childhood events, varying in severity and often chronic, occurring within a child’s family or social environment that cause harm or distress, thereby disrupting the child’s physical or psychological health and development.”⁵ ACEs are common across socioeconomic strata, with those who identify as Black or biracial, who have less high school education, grow up in poverty, or identify as gay/lesbian/bisexual/transgender/queer (LGBTQ) at higher risk of ACEs.¹ Originally operationally defined as 10 types of interpersonal adversity (Figure 2), subsequent research has expanded the types of ACEs being measured to include what are often referred to as “community ACEs.”⁶ These include growing up in poverty, witnessing community violence, and experiencing discrimination (racism), among others (Figure 3). The cumulative nature of ACEs contributes to toxic stress, which is adversity that is prolonged; lacking sufficient adult support, children with toxic stress have overwhelmed coping mechanisms, and the hypothalamic-pituitary-adrenal (HPA) axis stress response shifts from adaptive to maladaptive.⁷

Ongoing research is establishing a causal link between ACEs and poor health outcomes.⁸ These associations are due in part to increased health-risk behaviors (HRBs): a dose–response relationship has been demonstrated between ACEs and smoking, alcohol, disordered eating, physical inactivity, and high-risk sex behaviors.⁹ ACEs impact brain development, disrupt immune and hormone systems function, and influence genetic expression; these influences result in biologic embedding of child adversity and often persist throughout the lifespan. Persistent or frequent physiologic responses to toxic stress take their toll, causing premature “wear and tear” on the body that has been described as allostatic load.⁸ Although one operational definition has not been universally accepted, allostatic load can be measured by aggregating such disease risk markers as blood pressure, body mass index (BMI), waist circumference, and blood glucose. Additional biomarkers include C-reactive protein and interleukin-6.¹⁰

Positive childhood experiences. Positive childhood experiences (PCEs), sometimes referred to as benevolent or counter-ACEs, and advantageous childhood experiences, are being researched and discussed in academic literature, with results demonstrating that a higher ratio of counter-ACEs to ACEs mitigates the impact of childhood adversity on health outcomes.^11-14 Examples of PCEs include having at least 1 caregiver with whom one felt safe; building a relationship with at least 1 good friend; having beliefs that gave one comfort; enjoying school; having good neighbors; and establishing a predictable home routine.¹⁴ Screening for PCEs alongside screening for ACEs is increasingly being recommended as a strengths-based approach; this approach may provide hope both for families that experience an ACEs screening as negative as well as for health care providers who are uncomfortable with screening.¹¹ PCE research points to evidence-based preventive interventions in pediatric patients. Lived experience, both good and bad, becomes a person’s biology; researchers hypothesize that the presence of PCEs increases the ability to manage stress, thereby decreasing allostatic load.¹⁵

Mediators for biological embedding.

Brain development. Between the ages of 0 and 3 years, the brain makes 1 million connections every second based on lived experience, both good and bad. As the cortex develops, pruning of unused circuits also occurs.¹⁶ Reduced global volume, alterations in limbic circuitry that are responsible for emotion, and alterations in prefrontal cortex development have been demonstrated in trauma-impacted individuals.¹⁶ Children raised with good-enough parenting develop more cortisol (stress hormone) receptors, allowing for rapid stress response resolution; those with ACEs without good-enough parenting have brains that have fewer cortisol receptors, thereby wired for slower stress response resolution.¹⁶

Epigenetics. Epigenetic research demonstrates the intimate connection between environment and genetic expression. Only 2% of genetic expression is due to an individual’s genetic template; the remaining 98% is mediated by the influence of epigenomes, proteins that essentially turn on and off genes.¹⁷ In his cross-discipline literature review of human population studies and animal model experimental studies, Cunliffe¹⁷ demonstrated how prolonged social stress becomes biologically embedded. The experience of social adversity, including low socioeconomic status and poor social determinants of health, during fetal gestation and through childhood can induce changes in genetic expression through DNA methylation; stress disorders are transmitted intergenerationally in both animal models (3 generations) and human models (1 generation to date).¹⁸

Vagus nerve. The vagus nerve is the largest nerve in the body, allowing for bidirectional communication between internal organs and the brain. Traditionally understood through the lens of efferent (brain to organs) communication, the vagus nerve is, in fact, primarily afferent, with 90% of communication flowing from internal organs to the brain.¹⁹ Commonly referred to as the “brain-gut axis,” or “microbiota-gut-brain axis,” the vagus is intimately interconnected with the enteric nervous system as well as intestine microbiota, influencing the immune system and inflammation. The vagus nerve is considered the sixth sense due to its interoceptive awareness,²⁰ and it is increasingly a therapeutic target for GI disorders, such as IBD.¹⁹ Porges(21) has developed the polyvagal theory, which asserts that the autonomic nervous system, in mammals, evolved to have two branches of the vagus nerve. The dorsal branch innervates organs below the diaphragm, giving us a “gut sense,” and is responsible for the parasympathetic survival pattern of freeze. The ventral branch innervates organs above the diaphragm, forming the ventral vagal complex (VVC), also known as the “social engagement system.” The VVC innervates lower facial muscles, influencing expression; the inner ear, influencing the ability to tune into one person’s voice; the larynx, influencing tone of voice; and organs above the diaphragm, influencing heart rate, breathing, and digestion.²¹ This discovery is deepening the understanding of the inseparability of the body and mind and the dose–responsive relationship between childhood adversity and health outcomes. Vagal tone, which is measurable on an electrocardiogram tracing by the amount of sinus arrhythmia present, reflects the degree of vagus nerve myelination; increased myelination facilitates nerve conduction.¹⁹ Pellisier et al conducted a paired cohort study (n = 96), in which a reduction in vagal tone was demonstrated in IBS and IBD.²²

Microbiome. Gut microbiota, including bacteria, eukaryotes, and yeast, evolved as humans evolved, developing a symbiotic relationship. Microbes communicate with the brain through multiple pathways, including the immune system, the vagus nerve, and hormonal messaging, influencing brain development and likely emotional regulation and cognition.²³ A review article has shown that the cross-talk between the brain and the GI tract is complex and works in a bidirectional fashion.²⁴ Microbial dysbiosis is well documented in GI disorders, with speculation that it may be a contributing factor to chronic disease; the microbiota-gut-brain axis is thought to influence intestinal permeability and pro- or anti-inflammatory vagus nerve reflexes.²⁰ Dietary factors inform epigenetic influence on gene expression; it is postulated that microbiota mediate interactions between genes and the environment. In mice, anxiety and inflammation increased when obesity-associated microbiota were transplanted, microbiome composition changed with stress, and microbiota depletion via administration of antibiotics resulted in cognitive deficits.²³

The gut–brain axis plays a role in the neurobiology of appetite and eating behaviors. Obesity, which affects over one-third of the world’s population,²⁵ is increasing in global prevalence. The GI tract is the largest endocrine organ in the body, releasing more than 20 peptide hormones. Ghrelin, a GI hormone, is orexigenic (ie, appetite stimulating). Ghrelin stimulates brain centers to drive food consumption. Eating behaviors and appetite result from these gut microbiota-hormonal-brain interfaces.²⁴ Although the science is still in nascent stages, the gut microbiota may provide a link among neurohormonal, immunologic, and environmental influences on subsequent human health, especially for GI diseases and unhealthy eating patterns.

The authors conducted a search of English-language literature (2015 through 2020) about ACEs and adult GI and GU disorders. In MEDLINE, the term ACEs generated 2807 citations; when combined with GI disorders, the number dropped to 8. ACEs and GU disorders generated 0 citations. More discrete wording yielded selected citations. ACEs and pelvic pain generated 6 citations.

In searches of the Cumulative Index of Nursing and Allied Health Literature (CINAHL) database, the term ACEs generated 1953 citations. When combined with GI disorders, 4 citations were identified. ACEs and GU disorders generated 0 citations. However, ACEs and pelvic pain generated 5 citations. Using more discrete wording yielded selected citations. ACEs and irritable bowel syndrome identified 3 citations whereas ACEs and inflammatory bowel disease yielded 7 citations. In CINAHL, the combined terms ACEs and cancer generated 75 citations. In MEDLINE, this same search generated 138 citations. The abstracts and titles were reviewed and culled for inappropriate focus and duplications.

Searches were conducted in PubMed with the same parameters. ACEs and GI disorders yielded 10 articles, 3 of which were excluded. ACEs and IBS and ACEs and IBD yielded 3 and 5 articles, respectively, of which 5 were excluded. ACEs and encopresis yielded 0 articles. ACEs and GU disorders yielded 5 articles, 2 of which were pertinent. ACEs combined with the terms interstitial cystitis, prostatitis, and enuresis yielded 2, 5, and 2 articles, respectively. Of those, a total of 5 articles were pertinent. ACEs and gynecological cancer identified 3 useful articles.

A search was conducted in Web of Science for recent articles (2020). When ACEs and obesity (as a risk factor) were combined, 35 articles were identified. Obesity was included to ascertain any potential overlap with cancer, GI, and GU disorders.

During a final review of all pertinent articles, those determined to have an inappropriate focus were removed, and duplicates were omitted. A total of 58 citations was used.

GI disorders. Several GI disorders, including cancer (eg, colorectal cancer) and cancer screening have been studied in relation to ACEs as a predictive factor for adult cancer incidence, cancer survival, IBS, IBD, GI disorder symptom severity, aerophagia, abdominal pain, and constipation (Table and Table continued). The impact of adversity on the GI tract and food consumption has been scrutinized via analysis of ACEs and obesity and bariatric surgery.

As a disease entity, cancer has received significant emphasis related to ACEs. Alcalá et al²⁶ used ACEs data from the Behavioral Risk Factor Surveillance System (BRFSS), including Americans over age 18 years from 10 states (N = 11 794), and linked results to reported adult diseases. Logistic regression modeling was used to estimate odds of ever having been diagnosed with cancer after experiencing ACEs. The analyses were adjusted for potential confounders and stratified by gender. For women, higher odds of cancer were associated with physical, sexual, emotional abuse, living with a mentally ill person, a problem drinker, a drug user, and a violent household. For men, only emotional abuse was associated with higher odds of cancer. The adjusted odds ratios (AORs) for all participants for cancer occurrence were highest for sexual abuse (AOR = 1.63; 95% confidence interval [CI] = 1.36-1.94) and living with a drug user (AOR = 1.52; 95% CI, 1.21-1.91). For women, these same 2 ACEs were identified as highest odds, whereas for men only emotional abuse was associated with higher odds (AOR = 1.41; 95% CI, 1.13-1.77). The researchers described biological and behavioral pathways by which ACEs can increase the risk of cancer. For women, sexual abuse exposes more women than men to virally associated cancers (ie, cervical cancer).

Holman et al²⁷ conducted a systematic review of the literature on ACEs and adulthood cancer risk. They used PUBMED original research that quantified the association between ACEs and cancer incidence in adults and was published on or before May 31, 2015. Twelve (12) studies were identified in the review. Although they were unable to compute a summary effect size estimate, the researchers did find associations that were significant. Physical and psychological abuse victimization were associated with risk of any cancer (including GI) in 3 and 2 studies, respectively. Sexual abuse was significantly associated with increased risk of cervical cancer and, in 1 study, for any cancer. Conversely, 2 studies reported no significance between ACEs and adult cancer incidence. Heterogeneity of the studies was an impeding factor for meta-analysis. The researchers suggested that childhood adversity in various forms may increase adult cancer risk, and ACEs may be a component of the ecological and biological developmental factors contributing to a growing cancer burden in the United States.

Hovdestad et al²⁸ conducted an analysis of a population-based survey (2012 Canadian Community Health Survey) exploring associations between adult cancer and 3 types of childhood maltreatment: childhood physical abuse (CPA), childhood sexual abuse (CSA), and childhood exposure to intimate partner violence (CEIPV). The researchers also looked at possible mediators: smoking, depression, alcohol abuse, life stress, obesity, and physical activity. The data analyzed included 9783 men and 12 132 women.

Their findings showed that, for women but not for men, the experience of maltreatment in childhood was significantly associated with a cancer diagnosis in adulthood, even when age and sociodemographic characteristics were controlled. When the severity of CPA, CSA, and CPEIV were analyzed, a dose–response relationship was noted for CPA (odds ratio [OR] = 3.1; 95% CI, 1.7-5.4) and CSA (OR = 1.7; 95% CI, 1.1-2.7). Smoking, life stress, depression, and alcohol abuse reduced the strength of associations with cancer in women, but most were still statistically significant.

Mouton et al²⁹ studied adult cancer risk and screening behaviors in connection with ACEs in a low-income population in the United States. The ACE questionnaire was administered to nearly 22 000 adults 40 years and older in the Southern Community Cohort study. The prevalence of smoking, alcohol consumption, BMI, and 5 cancer screening methods was analyzed in relation to ACE score.

More than 50% of participants reported at least 1 ACE, with a higher percentage of women (61%) reporting such an experience. Range of ACEs scores reported by Mouton et al²⁹ are as follows: Among all respondents, 22% reported 1 event (ACE), 12% reported 2 events, 7% reported 3 events, and 18% reported 4 or more. Higher ACEs are quantified as being at or above 4 out of 10 possible; however, they did look at lower ratings too. Higher ACE scores correlated to increased smoking prevalence (OR range, 1.25 [CI, 1.05-1.50] to 2.33 [CI, 1.96-2.77]). Those with the highest ACE scores were more than twice as likely to be current smokers. ACE scores were not associated significantly with BMI or alcohol use. Race and gender did not confound the findings. Notably, as ACE scores increased, mammography and cervical cancer screening rate decreased. The researchers note that ACEs are associated with cancer risk behaviors affecting all systems, including the GI system, and provide an opportunity for intervention.

Ports et al³⁰ conducted a scoping review of the literature from 2005 to 2015 on ACEs and the presence of cancer risk factors. The review included 155 quantitative peer-reviewed articles that examined associations between ACEs and modifiable and nonmodifiable cancer risk factors, including alcohol use, environmental carcinogen exposure, chronic inflammation, sex hormones, immunosuppression, infectious agents, obesity, radiation, ultraviolet radiation exposure, and tobacco use among US adults. Studies specific to women (N = 43) were more prevalent, particularly for alcohol and obesity outcomes. The thematic result of the extensive literature review was the connection of ACEs to cancer risk factors of alcohol use, obesity, and tobacco use. A few studies showed a relationship between ACEs and chronic inflammation or infectious agents. By engaging in high-risk behaviors, people can be exposed to sexually transmitted infections, like human papillomavirus and subsequent potential cancer development, or hepatitis C infection with possible liver cancer development. No studies investigated ACEs and their association with environmental carcinogens, hormones, immunosuppression, radiation, or ultraviolet radiation. The researchers suggested that mitigating ACEs upstream may help decrease the impact of the known cancer risk factors of alcohol and tobacco use and obesity.

Cancer screening behaviors in adulthood and their correlation to ACE scores have also been studied. Alcalá et al³¹ studied how ACEs were associated with utilization of screening modalities for prostate, breast, cervical, and colorectal cancer (CRC). The researchers analyzed 11 794 respondents’ data from the 2014 Kansas Behavioral Risk Factor Surveillance System. Using both individual ACE-type scores and the total count of ACEs, the authors found individual ACE items that were associated with lower odds of respondents adhering to physician recommendations for prostate-specific antigen (PSA) screening, clinical breast examinations, and Papanicolaou test cervical cancer screening. Physical abuse was most consistently associated with decreased provider-recommended regular cancer screenings. However, even when adjusted for selected factors, physical abuse (AOR = 0.78; CI, 0.69-0.98), living with a drug user (AOR = 0.68; CI, 0.48-0.97), and divorced parents (AOR = 0.73; CI, 0.57-0.92) were associated with decreased PSA screening. Selected ACEs were associated with increased CRC screening; that is, women with higher ACEs were more likely to get screened than men with higher ACEs. Sexual and emotional abuse significantly increased the odds of regular recommended screening for women, with AORs of 1.28 (95% CI, 1.01-1.62) and 1.30 (95% CI, 1.07-1.58), respectively. The authors suggest that women with higher ACEs (sexual/emotional abuse) developed disease earlier than women without higher ACEs and are therefore screened more regularly. The most significant associations showed that specific ACEs were associated with lower odds of cancer screening. 

Alcalá et al³² analyzed the association between ACEs and CRC screening habits in adults aged 50 and older. The researchers utilized the 2011 Behavioral Risk Factor Surveillance System (BRFSS; 2 states) to model odds of regular, routine, recommended CRC screening in 24 938 adults reporting 9 different ACEs. Using bivariate models, the researchers found that physical abuse (OR = 0.89; CI, 0.81-0.99), having divorced or separated parents (OR = 0.90; CI, 0.81-0.99), and living in a violent household (OR = 0.86; CI, 0.78-0.96) were associated with lower odds of engaging in CRC screening. In multivariate models that accounted for confounders, emotional abuse (AOR = 1.09; CI, 1.01-1.18) and sexual abuse (AOR = 1.18; CI, 1.06-1.33) were associated with higher odds of engaging in CRC screening. The researchers suggested that correlations between ACEs and adult behaviors needs further investigation as emotional and sexual abuse may be associated with sicker adults who engage in more preventive services.

Alcalá et al³³ explored the relationship between ACEs and patterns of Papanicolaou testing for cervical cancer screening. Using Tennessee’s BRFSS data (N = 1527), they found that women who had grown up in a violent household were more likely to have Papanicolaou tests, but a history of CSA decreased these odds.

Sexual abuse as a specific ACE was studied in relation to experiences of cancer treatment. Schnur et al³⁴ conducted an online survey of men and women by using Amazon Mechanical Turk (N = 159). Inclusion criteria included history of CSA; diagnosis of CRC, gynecologic, breast, or skin cancer; and any triggers or difficulties during cancer treatment. A recurring theme that emerged from the open-ended questions centered on the relationship between treatment-related triggers and a tendency to question the meaning of cumulative trauma (“Why me again?”). The researchers noted that CSA survivors experienced triggering thoughts and emotions associating the original abuse with negative evaluations of themselves, the world, and their future. These observations suggest that cancer care providers need to be cognizant of CSA and provide sensitive care, especially with invasive procedures.

Steel et al³⁵ analyzed the potential impact of ACEs on adult patients with cancer who were recruited from an outpatient oncology clinic using a battery of questionnaires (eg, exposure to traumatic events, depression). Their study aimed to 1) examine the rates and types of ACEs in patients diagnosed with cancer; 2) investigate the association of ACEs with circulating cytokines (immune status); and 3) test whether immune markers mediated the association between ACEs and cancer survival while adjusting for other factors associated with immunity (eg, fatigue) and survival (eg, depression). Of 408 patients with cancer, 66% reported at least 1 ACE. After adjusting for demographic, disease-specific, and psychological/behavioral factors, the experience of major upheaval between parents during childhood or adolescence was associated with poorer survival (B = -0.702; hazard ratio = 0.496; P = .034). Lower levels of interleukin-2 were noted with higher ACEs.

IBS has also been studied in relation to ACEs. Berens et al³⁶ examined the association between ACEs and illness anxiety in IBS, focusing on gender. Using a cross-sectional multicenter study design, they compared patients with IBS versus healthy controls (HCs). Overall, 127 gender- and education-matched participants per group were assessed using measures of ACEs, illness anxiety, generalized anxiety, and depressive symptoms. Compared with HCs, IBS patients had a higher prevalence of ACEs (63.8% vs 48%; P = .02; OR = 1.33) and increased levels of illness anxiety (P < .001). For women with IBS, there was a significant correlation between ACEs and illness anxiety, but this association was not seen in men with the disease (r = 0.242, P = .03 vs r = 0.0162, P = .29). The researchers suggested that gender-specific illness anxiety in female patients with IBS may be associated with increased depression and anxiety.

IBD and its association with anxiety disorder have also been analyzed, considering sociodemographic factors, depression, substance abuse, pain, and ACEs. Using data from the nationally representative Canadian Community Health Survey, researchers³⁷ studied patients with IBD (n = 269) and those without the disease (n = 22 522) to estimate the ORs for generalized anxiety disorder. Participants with IBD were more than twice as likely to have anxiety than those without IBD, even when controlling for potential explanatory factors (OR = 2.18; CI, 1.50-3.16). For those with IBD, a history of childhood sexual abuse, female gender, and chronic pain were the strongest correlates of anxiety. Patients with Crohn’s disease and ulcerative colitis were equally vulnerable. Notably, a history of childhood sexual abuse was associated with almost 7 times the odds of anxiety disorders in those with IBD. IBD itself may be associated with ACEs. Drossman³⁸ revealed that 37% of those with organic GI diagnoses, including IBD, reported a history of childhood sexual abuse.

Witges et al³⁹ studied the relationship between ACEs and health care use in persons with IBD. Using the cohort of patients from the Manitoba IBD population-based study, the researchers surveyed 345 participants approximately 5.3 years (on average) following IBD diagnosis to collect data regarding their histories of ACEs. At least 1 ACE was reported in 74.2% of participants. No statistically significant association was identified between ACE score and health care use. However, unadjusted mean annual non–IBD-related primary care visits were significantly higher for those exposed to physical and sexual abuse. ACEs may affect patient anxiety about their health.

Obesity. ACEs may impact disease prevalence indirectly through an associated increase in risk of obesity in adulthood. Several studies support that higher frequencies of ACEs influence obesity risk. Danese and Tan⁴⁰ conducted a systematic review and meta-analysis of 41 studies (190 285 participants) that examined childhood maltreatment and risk of developing obesity over the lifespan. Their analysis identified an OR of 1.36 (CI, 1.26-1.47) supporting an elevated risk. The association was stronger in samples including more women and white participants. Obesity is a risk factor for multiple diseases, including type 2 diabetes, cardiovascular disease, and some forms of cancer, including GI cancers.

Huffhines et al⁴¹ conducted a questionnaire-based survey to examine the influence of childhood adversity on obesogenic food consumption through child and caregiver emotional dysregulation. Participants included 190 low-income caregiver-child (mean age, 4.31 years) dyads. The researchers compiled adverse event data in study-created measures of lifetime adversity and emotional regulation. They identified that adversity exposure and caregiver emotion dysregulation were associated with child emotion dysregulation (P = .001), which, in turn, predicted greater obesogenic food consumption (P = .001). The researchers concluded that low-income preschool children who had a higher frequency of ACEs were more likely to have emotion dysregulation, particularly when caregiver emotion dysregulation was high.

Using a correlational time series approach, Shinagawa et al⁴² analyzed the influence of ACEs on postoperative weight loss outcomes following bariatric surgery, a treatment of significant obesity. Using a measure of ACE scores, the researchers examined percent total weight loss over baseline in 198 patients at 1, 3, and 6 months following bariatric weight loss surgery. Of these 198 patients, 25% had ≥ 4 ACEs. The researchers found no effect or association between ACE score and postoperative weight loss, suggesting that robust postoperative psychological care through the weight loss clinic likely modified the negative effect resulting from ACEs. These findings support the use of bariatric surgery in obese patients with high ACE scores.

Wiss and Brewerton⁴³ also studied ACEs and adult obesity. Using a systematic review of plausible mechanisms and meta-analysis of cross-sectional studies, the researchers identified 18 articles for qualitative analysis (for themes) and 10 observational studies (N = 118 691) that were quantitatively summarized. Qualitative analysis revealed the most-cited mechanisms linking ACEs to obesity included: social disruption, health behaviors, and chronic stress response. For the quantitative analysis, a positive association between ACEs and adult obesity had a pooled OR of 1.46 (CI, 1.28-1.64). In other words, the results supported a 46% increase in average odds for adult obesity following exposure to multiple ACEs. The researchers suggested that improved (more consistent) ACEs screening, trauma-informed care, and improved food environments (ie, consistent access to and knowledge about healthier food) could improve downstream health outcomes in patients with a history of ACEs.

GU disorders. ACEs have been studied in relation to several GU disorders, including chronic pelvic pain (CPP), endometriosis, cervical cancer (and cervical cancer screening), pain during pregnancy, premenstrual pain, and occurrence of oophorectomy and hysterectomy. While correlation is not causation, an emerging database of population-based studies and other well-designed research trials are supporting the significant impact of ACEs, especially for those who have experienced violence and/or sexual abuse, as a risk factor for later adult-onset pathology. In addition, current physical abuse as an adult may play a role.

Gazzuola Rocca et al⁴⁴ conducted a population-based case-control study in Olmsted County, MN. The researchers sampled 128 women who underwent bilateral oophorectomy before the age of 46 years for a noncancerous condition and 128 age-matched controls. The researchers measured ACEs using a summarized ACE score. They found associations between bilateral oophorectomy and a history of verbal or emotional abuse, physical abuse, any abuse, and substance abuse in the household (OR = 3.23; CI, 1.73-6.02; P < .001). Physical abuse in adulthood was also associated with bilateral oophorectomy (OR = 4.33; CI, 1.23-15.21; P = .02). In an editorial on ACEs and adult abuse as predictors of oophorectomy and hysterectomy, Gazzuola Rocca et al⁴⁵ noted that psychological factors appear to play a causative role in influencing biological mechanisms leading to gynecological symptoms (eg, CPP), and a disproportionate number of women with higher ACE scores are opting for hysterectomy/oophorectomy to manage minor gynecologic symptoms. The researchers emphasized that care providers should be aware that childhood and adult adverse experiences are common, citing the importance of gathering high-quality, detailed medical and social histories.

Pain during pregnancy was studied by Drevin et al⁴⁶ Using a cross-sectional study design, the researchers contacted participants in 18 antenatal clinics in southern and central Sweden. Of 293 women, 232 (79%) agreed to participate in the survey during early pregnancy and were assessed in later pregnancy. Questionnaires were used to collect sociodemographic data and ACEs, and participants were asked to report pain location by drawing on a figure; pain intensity was reported by visual analog scale. ACEs were measured using the 8 categories of abuse, neglect, and household dysfunction. In late pregnancy, 62% of women reported any ACE, and 72% reported a pain location. Mean pain intensity was higher (P < .01) in women with higher ACE scores. Accumulated ACE score had a positive association (r = 0.19; P = .02) with the number of reported pain locations in late pregnancy, even after adjusting for such background factors as age and income (P = .01). Women reporting CPA reported a higher prevalence of sacral and pelvic pain (P = .0003 and P = .02, respectively). The OR for sacral pain in late pregnancy for those with a history of CPA was 4.4 (CI, 1.7-11.4; P = .002). The CPA finding corresponds well with previous research showing that such abuse is associated with poor health status among young people and persists into adulthood.

The GU disorders of endometriosis and polycystic ovary syndrome (PCOS) have also been studied in relationship to ACEs. Harris et al⁴⁷ studied the association between childhood or adolescent physical and sexual abuse and risk of laparoscopically confirmed endometriosis. The researchers incorporated prospective cohort design using data collected from 60 595 premenopausal women from 1989 to 2013 as part of the Nurses’ Health Study II cohort. Participants completed a questionnaire using several scales to measure violence in childhood (up to age 11), adolescence (age 11-17 years) and adulthood, including “harsh and punitive” parenting, physical abuse, and sexual abuse. For endometriosis, 3394 cases were diagnosed over the 24 years. For those reporting severe physical abuse, the relative risk (RR) of endometriosis was 1.20 (95% CI, 1.06-1.37). For severe sexual abuse, the RR was 1.49 (95% CI, 1.24-1.79).

Among participants reporting severe chronic abuse of multiple types, there was a 79% increased risk of endometriosis (95% CI, 1.44-2.22). The risk was increased in a dose–response manner. The researchers suggested that abuse exposure alters neuroendocrine function, affecting pain syndromes by sensitizing the central nervous system and possible inflammatory response. They noted that psychological factors may contribute to the chronic pain of endometriosis but underlying biologic mechanisms are also of importance.

Tay et al⁴⁸ investigated the impact of ACEs in women with self-reported PCOS in an Australian population-based study. PCOS is a condition associated with acne, hirsutism, menstrual irregularities, and obesity, all of which carry the potential for psychological repercussions. Australian women in 4 age cohorts (born 1973–1978, 1946–1951, 1921–1926, and 1985–1995) were studied in a longitudinal manner. The described study was the cross-sectional analysis of only the 1989 to 1995 cohort when these women were aged 19 to 26 years. Participants were surveyed about psychiatric disorders and various factors: social support, BMI, perceived stress, and ACEs using the 2020 ACEs survey from the Centers for Disease Control and prevention(CDC).² Of the 8961 women, 760 reported a PCOS diagnosis. Overall, 64.1% of women with PCOS reported diagnosis/treatment of a psychiatric disorder compared with 46.8% of women who did not have PCOS. In women with PCOS, psychiatric disorders were reported more frequently in participants with at least 1 ACE (19.3%) versus those without ACEs (9.2%). The most significant factor associated with psychiatric illness was ACEs ≥ 4, which tripled the odds (adjusted OR = 2.9; 95% CI, 2.4-3.5). The most common ACEs reported were household member with mental illness (49.5%), household member with substance abuse (31.0%), and psychological abuse (34.0%).

Pelvic pain syndrome (also called urological chronic pelvic pain syndrome, or UCPPS) has been studied in relation to adverse life events in early life in both animal and human models. In an animal study, Fuentes et al⁴⁹ studied the effect of early life stress and acute adult stress on perigenital or urogenital sensitivity in male mice. Neonatal maternal separation was performed for 3 hours daily from postnatal days 1 to 21, and the young mice were unhandled. In addition, the pups were stressed with a water avoidance test. Using hormonal response as indicators, the researchers found that early life stress induced perigenital mechanical hypersensitivity and increased bladder output with histological evidence of enhanced mass cell degranulation in tissues of the bladder and prostate. The researchers suggested that mice may in the future be used as a preclinical model for investigating pharmacological and interventional therapies for CPP in humans.

Gupta et al⁵⁰ used a case-control design to study the impact of ACEs and gender (sex) on brain networks in patients with UCPPS. The study included 85 patients (56 female) with UCPPS and 86 HCs. Using magnetic resonance imaging scans, the researchers looked for differentials in brain measures of “centrality,” which characterize information flow, communication, and integration processes. Men and women with ACEs had different brain location signals compared with each other and versus HCs. The researchers suggested that functional brain networks in patients with UCPPS are not only modified by ACEs but are also associated with clinical symptoms and decreases in disease-related quality of life, especially for women. They emphasized the importance of assessing history of childhood trauma in patients with CPP.

Krantz et al⁵¹ conducted a case-control study in which patterns of ACEs were compared in women with and without CPP. The researchers used the CDC ACE survey to study 60 patients with CPP matched to a group of 60 women without the condition. The ACE survey was contained within the CDCBRFSS (the ACE module). The total number of ACEs reported was higher in the CPP group than in the control group (median 4 vs median 1, respectively). Notably, 53% of patients with CPP had ≥ 4 ACEs versus 27% of the control group (OR = 3.14; 95% CI, 1.46-6.75). All categories of abuse were more prevalent in the CPP group compared with the control group, with physical abuse (43% vs 15%; OR = 4.3; 95% CI, 1.8-10.4; P = .001) and sexual abuse (55% vs 23%; OR = 4.0; 95% CI, 1.8-8.8; P < .001) histories having the most significant differences. Witnessing domestic violence was also more prevalent in the CPP group versus the control group (35% vs 8%; OR = 5.9; 95% CI, 2.1-17.1; P < .001. Psychological and behavioral counseling may be beneficial in addition to routine CPP care for these patients.

Schrepf et al⁵² sought to characterize the prevalence of ACEs in a large cohort of patients with UCPPS patients versus HCs. The researchers also looked at associations between ACE severity and psychological factors known to impact physiological pain experience. Participants were recruited from a CPP research network (multiple centers) in the United States. In this longitudinal analysis using a path analysis framework, the researchers⁵² examined self-reported ACEs severity in relation to urinary symptom severity over the course of 1 year in patients with UCPPS. At baseline, 421 (232 women) UCPPS participants and 414 (233 women) HCs completed measures of ACE severity using the Childhood Traumatic Events Scale, functional symptoms (sleep, fatigue), and GU pain/urinary symptoms as well as demographic variables. Compared with HCs, the participants with UCPPS reported more categories of ACEs and greater ACE severity (P < .001). More ACEs of sexual abuse, physical violence, illness/injury, and “other trauma” were reported in participants with UCPPS than in HCs (all P < .01). Participants with UCPPS also reported more episodes of depression, anxiety, perceived stress, and pain-catastrophizing functional symptoms as well as worse overall mental and physical health than HCs (all P < .01). The researchers concluded that ACEs occurrence and severity modulated the severity and persistence of UCPPS symptoms.

Azoulay et al⁵³ conducted a survey to examine the association between ACEs and premenstrual symptoms (eg, pelvic pain, irritability). A total of 118 female students were recruited from a university in Israel; participants had no history of psychiatric disorders or neurologic or endocrine disorders, and were not pregnant, breastfeeding, or using hormonal contraception. Participants were given self-report instruments targeting premenstrual symptoms (Premenstrual Symptoms Screening Tool, or PSST), ACEs (Childhood Trauma Questionnaire, or CTQ), and difficulties in emotional regulation. Data were collected over 3 years. The women were separated into 3 groups according to their responses on the PSST: those reporting premenstrual dysphoric disorder (PMDD), those with partial symptoms of PMDD, and those with “no or mild” premenstrual symptoms.

The researchers collapsed the PMDD and partial PMDD group into one and compared it to the no/mild group using chi-square, t-tests, and Pearson correlations. ACEs were reported in the PMDD/PMS group at 28.9% (n = 11) versus 10% (n = 8) in the no/mild group (P = .015). The average score on the CTQ was higher in PMDD group versus the no/mild symptom group (44.72 vs 38.21; P = .005). The researchers concluded that the number and severity of premenstrual symptoms increased with more exposure to childhood trauma and adversity, demonstrating a relationship between childhood trauma and emotional dysregulation surrounding the premenstrual period. Notably, analysis of the CTQ scores showed that sexual abuse and emotional neglect were significantly associated with premenstrual symptoms.

Other researchers examined childhood maltreatment and anxiety/depression in women with CPP. Poli-Neto et al⁵⁴ examined the prevalence of ACEs in women with CPP and whether these occurrences were associated with pain, anxiety, and depression. Using a case-control study design, the researchers followed 154 Brazilian women (77 with CPP; 77 HCs) for 1 year. The CTQ and the Hospital Anxiety and Depression (HAD) Scales were used to collect data for those factors. The prevalence of childhood maltreatment was 77% and 64.9% for women with CPP and HCs, respectively. Emotional neglect was reported more frequently in women with CPP versus HCs (58.4% vs 41.5%; P = .04). A moderate correlation was noted between CTQ scores and anxiety and depression symptoms for women with CPP. (Spearman correlations of 0.57 to 0.52 for CTQ total and subscales; all P < .01). The researchers noted that childhood adversity is substantial in Brazil and may have affected outcomes.

This paper addresses a gap in academic literature by exploring connections between childhood adversity and adult GI and GU disorders. Existing research on ACEs and adult diseases suggests that ACEs do significantly affect lifelong health. The research also suggests that the severity and nature of ACEs may play a role in how disease and disease risk factors display in adulthood. Gender appears to play a role in these relationships, with some ACEs proving more deleterious and prevalent for women. Collectively, these observations offer a powerful perspective on the role of ACEs in adult disease pathologies.

The science of ACEs and human physiology is continually evolving. The impact of ACEs on brain development, the hormonal system, the immune system, and genetic expression has been elucidated, and the critical role of epigenetic mechanisms and biomarkers to monitor physiologic changes holds promise for the future. Both preclinical and clinical research demonstrate a relationship between ACEs and adult morbidity/ mortality and health risk behaviors. Although correlation is not causation, larger population studies are suggesting a causative relationship between higher ACEs and adult disease; biologic plausibility for causation is supported through neuroscientific and epigenetic research.^{8,9,17-20,23,24,35,55,58,59} This review found that research on the relationship between ACEs and GI and GU disorders is heterogeneous, notably due to wide variations in how types of ACEs are defined and screening methods used. Despite these limitations, associations are demonstrated, which is consistent with the hypothesis.

Gender plays a critical role in ACEs relationship to adult GI and GU disorders. Although both sexes are affected by ACEs, women are more likely to have experienced childhood sexual abuse.^30,32,33 A differential impact is occurring wherein some research shows disease occurrence rates and screening test rates can be negatively impacted by ACEs, especially sexual abuse. Another mechanism may be occurring, too. Alcalá et al³² found that ACE severity did not predict CRC screening rates in older persons. The researchers noted that a likely factor was that older patients did not survive to be included for a full analysis.

Implications for nurses and other health professionals. As 1 in 4 children will experience some form of maltreatment in their lifetime,⁵⁵ a correlating rise in the incidence of GI and GU disorders (and subsequent rise in chronic illness and decreasing life expectancy) should not be unanticipated.⁵⁶ Practitioners can become trauma informed and include ACE screening in their practice. Furthermore, wound, ostomy, and continence nurses and other clinicians can benefit from learning about psychoneuroimmunology and the impact of ACEs on adult pathologies.⁵⁷

The literature on ACEs and their relationship to such adult chronic diseases as cancer, IBS, IBD, pelvic pain syndromes, and obesity has newly emerging themes related to best practices and optimizing clinical care. These themes include: knowledge of ACEs is powerful to improve clinicians’ practice; gender plays a critical role in how identified ACEs manifest in health status in adulthood; a more uniform approach to ACE measurement is critically needed; and ACEs can occur in all populations, but there is increased incidence in patients of lower socioeconomic status, those who identify as Black or biracial, those who identify as LGBTQ, and those who are obese. More research is needed to examine ACEs and genetic/epigenetic roles in disease causation. Given the prevalence of ACEs in the US population, trauma-informed care practices must inform clinicians’ delivery of care. These practices are needed at not only the individual clinic level but also more at systemic and societal levels via policy implementation.

Knowledge of a patient’s ACE history is powerful. The patient’s predilection for unhealthy behaviors and disease occurrence can be explanatory (and therapeutic) in the patient–provider relationship. For most patients, ACE history has often never been elicited; therefore, the listening and conversation can be healing for the patient.³

If clinicians encounter a patient in whom current child abuse is suspected, they have a responsibility to report the abuse and/or neglect as alert providers can provide help. This intervention is particularly necessary for female children, for whom sexual abuse occurs in much higher numbers.^30,32,33

Nurses wishing to inform themselves more about ACEs and adult morbidity may be challenged by different findings in various epidemiologic studies. A more uniform approach to the measurement of ACEs is necessary as several scales exist (eg, CDC ACEs instrument, CTQ). Also, studies need to describe clearly whether they are looking at discrete measures of ACEs (individual items) or summed scores.^30,58

Clinicians must also recognize that ACEs occur in all populations,²⁹ but selected factors increase the risk.¹ Social determinants of health influence ACE risk and severity, including growing up in poverty, being a person of color, or identifying as LGBTQ.¹ Optimal, preventive interventions are needed to occur upstream to decrease ACEs exposure and to foster positive childhood experiences that can counter the negative impact of childhood trauma. Policies are needed to address disparities and improve health equity, including increased access to health care. ²⁸

Obese persons, especially those who are morbidly obese, are at high risk of disease complications. ACEs are known to be a critical factor for this risk. Danese and Tan⁴⁰ identified an OR of 1.36(CI, 1.26-1.47) correlating ACEs to obesity. The finding of increased risk was also identified by Wiss and Brewerton.⁴³ They identified a 46% increased risk in odds of adult obesity related to ACEs. Thankfully, substantial ACEs do not seem to impair bariatric treatment. ACE scores did not negatively impact weight loss following bariatric surgery. Increased ACE scores did increase the odds of adult obesity but did not have a statistically significant negative impact on obesity therapy.⁴²

Nurses and other health professionals need to keep informed about the science of ACEs and the relationship to adult pathologies. Current science identifies the impact of ACEs on the brain, the HPA axis, and the immune system.³⁰ But a compelling theme is that much more research is needed on the relationship of ACEs to specific disorders like cancer and to determine what protective factors help to mitigate risk.²⁷ Much more research is needed on epigenetic modifications of genetic functioning. It is known that lengthening or shortening of telomere length, along with the influence of DNA methylation and histone functioning, are important factors in health and longevity. A need exists for better biomarkers to improve analytic strategies. ⁵⁹

Clinicians across the spectrum of care need to recognize the “public health” perspective of ACEs on adult health. A need exists for upstream, midstream, and downstream interventions for ACEs.¹² Upstream interventions need to consider the social and transgenerational context of health. Midstream interventions from pediatric nurses can identify at-risk children and families, recognize somatic complaints of children, and treat or even prevent ACEs.³⁰ The timing of interventions matters. Positive childhood experiences can help offset cumulative ACEs with lifelong positive effects.¹¹ Downstream interventions, when the person is already an adult, largely involve trauma-informed care, recognizing the effect of ACEs on disease screening behaviors (eg, breast and cervical cancer screening), and using evidence-based therapeutic interventions when indicated. Patients with higher ACE scores tend to pursue fewer screening activities. Women with pertinent risk factors (eg, obesity, smoking, history of sexual abuse) need to be targeted for more interventions.

Trauma-informed care. Trauma-informed care needs to be incorporated at all levels of patient interaction. Nurses can play a critical role in this respect. Asking patients about their ACE history can be empowering for both patients and providers. Sensitivity in providing pelvic area care may help mitigate “triggers” in patients who have experienced childhood sexual abuse.³⁴ If ACEs are identified, early intervention to treat this past trauma can help improve immune status in the context of cancer.³⁵ Interventions for ACEs can help decrease the risk of worsening psychopathology. ⁵⁸

Trauma-informed care also involves the notion of resiliency. For adults with substantial ACE history, the promotion of resiliency strategies, a strengths-based intervention, can help improve health status.⁶⁰ A referral to a behavioral health specialist may be helpful in managing this issue.¹⁵ Temperament may affect how individuals with ACEs react, influencing survival pattern responses to stress; behavioral therapy may help with this aspect as well.⁶¹

A component of trauma-informed care may include recognition of ACEs impact on adult anger and behavior. A study conducted in Japan demonstrated a positive association between higher ACE scores and bullying behaviors at work.⁶² Patients with GI and/or GU disorders may exhibit behaviors challenging a supportive patient/clinician relationship. Investigation into the cause of anger and resistance may reveal a history of ACEs.

Trauma-informed care needs to be incorporated at a health care system level as well. In society, schools and other support systems should be more fully integrated into care, with health care providers partnering with schools and support personnel to provide better counseling opportunities to ameliorate ACEs.¹⁵ Within health care systems, trauma-informed care can be addressed in several steps. First, history of ACEs needs to be ascertained for all patients, but particularly for high-risk populations like obese/morbidly obese patients; sexual abuse victims, and persons impacted by significant social determinants of health (eg, poverty, violence, dysfunctional households), and those who identify as nonwhite or LGBTQ.¹ Once identified, clinicians can ask how patients have coped with their past trauma.⁵⁷ In addition, referrals to specialists in healing modalities (ie, psychotherapy, mindfulness practice, yoga, social connections) can be used for optimal interdisciplinary care.^66-70

The limitations of epidemiological, population-level study design have been noted.^63,64 Observational studies cannot confer causation. However, there are an increasing number of studies on ACEs with larger sample sizes; both the World Health Organization and the CDC have acknowledged the importance of ACE in the setting of adult chronic disease, and other epidemiological studies on diet and cancer show that eventually causal relationships emerge.⁶³ Furthermore, some basic research on biological mediators of ACEs on body physiology has been done using animal models. More human studies are being conducted as the science progresses.

This narrative literature review supported the association of ACEs with adult GI and GU morbidities in a dose–response relationship. The literature also presents strong descriptions of biologically plausible explanations for the impact of ACEs on adult chronic disease including genetic/epigenetic influences. The following correlations between ACEs and adult health were found: adult cancer occurrence, cancer survival, cancer screening behaviors, IBS, IBD, obesity, CPP, pregnancy pain, premenstrual pain, and hysterectomy/oophorectomy. The “dose” of reported ACEs and their nature (eg, sexual abuse) has been correlated to types of disease occurrence. With increased understanding of ACE and its relationship to adult morbidities, clinicians will have new avenues to improve care, not just for the presenting problem (eg, CPP) but for more holistic care needs.⁶⁵ A goal of future research is to empower patients to see and understand interconnections of their lived experiences across the lifespan and how this insight may help catalyze deeper healing.

Dr Bryan is the Director of Community Engagement and Professional Development and Dr Beitz is a Professor of Nursing, WOCNEP Director, Rutgers University School of Nursing-Camden, Camden, NJ. Address all correspondence to: Rebecca Bryan, DNP, AGPCNP, APN, Rutgers University School of Nursing-Camden, 530 Federal St, Room 442, Camden, NJ 08102; email: Rebecca.bryan@rutgers.edu.