Adverse Adult Health Outcomes Research Articles

Childhood Obesity-Related Mechanisms: MicroRNome and Transcriptome Changes in a Nested Case-Control Study.

Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels as well as leptin protein levels in whole bloods of 12 obese and 24 normal children aged 6 years. miR-328-3p, miR-1301-3p, miR-4685-3p, and miR-6803-3p were negatively associated with all obesity indicators. The four miRNAs were also associated with 3948 mRNAs, and separate 475 mRNAs (185 among 3948 mRNAs) were associated with all obesity indicators. The 2533 mRNAs (64.2%) among the 3948 mRNAs and 286 mRNAs (60.2%) among the 475 mRNAs were confirmed as targets of the four miRNAs in public databases through miRWalk 2.0. Leptin protein was associated with miR-6803-3p negatively and all obesity indicators positively. Using DAVID bioinformatics resources 6.8, top three pathways for obesity-related gene set were metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway. The top three obesity-related disease classes were metabolic, cardiovascular, and chemdependency. Our results support that childhood obesity could be developed through miRNAs-related epigenetic mechanism and, further, these obesity-related epigenetic changes could control the pathways related with the development of various diseases.

Inequities in Children's Reading Skills: The Role of Home Reading and Preschool Attendance.

Children from socioeconomically disadvantaged backgrounds have poorer learning outcomes. These inequities are a significant public health issue, tracking forward to adverse health outcomes in adulthood. We examined the potential to reduce socioeconomic gaps in children's reading skills through increasing home reading and preschool attendance among disadvantaged children. We drew on data from the nationally representative birth cohort of the Longitudinal Study of Australian Children (N=5107) to examine the impact of socioeconomic disadvantage (0-1 year) on children's reading skills (8-9 years). An interventional effects approach was applied to estimate the extent to which improving the levels of home reading (2-5 years) and preschool attendance (4-5 years) of socioeconomically disadvantaged children to be commensurate with their advantaged peers, could potentially reduce socioeconomic gaps in children's reading skills. Socioeconomically disadvantaged children had a higher risk of poor reading outcomes compared to more advantaged peers: absolute risk difference=20.1% (95% confidence interval [CI]: 16.0%-24.2%). Results suggest that improving disadvantaged children's home reading and preschool attendance to the level of their advantaged peers could eliminate 6.5% and 2.1% of socioeconomic gaps in reading skills, respectively. However, large socioeconomic gaps would remain, with disadvantaged children maintaining an 18.3% (95% CI: 14.0%-22.7%) higher risk of poor reading outcomes in absolute terms. There are clear socioeconomic disparities in children's reading skills by late childhood. Findings suggest that interventions that improve home reading and preschool attendance may contribute to reducing these inequities, but alone are unlikely to be sufficient to close the equity gap.

Secondary hyperparathyroidism and adverse health outcomes in adults with chronic kidney disease.

BackgroundSecondary hyperparathyroidism (sHPT) develops frequently in patients with chronic kidney disease (CKD). However, the burden and long-term impact of sHPT on the risk of adverse health outcomes are not well studied.MethodsWe evaluated all adults receiving nephrologist care in Stockholm during 2006–11 who were not undergoing kidney replacement therapy and had not developed sHPT. Incident sHPT was identified by using clinical diagnoses, initiated medications or two consecutive parathyroid hormone (PTH) measurements ≥130 pg/mL. We characterized sHPT incidence by estimated glomerular filtration rate (eGFR) strata, evaluated clinical predictors and quantified the association between incident sHPT (time-varying exposure) and the risk of fractures, CKD progression, major adverse cardiovascular events (MACEs) and death.ResultsWe identified 2556 adults with CKD Stages 1–5 (mean age 66 years, 38% women), of whom 784 developed sHPT during follow-up. The incidence of sHPT increased with advancing CKD: from 57 cases/1000 person-years in CKD Stage G3 to 230 cases/1000 person-years in Stage G5. In multivariable analyses, low eGFR was the strongest sHPT predictor, followed by young age, male sex and diabetes. Incident sHPT was associated with a 1.3-fold (95% confidence interval 1.1–1.8) increased risk of death, a 2.2-fold (1.42–3.28) higher risk of MACEs, a 5.0-fold (3.5–7.2) higher risk of CKD progression and a 1.3-fold (1.5–2.2) higher risk of fractures. Results were consistent in stratified analyses and after excluding early events.ConclusionsOur findings illustrate the burden of sHPT in advanced CKD and highlight the susceptibility for adverse outcomes of patients developing sHPT. This may inform clinical decisions regarding pre-sHPT risk stratification, PTH monitoring and risk-prevention strategies post-sHPT development.

Sleep timing, sleep consistency, and health in adults: a systematic review.

The objective of this systematic review was to examine the associations between sleep timing (e.g., bedtime/wake-up time, midpoint of sleep), sleep consistency/regularity (e.g., intra-individual variability in sleep duration, social jetlag, catch-up sleep), and health outcomes in adults aged 18 years and older. Four electronic databases were searched in December 2018 for articles published in the previous 10 years. Fourteen health outcomes were examined. A total of 41 articles, including 92 340 unique participants from 14 countries, met inclusion criteria. Sleep was assessed objectively in 37% of studies and subjectively in 63% of studies. Findings suggest that later sleep timing and greater sleep variability were generally associated with adverse health outcomes. However, because most studies reported linear associations, it was not possible to identify thresholds for "late sleep timing" or "large sleep variability". In addition, social jetlag was associated with adverse health outcomes, while weekend catch-up sleep was associated with better health outcomes. The quality of evidence ranged from "very low" to "moderate" across study designs and health outcomes using GRADE. In conclusion, the available evidence supports that earlier sleep timing and regularity in sleep patterns with consistent bedtimes and wake-up times are favourably associated with health. (PROSPERO registration no.: CRD42019119534.) Novelty This is the first systematic review to examine the influence of sleep timing and sleep consistency on health outcomes. Later sleep timing and greater variability in sleep are both associated with adverse health outcomes in adults. Regularity in sleep patterns with consistent bedtimes and wake-up times should be encouraged.

The impacts of maternal childhood adversity, stress, and mental health on child development at 6 months in Taiwan: A follow-up study.

Exposure to adverse childhood experiences (ACEs) is not only associated with one's adverse health outcomes in adulthood but also increases the risk of child developmental problems in offspring. However, the mechanisms involved in the transmission of the effects of maternal ACEs to the offspring largely remain unexplored. This study sought to identify possible psychosocial pathways of intergenerational effects of maternal ACEs on child development at 6 months. Data from a longitudinal study on maternal childhood adversity and maternal psychosocial risk during pregnancy as well as maternal mental health problems and child development at 6 months postnatal were used. Structural equation modeling with bootstrapping was used to estimate the indirect effects of maternal ACEs on child development at 6 months. The model showed that maternal ACEs indirectly influenced offspring's development via maternal stressful events during pregnancy and pre- and postnatal mental health problems. This finding highlights the possible interventions at the prenatal and postnatal periods. Early identification of women who have ACEs or who are at psychosocial risk during pre- and postnatal periods is critical to provide interventions to buffer those negative effects on offspring's development. Future studies are needed to longitudinally assess the effects of maternal ACEs on child development over time.

Using latent class analysis to empirically classify maltreatment according to the developmental timing, duration, and co-occurrence of abuse types

BackgroundIndividuals can have vastly different maltreatment experiences depending on the types, developmental timing, and duration of abuse. Women and men may be differentially affected by distinct abuse patterns. ObjectiveTo examine whether maltreatment subgroups could be identified based on the types, developmental timing, and duration of abuse, and to determine their prevalence among a large, community-based sample. We also examined sex differences in associations of maltreatment subgroups with adverse health outcomes. Participants and SettingData came from 9310 women and men (95 % White) in the United States who responded to the Growing Up Today Study questionnaire in 2007 (aged 19–27 years). MethodsParticipants reported on physical, sexual, and emotional abuse occurring in childhood (before age 11 years) and adolescence (ages 11−17 years). We conducted latent class (LC) analyses using indicators for child and adolescent abuse. We examined associations of LCs with health outcomes using sex-stratified log-binomial models with generalized estimated equations. ResultsWe identified five LCs characterized by: 1) no/low abuse (59 %), 2) child physical abuse (16 %), 3) adolescent emotional abuse (9%), 4) child and adolescent physical and emotional abuse (16 %), and 5) child and adolescent sexual abuse (1%). LCs were uniquely associated adult health outcomes among both women and men. Associations of LCs with eating disorder behaviors appeared stronger for men than women. ConclusionsIndividuals experience distinct patterns of maltreatment based on the types, developmental timing, and duration of abuse. These patterns are uniquely associated with adverse health outcomes in adulthood, and can be identified using LCA.

EARLY-LIFE ADVERSITY AND ADULT MENTAL AND BEHAVIORAL HEALTH OUTCOMES: AN INTERSECTIONAL APPROACH

There is much research confirming the link between experiencing early life adversities (ELAs) and adverse health outcomes in adulthood. Further, experiencing co-occurring ELAs rather than one ELA appears to be the rule rather than the exception, and leads to poorer health outcomes. However, information on how ELAs cluster and differentially harm the health of different intersectional groups is lacking. The stress process model suggests that intersectional configurations of race and gender are differentially exposed to ELAs and as a result, some groups suffer worse outcomes than others. We examine the risks of experiencing different clusters of ELAs—low childhood socioeconomic status (SES), family instability, and child abuse—among four intersectional groups (white men, white women, Black men, Black women). We also investigate whether experiencing these ELAs is responsible for the association between having a particular racial and gender configuration and adverse mental and behavioral health outcomes. Data come from a subsample of the Midlife in the U.S. Study (n = 2,076). Black men and women have the highest risk of experiencing all three ELA configurations. Men, regardless of race, have a higher risk of experiencing low SES while women are more vulnerable to low SES/family instability and all three ELAs. Black men and women appear to suffer the worst mental health outcomes, while Black and white men experience more drug/alcohol abuse than their female counterparts. ELAs, especially the co-occurrence of all three ELAs, partially mediate most of these associations, but more so for women than men.

Early Parental Death and Cognitive Impairment in Late Life: A Cohort Study

The burden of dementia in China is expected to increase dramatically. This study aimed to estimate the potential impact of early parental death on cognitive functioning in late life and whether education is a possible mechanism underlying this association. Data were derived from the 2002 and 2005 waves of the Chinese Longitudinal Healthy Longevity Survey. The final sample consisted of 10,953 Chinese older adults aged 80 to 105 years. Logistic regression models were used to estimate the impact of early parental death and education on the odds of severe cognitive impairment in older men and women. Results showed that experiencing the death of a mother at or before 16 years of age significantly increased the risk of severe cognitive impairment in older men (but not women), independent of demographic, socioeconomic, and physical health conditions. This association did not persist over a 3-year follow-up period and was not mediated by education. These findings provide further evidence that childhood trauma is associated with adverse adult health outcomes, in this case the death of a mother in early life and cognitive impairment in late life. Potential mechanisms that may link early parental death to worse cognitive functioning over the life course were discussed.

Exercise capacity and cardiac function in adolescents born post-term

There is some evidence that children born post-term (≥42 weeks of gestation) have metabolic abnormalities that may be associated with an increased risk of adverse health outcomes in adulthood. However, there are no data as to whether adolescents born post-term display alterations in aerobic capacity or cardiovascular function. We studied 48 adolescents (56% males) in Auckland (New Zealand) with a mean age of 14.3 years (SD = 1.7): 25 born post-term and 23 born at term (37–41 weeks of gestation). Assessments included metabolic markers in blood, whole body DXA scans, 24-hour ambulatory blood pressure monitoring, maximal exercise capacity, as well as cardiac MRI scan at rest and during submaximal exercise. Exercise capacity was lower in the post-term than in control participants (44.5 vs 47.8 ml/kgffm/min; p = 0.04). There were no differences in left ventricular volumes at rest and during exercise between groups. The 24-hour ambulatory blood pressure monitoring also showed no differences between the two groups. Being born post-term was associated with reduced exercise capacity, but with no observed differences in central cardiac function. We speculate that the reduction in exercise capacity may be due to changes in the peripheral vascular system.

PP-1 The prematch study: an effort to quantify the impact of preterm birth on cardiovascular and renal health

<h3>Background and objectives</h3> The PREMATurity as pre-dictor of Children’s cardiovascular and renal Health (PRE-MATCH) is a case-control study in former ELBW children (2000–2005) and controls (term) at the median age of 12 years to compare the phenotype, including body compo-sition, renal function and cardiovascular assessment. <h3>Methods</h3> Growth (height, weight, head circumference, Z-scores), body composition (Bodystat), renal function (renal length, cystatin C converted to eGFR), cardiovascu-lar assessment and retinal vascular aspects were assessed in former ELBW children and controls. <h3>Results</h3> Former ELBW children still have difficulties to reach their target height. ELBW adolescents show lower neurocognitive performance, grip strength and high-er fat body mass. Catch–up growth for weight in ELBW children in the first two years of life was associated with lower fat body mass. Renal length and glomerular filtra-tion rate (cystatin C) were 0.28 cm (95% CI 0.09–0.47) and 11.5 mL/min/1.73 m2 (6.4–16.6) lower in cases. The odds of having systolic (pre)hypertension in former ELBW cases was 6.43 (2.52–16.4) and 10.9 (2.46–48.4) with a low renin mechanism. Microvascular retinal arteriolar narrowing is observed in former ELBW young adolescents. <h3>Conclusions</h3> The phenotype (growth, body composi-tion, renal function, retinal microvascularisation) of former ELBWs differs significantly from controls in early adoles-cence. All these findings reflect mechanisms related to a higher risk factor for adverse health outcomes in adult-hood.

Behavioral interventions to promote adequate sleep among women: protocol for a systematic review and meta-analysis

BackgroundShort and poor sleep have been associated with adverse health outcomes in adults, such as overweight/obesity and type 2 diabetes, especially among women. Women therefore represent an important target for interventions aimed at improving sleep and such interventions have been advocated to enhance maternal, fetal, and infant health. This systematic review will assess the efficacy or effectiveness of behavioral interventions aimed at promoting adequate sleep among women. The primary outcomes will be changes in sleep duration and/or sleep quality from baseline to post-intervention and to the last available follow-up measured either through self-reports or objectively. Secondary outcomes will be assessing the behavior change techniques that are responsible for the changes in sleep duration and quality among women.MethodsBehavioral interventions that are non-pharmacological and target either sleep directly or sleep hygiene behaviors will be included. Randomized controlled trials, quasi-experimental, and one-group pre-post studies will be included, but treated separately in the analyses, given that a limited number of studies on the topic of sleep is expected. MEDLINE/PubMed, PsycINFO, CINAHL, EMBASE, and Proquest Dissertations and Theses will be investigated. There will be no restriction on the year of publication of the articles, but we will include only the ones written in English or French. Two authors will independently assess articles for eligibility and will extract data using a standardized data extraction form that will have been previously pilot-tested. The quality of the studies will be assessed using the Effective Public Health Practice Project tool for quantitative study designs. The intervention procedures will be classified according to the latest validated taxonomy of behavior change techniques. If there is a sufficient number of studies (k > 5), a meta-analysis of the results will be performed with a random-effect model. If the heterogeneity is high (I2 ≥ 75%), it will be investigated through sensitivity analyses and meta-regression.DiscussionThis review will provide valuable information to those interested in promoting adequate sleep among women and, hopefully, encourage additional research in this important field to promote maternal, fetal, and infant health.Systematic review registrationThe study protocol was registered in PROSPERO in October 2016 (CRD42016049538).

Childhood adversities and distress - The role of resilience in a representative sample.

While adverse childhood experiences have been shown to contribute to adverse health outcomes in adulthood, specifically distress and somatic symptoms, few studies have examined their joint effects with resilient coping style on adult adjustment. Hence, we aim to determine the association between resilient coping and distress in participants with and without reported childhood adversities. A representative German community sample (N = 2508) between 14–92 years (1334 women; 1174 men) was examined by the short form of the Childhood Trauma Questionnaire, the Brief Resilience Coping Scale, standardized scales of distress and somatoform symptoms. Childhood adversity was associated with reduced adjustment, social support and resilience. It was also strongly associated with increased distress and somatoform complaints. Resilient coping was not only associated with lower distress, it also buffered the effects of childhood adversity on distress. Our study corroborates the buffering effect of resilience in a representative German sample. High trait resilient subjects show less distress and somatoform symptoms despite reported childhood adversities in comparison to those with low resilient coping abilities.

Catch–up growth in the first two years of life in Extremely Low Birth Weight (ELBW) infants is associated with lower body fat in young adolescence

AimTo investigate growth patterns and anthropometrics in former extremely low birth weight (ELBW, <1000 g) children and link these outcomes to neurocognition and body composition in childhood.MethodsELBW children were examined at birth (n = 140), at 9 and 24 months (n≥96) and at approximately 11 years within the framework of the PREMATCH (PREMATurity as predictor children’s of Cardiovascular and renal Health) case–control (n = 93–87) study. Regional growth charts were used to convert anthropometrics into Z–scores. Catch–up growth in the first two years of life was qualified as present if ΔZ–score >0.67 SDS. At 11 years, anthropometrics, neurocognitive performance, body composition, grip strength and puberty scores were assessed.ResultsELBW neonates displayed extra–uterine growth restriction with mean Z–scores for height, weight and head circumference of –0.77, –0.93 and –0.46 at birth, –1.61, –1.67 and –0.72 at 9 months, –1.22, –1.61 and –0.84 at 24 months, and –0.42, –0.49 and –1.09 at 11 years. ELBW children performed consistently worse on neurocognitive testing with an average intelligence quotient equivalent at 11 years of 92.5 (SD 13.1). Catch–up growth was not associated with neurocognitive performance. Compared to controls, ELBW cases had lower grip strength (13.6 vs. 15.9 kg) and percentage lean body weight (75.1 vs. 80.5%), but higher body fat (24.6 vs. 19.2%) and advanced puberty scores at 11 years (all P≤0.025). Catch–up growth for weight and height in the first two years of life in cases was associated with a lower percentage body fat compared to cases without catch–up growth (16.8% catch-up growth for weight vs. 25.7%, P<0.001; 20.9% catch-up for height vs. 25.8%, P = 0.049).ConclusionsIn young adolescence, former ELBW children still have difficulties to reach their target height. Compared to normal birth weight controls, ELBW adolescents show lower neurocognitive performance and grip strength and a higher percentage body fat, a potential risk factor for adverse health outcomes in adulthood. Our key finding is that catch–up growth in ELBW children in the first two years of life is associated with a lower percentage body fat and is therefore likely to be beneficial.

The Complex Interplay of Adverse Childhood Experiences, Race, and Income.

An extensive research base shows evidence of racial disparities in health outcomes, and a growing body of evidence points to associations between adverse childhood experiences (ACEs) and poor health. This study uses data from the 2011 and 2012 Wisconsin Behavioral Risk Factor Surveillance System surveys to identify the relative contributions of ACEs, race, and adult income to predicting three sets of adverse adult health outcomes. The authors found that controlling for demographic factors, ACEs strongly predict health risk behaviors, indicators of poor general health, and chronic health conditions. Adult low-income status is associated with poor general health and chronic health conditions, but not health risk behaviors. African American race is marginally associated only with indicators of poor general health, and this association is attenuated when ACEs and adult income are controlled. These findings suggest a complex interplay among ACEs, race, and income.

Treatment Controversies in Adult ADHD.

Treatment Controversies in Adult ADHD.

The impact of poor adult health on labor supply in the Russian Federation

We examine the labor supply consequences of poor health in the Russian Federation, a country with exceptionally adverse adult health outcomes. In both baseline OLS models and in models with individual fixed effects, more serious ill-health events, somewhat surprisingly, generally have only weak effects on hours worked. At the same time, their effect on the extensive margin of labor supply is substantial. Moreover, when combining the effects on both the intensive and extensive margins, the effect of illness on hours worked increases considerably for a range of conditions. In addition, for most part of the age distribution, people with poor self-assessed health living in rural areas are less likely to stop working, compared to people living in cities. While there is no conclusive explanation for this finding, it could be related to the existence of certain barriers that prevent people with poor health from withdrawing from the labor force in order to take care of their health.

The Search for Biomarkers of Long-Term Outcome after Preterm Birth.

Preterm birth and survival rates are rising globally, and consequently there is a growing necessity to safeguard life-long health. Epidemiological and other studies from around the world point to a higher risk of adverse adult health outcomes following preterm birth. These reports encompass morbidities in multiple domains, poorer reproductive health, and reduced longevity. The contributions of genetic inheritance, intrauterine exposures, and postnatal care practices to this altered adult phenotype are not known. Early detection is essential to implement preventive measures and to test protective antenatal and neonatal interventions to attenuate aberrant health trajectories. A satisfactory biomarker of outcome must be predictive of later functional health and ideally remain stable over the period from infancy to childhood and adult life. To date, blood pressure is the index that best fulfils these criteria. High throughput 'omic' technologies may identify biomarkers of later outcome and health risk. However, their potential can only be realized with initial investment in large, longitudinal cohort studies, which couple serial metabolomic profiling with functional health assessments across the life course.

Vitamin D Deficiency in BALB/c Mouse Pregnancy Increases Placental Transfer of Glucocorticoids.

The prevalence of vitamin D deficiency in pregnancy is increasing and implicated in adverse consequences for the health of offspring in later life. The aim of this study was to determine whether vitamin D deficiency increases fetal exposure to glucocorticoids, which are known to alter fetal development and result in adverse adult health outcomes. Female BALB/c mice were placed on either a vitamin D control (2195 IU/kg) or deficient (0 IU/kg) diet for 5 weeks before and during pregnancy. Maternal serum, placentas and fetal brains were collected at embryonic day 14.5 or 17.5 for morphological and gene expression analysis. Vitamin D deficiency during pregnancy increased maternal corticosterone concentrations and reduced placental weight. Maternal vitamin D deficiency decreased placental expression of 11β-hydroxysteroid dehydrogenase type II, which inactivates glucocorticoids thereby protecting the fetus from inappropriate glucocorticoid exposure. There was a corresponding increase in placental and fetal expression of the highly glucocorticoid-sensitive factor glucocorticoid-induced leucine zipper. Furthermore, placental expression of the angiogenic factor vascular endothelial growth factor-A was reduced in vitamin D-deficient pregnancies, with a corresponding decline in fetal capillary volume within the placenta. Overall, we show that prenatal vitamin D deficiency leads to an increase in maternal corticosterone, alterations in genes indicative of increased fetal glucocorticoid exposure and impairment in placental vascular development. Thus, the long-term adverse health consequences of vitamin D deficiency during early development may not just be due to alteration in direct vitamin D-related pathways but also altered fetal glucocorticoid exposure.

Attention-deficit/hyperactivity disorder and adverse health outcomes in adults.

Whereas the adverse impact of attention-deficit/hyperactivity disorder (ADHD) on emotional and psychosocial well-being has been well investigated, its impact on physical health has not. The main aim of this study was to assess the impact of ADHD on lifestyle behaviors and measures of adverse health risk indicators. Subjects were 100 untreated adults with ADHD and 100 adults without ADHD of similar age and sex. Unhealthy lifestyle indicators included assessments of bad health habits, frequency of visits to healthcare providers, and follow through with recommended prophylactic tests. Assessments of adverse health risk indicators included measurements of cardiovascular and metabolic parameters, weight, body mass index, and waist circumference. No differences were identified in health habits between subjects with and without ADHD, but robust differences were found in a wide range of adverse health risk indicators. ADHD is associated with an adverse impact in health risk indicators well known to be associated with high morbidity and mortality.

Do sugar-sweetened beverages cause adverse health outcomes in adults? A systematic review protocol.

BackgroundChronic diseases, such as cardiovascular disease and type 2 diabetes, impose significant burden to public health. Most chronic diseases are associated with underlying preventable risk factors, such as elevated blood pressure, blood glucose, and lipids, physical inactivity, excessive sedentary behaviours, overweight and obesity, and tobacco usage. Sugar-sweetened beverages are known to be significant sources of additional caloric intake, and given recent attention to their contribution in the development of chronic diseases, a systematic review is warranted. We will assess whether the consumption of sugar-sweetened beverages in adults is associated with adverse health outcomes and what the potential moderating factors are.Methods/DesignOf interest are studies addressing sugar-sweetened beverage consumption, taking a broad perspective. Both direct consumption studies as well as those evaluating interventions that influence consumption (e.g. school policy, educational) will be relevant. Non-specific or multi-faceted behavioural, educational, or policy interventions may also be included subject to the level of evidence that exists for the other interventions/exposures. Comparisons of interest and endpoints of interest are pre-specified. We will include randomized controlled trials, controlled clinical trials, interrupted time series studies, controlled before-after studies, prospective and retrospective comparative cohort studies, case-control studies, and nested case-control designs. The MEDLINE®, Embase, The Cochrane Library, CINAHL, ERIC, and PsycINFO® databases and grey literature sources will be searched. The processes for selecting studies, abstracting data, and resolving conflicts are described. We will assess risk of bias using design-specific tools. To determine sets of confounding variables that should be adjusted for, we have developed causal directed acyclic graphs and will use those to inform our risk of bias assessments. Meta-analysis will be conducted where appropriate; parameters for exploring statistical heterogeneity and effect modifiers are pre-specified. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used for determining the quality of evidence for outcomes.Systematic review registrationPROSPERO CRD42014009638