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Table S1. Studies examining childhood adversity in association with cardiovascular diseases and biological risks, organized by primary study outcome Author, year Sample Age at outcome Timing of adversity Adversity definition, measures How adversity treated in analysis Outcomes examined Primary findings Mean 4.6 years, prospective Parental separation (evacuation abroad without parents during WWII) Single variable Medication use for coronary heart disease and hypertension; hospitalization for coronary events, stroke; all cause and cardiovascular deaths 56 years <18 years, retrospective Adverse childhood experiences (ACEs), assessed via the ACEs questionnaire Unweighted summary score Ischemic heart disease Adults who were separated from parents as children used coronary heart disease medications more frequently; No associations between separation and hospitalizations or mortality observed. Dose response association between ACEs and heart disease risk. 56.1 years <18 years, retrospective Adverse childhood experiences, assessed via the ACEs questionnaire Unweighted summary score 25-74 years <18 years, retrospective 27 adversities in childhood, including: Sent away from home, unemployed parent(s) parental drinking/drug problem, death of parent, physical or sexual assault, divorce, Unweighted summary scores for quantity, timing and type. Chronic conditions including ischemic heart disease, and stroke; Also examined cardiovascular risks including obesity and smoking. Diabetes, heart disease, obesity Cardiovascular Disease Endpoints (n=10) Over 60 Alastalo et al. n=12,915 years of (2012) follow up Finland Helsinki Birth Cohort Study Dong et al. (2004) n=17,337 USA Felitti et al. (1998) Adverse Childhood Experiences Study n=9,508 USA Friedman et al. (2015) Adverse Childhood Experiences Study n=3,996 USA Midlife in the United States study (MIDUS) Dose-response association between ACEs and adulthood chronic conditions and risk factors. Dose-response association between ACEs and cardiometabolic risk. Heart disease risk higher among women experiencing abuse at ages 6-10 years. 1 lost home to fire/flood/disaster, jail. Hakulinen et al. (2016) n=2265 27 years 3-18 years, prospective Composite of 20 factors relating to four domains: stressful life events, parental health behaviors, socioeconomic factors, socioemotional factors. Parental divorce/separation, financial difficulties, serious conflicts, fear of a family member, major family illness, alcohol problem. Unweighted summary score Carotid intima media thickness (IMT) in 2007, and IMT progression from 2001-2007 49.9 55.3 years <18 years, retrospective Unweighted summary score High childhood adversity and high adult neighborhood disadvantage jointly associated with CVD and CVD risks. <18 years , retrospective Risky family environment, assessed via Risky Family Questionnaire Unweighted summary score Coronary heart disease, cerebrovascular disease, and CVD risks including hypertension, dyslipidemia, diabetes, and obesity. Carotid intima media thickness (IMT) directly assessed via ultrasound 37-52 years 25-74 years <18 years, retrospective Socioeconomic, household structure, maltreatment, poor health domains. Unweighted summary score Myocardial infarction (MI) Accumulated childhood adversity associate with increased MI risk. ≥55 years 0-16 years , retrospective Early disadvantage, fatherless, poor childhood health Derived 3 latent clusters of adversity Heart attack Early disadvantage and poor childhood health associated with risk of heart attack. Finland Young Finns Study Halonen et al. (2015) n=37,699 Finland Finnish Public Sector Study Loucks et al. (2014) n=2,659 USA Morton et al. (2014) Coronary Artery Risk Development in Young Adults study (CARDIA) n=3,032 USA O’Rand and Hamil-Luker (2005) MIDUS n=9,760 USA Associations strongest among more severe types of adversity. Cumulative adversity was associated with higher IMT in 2007 and increased IMT progression from 2001 to 2007. Higher risky family scores associated with increased IMT in white but not black participants. Health and Retirement Study 2 Wilson et al. (2012) n=192 88.5 years <18 years, retrospective Adapted Childhood Trauma Questionnaire, includes subscores of emotional neglect, parental intimidation, violence, family turmoil/divorce, financial need Unweighted summary scores Cerebral infarctions, directly assessed via post mortem brain autopsy Higher adversity scores associated with higher cerebral infarction risk. Cardiometabolic Biomarkers (n=8) n=650 Mean Bleil et al. 39.9 (2013) USA years <18 years, retrospective Family environment, assessed via Family Environment Scale; Stressful life events, assessed with an adapted Life Events Checklist Unweighted summary scores Total cholesterol, HDL, LDL, triglycerides, fasting glucose, body composition, hypertension 32-47 years <18 years, retrospective Risky family environment, assessed via Risky Family Questionnaire (warmth and abuse subscales) Unweighted summary score 32 years <10 years, prospective Socioeconomic status, maltreatment/abuse, social isolation. Unweighted summary score, also examined independent effects of adversities Allostatic load: Count of high risk levels of blood pressure, heart rate, norepinephrine and epinephrine, cortisol, cholesterol, triglycerides, glucose, insulin, waist circumference, C-reactive protein fibrinogen, IL-6 CRP and metabolic risk factor clustering (high body mass, blood pressure, cholesterol, HbA1c, 02 consumption). In a structural equation model, greater childhood adversity was related to younger menarcheal age and younger menarcheal age was related to greater CVD risk. Direct and indirect effects of childhood adversity on CVD risk were non-significant. Risky family environment and childhood abuse associated with greater allostatic load. Higher parental warmth scores mitigated risk. USA Rush Memory and Aging Project Ovarian Aging Study Carroll et al. (2013) n=756 USA CARDIA Danese et al. (2009) n=1,037 New Zealand Dunedin Multidisciplin Independent and cumulative adverse childhood experiences associated with elevated inflammation and metabolic risk. 3 Friedman et al. (2015) ary Health and Development Study n=1,180 25-74 years <18 years, retrospective Composite of socioeconomic adversity, parental death, divorce, abuse Unweighted summary score 42.5 years 0-7 years, prospective Parental reported family stability (e.g., sibling death, moved residence) and socioeconomic risks (poverty, unemployed father, crowded dwelling). Unweighted summary score USA MIDUS Non et al. (2014) n=387 USA New England Family Study (NEFS) Schooling et al. (2011) n=28,771 China Guangzhou Biobank Cohort Study ≥50 years <18 years, retrospective Early life parental death Single variable, also considered timing of parental death Allostatic load: count of high risk levels of blood pressure, resting pulse, CRP, fibrinogen, IL-6, epinephrine, norepinepherine, heart rate variability, cortisol Cardiometabolic Risk Score: Count of biomarkers indicating clinical risk (blood pressure, triglycerides, cholesterols, HbA1c, waist circumference, CRP) Chronic Disease Score: Count of selfreported conditions including: heart disease, COPD, cancer, diabetes, hypertension, hypercholesterolemi a, arthritis. Blood pressure, fasting glucose, LDL, HDL, triglycerides, BMI, waist-hip ratio, white blood cell count, seated height Cumulative adversity positively associated with allostatic load. Increased childhood social disadvantage associated with higher adult cardiometabolic and chronic disease scores. Mixed findings. Parental death associated with shorter height, lower BMI, and triglicerides. No associations found for blood pressure, cholesterols, or glucose. 4 Slopen et al. (2014) n=550 44.3 years <12 years, retrospective Composite of frequency of physical abuse, verbal abuse, felt loved, physically held, participated in school activities, read to, went to bed hungry, and socioeconomic affluence Composite of child in care, neglect, household dysfunction, parental separation, family member with mental illness/alcohol abuse/criminal offender. Unweighted summary score 44-45 years 7, 11, and 16 years, prospective 57.3 years <18 years, retrospective Childhood trauma questionnaire, items including physical/emotional/sexu al abuse, neglect, divorce, parent abusing alcohol or drugs, and parental depression. 44 years <16 years, prospective 15-19 <18 years, USA Chicago Community Adult Health Study Solis et al. (2015) n=7,535 Great Britain National Child Development Study (NCDS) Inflammation (n=11) Hostinar et al. n=1,180 (2015) USA MIDUS Lacey et al. (2013) n=7,462 Great Britain Miller and National Child Development Study n=147 Count of biomarkers exceeding clinical risk levels including: blood pressure, resting heart rate, CRP, waist circumference, hemoglobin A1c, cholesterol Allostatic load: cortisol, IGF1, CRP, fibrinogen, IgE, cholesterol, triglycerides, glycosylated hemoglobin, blood pressure, peak expiratory flow Childhood adversity associated with elevated cardiometabolic risk in adulthood. Unweighted summary score, timing of exposure assessed CRP, IL-6, fibrinogen, Eselectin, ICAM-1 Parental separation (divorce, breakdown of parents relationship) Single variable CRP Child adversities independently associated with inflammation; effects of child adversities and adult stressors were additive. Relationship partially mediated by waist circumference and CV risk behaviors. Those with parental separation have higher CRP levels as adults. Association mediated by BMI, material and psychosocial factors. Index indicating birth to Unweighted CRP, IL6, depression Unweighted summary score Child adversities associated with higher allostatic load. Relationship largely mediated by adulthood factors (health behaviors, education, wealth, smoking, BMI). Higher levels of 5 Cole (2012) females years retrospective teenage mother, familial disruption, history of affective illness in parents, low household education, limited economic resources Index indicating separation from mother, paternal involvement, residential relocations, duration of breastfeeding. Questionnaire based indicators of father's occupation, parents owned home, bully victim, parents owned car, overcrowding, leg length, trunk length. Maternal psychopathology, parental discord, harsh discipline, family income, parental criminal behavior. summary score 44-46 years 0-7 years, prospective 35-64 years At age 11, retrospective 22-25 years 0-5 years, prospective 42.9 years <18 years old, retrospective 35-86 years <18 years old, Canada Nettle (2014) n=8,959 women Great Britain Packard et al. (2011) NCDS n=666 Scotland Raposa et al. (2014) n=389 Australia Runsten et al. (2013) MaterUniversity of Queensland Study of Pregnancy n=116 women Finland Slopen et al. (2010) Health and Social Support Study (HeSSup) n=999 childhood adversity associated with inflammation and depression. Unweighted summary score CRP Higher levels of adversity associated with increased adulthood CRP. No summary score; each childhood factor examined individually CRP, IL-6, ICAM Father's occupation and childhood home status associated with inflammation and endothelial function. Unweighted summary score CRP and sTNF-RII, body mass index Early adversity associated with higher levels of inflammation; potential mediation by smoking and BMI Risky Families Questionnaire, HeSSup questionnaire listing 17 adverse childhood events Unweighted summary score CRP Interaction effect between adulthood social support and childhood adversity in relation to CRP. Social support may buffer effects of childhood adversity. Failing school, parental drug problem, moved Unweighted summary score CRP, IL-6, fibrinogen, E- Early life adversity associated with each 6 USA retrospective MIDUS Slopen et al. (2013) n=4,6553,286 Slopen et al. (2015) n=210 Adverse events in middle childhood and cumulative adversity from birth to age 8 associated with higher CRP and IL-6 and CRP at age 10. Cumulative adversity and adverse events in early or middle childhood associated with higher CRP at age 15. Prenatal and childhood adversity associated with CRP in adulthood. When modelled together, prenatal and not age7 adversity was associated with elevated adult CRP. Prenatal and age 7 assessments of family stability (e.g., moved residence, sibling death) and socioeconomic risks (e.g., poverty, unemployed father, crowded dwelling). Unweighted summary scores CRP 32-47 years <18 years, retrospective Childhood SES, and risky family environment as assessed with the Risky Family questionnaire Unweighted summary score CRP, BMI, psychosocial functioning Childhood SES and risky family scores associated with adult CRP via adult psychosocial functioning. 8.13 years (range 021 years) 8.13 years (range 0-21 years) Unweighted summary score Overweight/obesity, behavior/learning problems as listed in the medical record 45.8 years <18 years, retrospective Adverse childhood experiences assessed with and adapted ACEs checklist, collected via medical chart review Summarized information from the Derived four measures of BMI, obesity and waist-hip ratio Higher ACE scores associated with risk of overweight/obesity and learning/behavior problems. Overall adversity significantly with waist- CARDIA Davis et al. (2014) CRP, IL-6 Prenatal, age 7 years, prospective USA Anthropometry (n=8) Burke et al. n=701 (2011) USA Derived an unweighted summary score, and also a perceived impact score 42.2 years New England Family Study (NEFS) n=3,248 inflammatory marker for black adults, but not for white adults. 0-7 years, prospective USA Taylor et al. (2006) selectin, sICAM-1 10, 15 years United Kingdom Avon Longitudinal Study of Parents and Children (ALSPAC) n=355 neighborhood >2 times, relationship with parents, verbal and physical abuse. Repeated measures of 5 adverse events at 7 time points including: child taken into foster care, physically hurt by someone, sexually abused, separated from mother, separated from father. 7 USA Evans et al. (2012) n=244 Evaluation of Lifetime Stressors Interview, SCID, and an attachment assessment 13 years 9 years, prospective 36.6 years <18 years old, retrospective USA Gunstad et al. (2006) n=696 Multiple countries (Australia, USA, United Kingdom, the Netherlands) Composite of 9 risk factors including poverty, single-parent status, maternal high school drop-out, residential crowding, noise, housing problems, family turmoil, child separation from family, exposure to violence. Child Abuse and Trauma scale, including experiences of physical/sexual abuse, family conflict, war, divorce/separation, bullied, poverty/neglect, natural disaster, death in family, illness in family, violence, extended illness, surgery/hospital, adoption. adversity: (1) Cumulative (number of events, unweighted); (2) Severity (weighted sum score); (3) Chronicity (chronic, single episode, or mixed); (4) Overall adversity (combined cumulative, severity and chronicity). Unweighted summary score Unweighted summary score hip ratio and BMI; more sensitive predictor than cumulative adversity. Body mass index Higher childhood adversity associated with greater adiposity gains from age 9 to 13. Obesity Early adversity positively associated with obesity in men, but not women. 8 Pretty et al. (2013) n=1,234 11-14 years <14 years, retrospective 15 events adapted from the Childhood Trust Events Survey., e.g., parental death, divorce, major illness, attacked by an animal, saw someone get badly hurt. Unweighted summary score Body mass index, obesity, waist circumference, blood pressure and resting heart rate. Significant doseresponse associations between adverse child experiences and heart rate, body mass index, obesity, and waist circumference. 7, 11 years 0-7 years, prospective Repeated measures of 8 social risk domains including: maternal psychopathology, one adult in household, legal problems, child taken into care, physical injury, sexual abuse, financial strain, neighborhood disadvantage. Maternal reports of intimate partner violence, food insecurity, housing insecurity, maternal depressive symptoms, maternal substance abuse, father’s incarceration. Examined 16 retrospective selfreported types of abuse, neglect, household dysfunction. Also examined prospective maternal reports of 13 adversities related to Derived unweighted scores for average adversity over time and chronic exposure to high adversity; examined as separate predictors. BMI, blood pressure. High adversity and chronic adversity associated with higher BMI and behavior problems, but not blood pressure at age 7. Adversity did not predict change in BMI or BP from age 7-11. Derived unweighted summary score and timing of exposure/ chronicity BMI and obesity Significant associations between cumulative adversities, timing of adversities with obesity risk at age 5 among girls. No associations among boys. Examined each childhood factor as separate predictors. BMI, waist circumference, Hba1c. Some forms of adversity associated with obesity, central adiposity, and Hba1c. Strongest associations among serious forms of adversity like physical abuse. Canada Slopen et al. (2014) Heart Behavioural and Environmenta l Assessment Team (HBEAT) study n=4,361 and n=3,348 United Kingdom ALSPAC Suglia et al. (2012) n=1,605 5 years 1 and 3 years, prospective 45 years 0-16 years, retrospective; and 7, 11, 16 years prospective USA Thomas et al. (2008) Fragile Families and Child Wellbeing Study n=9,310 Great Britain NCDS Behavior problems via Strengths and difficulties questionnaire. 9 neglect and household dysfunction. Blood Pressure and Hypertension (n=6) Alastalo et al. n=1361 non- Mean 62 years (2013) obese Mean 4.6 years, prospective Parental separation (evacuation abroad without parents during WWII) Single variable, also considered duration and age of separation Directly assessed blood pressure, use of blood pressure medication Early childhood parental separation associated with higher blood pressure in adulthood, Age at separation and duration also associated blood pressure. 35-55 years <18 years, retrospective Summarized information from the Evaluation of Lifetime Stressors Interview, SCID, and an attachment assessment Mean arterial pressure, systolic and diastolic blood pressures Path analysis indicates overall and cumulative child adversity to affect mean arterial and blood pressures via hip-waist ratio, leptin, and diet. 10-14 years <14 years, retrospective 15 events adapted from the Childhood Trust Events Survey., e.g., parental death, divorce, major illness, attacked by an animal, saw someone get badly hurt. Derived four measures of adversity: (1) Cumulative (number of events, unweighted); (2) Severity (weighted sum score); (3) Chronicity (chronic, single episode, or mixed); (4) Overall adversity (combined cumulative, severity and chronicity). Unweighted summary score ECG assessed pulse wave velocity, a measure of systemic arterial stiffness Significant sex by adversity interaction observed whereby four or more ACEs was associated with greater arterial stiffness among boys. 33-45 <18 years, Childhood SES; risky Unweighted Blood pressure Harsh family Finland Crowell et al., 2015 Helsinki Birth Cohort Study n=210 USA Klassen et al. (2016) n=221 Canada HBEAT study Lehman et al. n=2,738 10 (2009) years retrospective family environment assessed via the Risky Family Questionnaire summary score (initial blood pressure and change over time) 21-98 years <18 years, retrospective Physical abuse, sexual abuse, neglect, parental death, divorce, parental loss, parental mental disorder, substance use, criminal behavior, family violence, family economic adversity Unweighted summary score Hypertension 5-38 years <18 years, retrospective Adverse childhood experiences, assessed via the ACEs questionnaire Unweighted summary score Blood pressure, directly measured up to 16 times over 23 years USA CARDIA Stein et al. (2010) n=18,630 Multiple countries Su et al. (2015) WHO World Mental Health Surveys n=394 USA Georgia Stress and Heart Study environment and low parental SES associated with adult blood pressure and change in blood pressure over time, mediated by emotionality and health behaviors. Presence of 3 or more childhood adversities associated with hypertension. Multiple ACEs associated with higher adulthood blood pressure levels. Number of ACEs associated with different blood pressure trajectories. 11