Physical activity and cardiovascular risk factors in

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Preventive Medicine 69 (2014) 54–62

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Preventive Medicine journal homepage: www.elsevier.com/locate/ypmed

Review

Physical activity and cardiovascular risk factors in children: meta-analysis of randomized clinical trials Claudia Ciceri Cesa a, Graciele Sbruzzi a,b, Rodrigo Antonini Ribeiro c, Sandra Mari Barbiero a, Rosemary de Oliveira Petkowicz a, Bruna Eibel a, Natássia Bigolin Machado a,d, Renata das Virgens Marques a,d, Gabriela Tortato a,d, Tiago Jerônimo dos Santos a, Carina Leiria a, Beatriz D'Agord Schaan a,e, Lucia Campos Pellanda a,d,⁎ a

Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia, Avenida Princesa Isabel, 370/3 andar. Porto Alegre, Rio Grande do Sul 90620-000, Brazil Universidade Federal do Rio Grande do Sul, School of Physical Education, Rua Felizardo Furtado, 750. Porto Alegre, Rio Grande do Sul90670-090, Brazil c Hospital Moinhos de Vento, Institute of Education and Research, Rua Ramiro Barcelos, 910. Porto Alegre, Rio Grande do Sul 90035-001, Brazil d Universidade Federal de Ciências da Saúde de Porto Alegre, Avenida Osvaldo Aranha, 245. Porto Alegre, Rio Grande do Sul 90050-170, Brazil e Endocrine Division, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2350, prédio 12, 4 andar, Porto Alegre, Rio Grande do Sul 90035-003, Brazil b

a r t i c l e

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a b s t r a c t

Available online 29 August 2014

Objective. To assess the effects of physical activity interventions in preventing cardiovascular risk factors in childhood through a systematic review and meta-analysis of randomized clinical trials (RCTs). Methods. A search of online databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted from inception until June 2013. RCTs enrolling children 6–12 years old conducted physical activity interventions longer than 6 months, assessing their effect on body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), total cholesterol (TC) and triglycerides (TG) were included. Data analysis was performed using a random-effects model. Results. Of 23.091 articles retrieved, 11 RCTs (10.748 subjects) were included. Physical activity interventions were not associated with reductions of BMI [−0.03 kg/m2 (95%CI −0.16, 0.13) I2 0%]. However, there was an association between the interventions and reduction of SBP [− 1.25 mmHg (95%CI − 2.47, − 0.02) I2 0%], DBP [−1.34 mmHg (95%CI −2.57, −0.11) I2 43%] and TG [−0.09 mmol/L (95%CI −0.14, −0.04) I2 0%], and increase of TC [0.14 mmol/L (95%CI 0.01, 0.27) I2 0%]. Conclusion. As physical activity intervention programs lasting longer than 6 months are associated with reductions in blood pressure levels and triglycerides, they should be considered to be included in prevention programs for cardiovascular diseases in schoolchildren. © 2014 Elsevier Inc. All rights reserved.

Keywords: Motor activity Exercise Child Obesity Blood pressure Lipids

Contents Background . . . . . . . . . . . . Methods . . . . . . . . . . . . . . Eligibility criteria . . . . . . . . Information sources . . . . . . . Study selection and data extraction Assessment of risk of bias . . . . Data analysis . . . . . . . . . .

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⁎ Corresponding author at: Instituto de Cardiologia do Rio Grande do Sul / Fundação Universitária de Cardiologia, Avenida Princesa Isabel, 370/3 andar, Porto Alegre, Rio Grande do Sul, 90620-000 Brazil. E-mail addresses: [email protected] (C.C. Cesa), [email protected] (G. Sbruzzi), [email protected] (R.A. Ribeiro), [email protected] (S.M. Barbiero), [email protected] (R. de Oliveira Petkowicz), [email protected] (B. Eibel), [email protected] (N.B. Machado), [email protected] (R.V. Marques), [email protected] (G. Tortato), [email protected] (T.J. dos Santos), [email protected] (C. Leiria), [email protected] (B.D. Schaan), [email protected], [email protected] (L.C. Pellanda).

http://dx.doi.org/10.1016/j.ypmed.2014.08.014 0091-7435/© 2014 Elsevier Inc. All rights reserved.

C.C. Cesa et al. / Preventive Medicine 69 (2014) 54–62

Results . . . . . . . . . . . . . . . . Description of studies . . . . . . . . Risk of bias . . . . . . . . . . . . Effects of interventions . . . . . . . Body mass index . . . . . . . . Blood pressure . . . . . . . . . Lipid profile . . . . . . . . . . . . Total cholesterol and triglycerides Type of intervention . . . . . . Discussion . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . List of abbreviations . . . . . . . . . . Conflict of interest statement . . . . . . Acknowledgments . . . . . . . . . . . Appendix I . . . . . . . . . . . . . . Appendix II . . . . . . . . . . . . . . References . . . . . . . . . . . . . .

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Background The prevalence of obesity in children (from 6 to12 years old) has been increasing worldwide in the last decades. From 1980 to 2013, prevalence in developing countries has increased in children and adolescents, from 8.1% to 12.9% for boys and from 8.4% to 13.4% in girls (Ng et al, 2014). If the trend continues, this may represent more than 60 million children in 2020 who struggle with weight issues (de Onis et al., 2010). In children, obesity is the most important risk factor in developing other cardiovascular risk factors, such as high blood pressure and dyslipidemia, both during childhood and in the future adult (Raghuveer, 2010). Many countries and organizations have issued physical activity recommendations to prevent or treat pediatric obesity and other cardiovascular risk factors for school-aged children and youth (Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents and National Heart, Lung, and Blood Institute, 2011; Back Giuliano Ide et al., 2005; Kavey et al., 2007; Williams et al., 2002). These recommendations are based on the concept that regular physical activity, along with other behavior modifications such as a healthy diet, would be beneficial in preventing obesity, hypertension, diabetes, dyslipidemia and, as a consequence, cardiovascular disease in adult life. The last Cochrane Collaboration Systematic Review's update showed strong evidence that interventions for children 6–12 years-old can help prevent childhood obesity (Waters et al., 2011). A few RCTs and systematic reviews were published, but none comprehensively studied the effects of long term physical activities interventions on risk factors for cardiovascular diseases other than obesity, such as lipid profile and blood pressure (Brown et al., 2013; Campbell et al., 2002; Dobbins et al., 2009, 2013; Ho et al., 2012; Kriemler et al., 2010; Oude Luttikhuis et al., 2009; Reilly and McDowell, 2003). Additionally, these reviews included a large age range. Since primary prevention strategies such as physical activity interventions must be tailored according to developmental stages, and expected weight gain is different according to age, this approach of including a large age range may dilute differences on response to such interventions (Oude Luttikhuis et al., 2009; Reilly and McDowell, 2003; Summerbell et al., 2005). It is possible that in children 6–12 years old, as compared to teenagers, early exposure to intervention may be more effective in the long term maintenance of healthy habits (von Kries et al., 2012). Likewise, more prolonged (6 months or more) interventions may be more effective than short interventions regarding permanent lifestyle modifications (Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents and National Heart, Lung, and Blood

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Institute, 2011; Back Giuliano Ide et al., 2005; Kavey et al., 2007; Williams et al., 2002). Thus, the aim of this systematic review with meta-analysis of randomized clinical trials (RCTs) was to compare the effect of interventions vs. no intervention or less intensive interventions of exercise training and physical activity counseling with duration 6 months or longer. Outcomes were body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), total cholesterol (TC) and triglycerides (TG), and studies focused children from 6–12 years old. Methods This systematic review was performed in accordance with the Cochrane Collaboration and is presented as suggested by the Preferred Reporting Items for Systematic Review and Meta-analyses: the PRISMA Statement (Moher et al., 2010). Eligibility criteria Studies included RCTs performed in schoolchildren 6 to 12 years old, irrespective of weight (normal body weight, overweight and obese). The intervention was considered any physical activity program lasting longer than 6 months, with at least 150 minutes per week as compared to a less intensive program or no intervention. This amount of 150 minutes per week (30 minutes per day) is considered the minimum target to be physically active (U.S. Department of Health and Human Services, 2008; Haskell et al., 2007). Our initial protocol was to analyze body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), non-high-density lipoprotein (non-HDL), fasting glucose and C-reactive protein (CRP). A RCT was included if it met the inclusion criteria and had at least one of the primary or secondary outcomes. Trials that did not provide information regarding the magnitude of the effect of the intervention, either in the experimental or in control groups, were excluded. If a trial had multiple publications (or substudies), only the most recent publication was included, while the other publications were used for supplemental information. The studies included in the present meta-analysis comprised physical activity as the only intervention carried out, or as the main component of the intervention. Studies that included some form of nutritional intervention were analyzed only if it was considered minimal (such as offering a healthy snack after class or healthy lifestyle classes for the control group). Information sources The review protocol was registered in the institutional research board. The search comprised three online databases – MEDLINE (accessed by PubMed), Cochrane Central Register of Controlled Trials (Cochrane CENTRAL) and EMBASE. The search lasted from inception to June 2013 and was comprised of the following terms: “obesity”, “overweight”, “child nutrition disorders”, “child”, “school”, “student”, “exercise”, “exercise therapy”, “exercise movement techniques”, “motor activity”, “sports”, “physical education and training”,

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“physical fitness”, in addition to a high sensitivity strategy for the search of randomized clinical trials (Robinson and Dickersin, 2002). There were no language restrictions. To identify primary studies, the authors searched and checked for reference lists of previously published systematic reviews and meta-analyses. The detailed strategies for PUBMED are in Appendix I. The strategies for other databases are available upon request. This strategy is part of a larger project. In the present article we show specifically the effects of physical activity interventions to prevent or treat childhood obesity. In another manuscript, we already examined the effects of educational interventions compared to usual care or no intervention for prevention or treatment of childhood obesity (Sbruzzi et al., 2013). Study selection and data extraction Two investigators (C.C.C. and S.M.B.), in duplicate, independently evaluated titles and abstracts of all articles identified by the search strategy. All abstracts that did not provide sufficient information regarding the inclusion and exclusion criteria were selected for full-text evaluation. In the second phase, the same reviewers independently evaluated these full-text articles and made their selection in accordance with the eligibility criteria. Disagreements between reviewers were solved by consensus, and, if disagreement persisted, by a third reviewer (L.C.P or B.D.S). To avoid possible double counting of patients included in more than one report of the same authors/working groups, the patient recruitment periods and areas were evaluated, and authors were contacted for clarification. The same two reviewers (C.C.C. and S.M.B) independently conducted data extraction with regard to the methodological characteristics of the studies, interventions and outcomes using standardized forms; disagreements were solved by consensus or by a third reviewer (L.C.P or B.D.S). Interventions were detailed regarding to length, intensity, type of activity and frequency. While study selection and data extraction was in progress, we observed that only some of the outcomes described in the eligibility criteria appeared consistently in the retrieved studies in order to be added in sub-analysis or sensitivity analysis. Based on this, the outcomes extracted were: BMI (kg/m2 − weight in kilograms divided by the square of the height in meters), SBP and DBP (mmHg), TC and TG (mg/dL). Assessment of risk of bias Study quality assessment included adequate sequence generation, allocation concealment, blinding of investigator, participants, assessors and outcomes assessors, intention-to-treat analysis and description of losses and exclusions. Studies had to have a clear description of an adequate sequence generation to be considered as fulfilling these criteria. The description of how the allocation list was concealed could include terms like “central”, “web-based” or “telephone randomization”, or a clear statement that the allocation list was concealed. Intention-to-treat analysis was considered as confirmation on study assessment that the number of participants randomized and the number analyzed were identical, except for patients lost to follow-up or who withdrew consent for study participation. Two reviewers independently performed quality assessment, and for each criterion studies were classified as adequate, not adequate or unclear/not reported. Data analysis Pooled-effect estimates were obtained using the final values (Higgins and Green, 2008). For continuous outcomes, if unit of measurement was consistent across trials, results were presented as weighted means difference with 95% confidence intervals (CIs). Calculations were performed using a random effects method and the statistical method used was inverse variance. A p value ≤ 0.05 was considered statistically significant. Statistical heterogeneity of the treatment effects among studies was assessed using the Cochran's Q test and the inconsistency I2 test, in which values above 25% and 50% were considered indicative of moderate and high heterogeneity, respectively (Higgins et al., 2003). All analyses were conducted using Review Manager version 5.1 (Cochrane Collaboration). In addition, sensitivity analysis of RCTs was performed to evaluate differences in the intervention approach (Intervention Group: physical education classes + physical exercise program, Control Group: Current curriculum physical education classes, and other type of intervention approaches, less intensive than main intervention). Heterogeneity between studies was also explored according to intensity and duration of the intervention and follow-up. Funnel plots were constructed to assess the risk of publication bias and are available in Appendix II.

Fig. 1. Flow diagram of included studies. Legend: no legend.

Results Description of studies From 23 091 potentially relevant citations retrieved from electronic databases and searches of reference lists, 11 RCTs met the inclusion criteria. Fig. 1 shows the flow diagram of studies in this review. The studies included comprised a total of 10 748 subjects. Table 1 summarizes the characteristics of these studies. Risk of bias Of the included studies, 50% presented adequate sequence generation, 20% reported adequate allocation concealment, and none reported blinding of the investigators. Of the outcomes assessors, 10% had reported blinding, 100% described losses to follow-up and exclusions and 60% performed intention-to-treat analyses (Table 2). Effects of interventions Body mass index Nine studies (Barbeau et al., 2007; Donnelly et al., 2009; Faude et al., 2010; Jansen et al., 2011; Kriemler et al., 2010; Li et al., 2010; Thivel et al., 2011; Vandongen et al., 1995; Weintraub et al., 2008) (n = 10 355) evaluated BMI. Physical activity interventions were not associated with reductions on BMI when compared to less intensive physical activity interventions or no intervention (Fig. 2). To investigate possible differences between studies, a sensitivity analysis related to period of intervention and intervention type was performed. Only one study (Donnelly et al., 2009) conducted an intervention longer than 12 months. In the 8 studies (Barbeau et al., 2007; Faude et al., 2010; Jansen et al., 2011; Kriemler et al., 2010; Li et al., 2010; Thivel et al., 2011; Vandongen et al., 1995; Weintraub et al., 2008) with interventions between 6 and 12 months, physical activity was not associated with BMI reductions [−0.01 kg/m2 (95% CI −0.16, 0.15), I2 0%]. In the 6 studies (Barbeau et al., 2007; Donnelly et al., 2009; Jansen et al., 2011; Kriemler et al., 2010; Thivel et al., 2011; Vandongen et al., 1995) (n = 5612) that employed physical exercise or increased

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Table 1 Characteristics of included studies. Study, year

Randomized patients (n) intervention/control

Participants

Intervention group

Control group

Duration of intervention

Vandongen et al., 1995 158/145

School children

Six times per week (30 minutes each) classroom sessions replacing the usual curriculum.

Regular curriculum

9 months

Barbeau et al., 2007;

118/83

School children (black girls)

Regular physical education classes

Weintraub et al., 2008

9 /12

School children

Donnelly et al., 2009

814/713

School children and parents

Walther et al., 2009

105/56

School children

Regular physical education classes plus 110 minutes after school physical activity program After-school team sports program Physical education classes (60 minutes per week) plus PAAC. PAAC: 90 minutes per week of moderate to vigorous physically active academic lessons (3.0–6.0 METS, 10 min each) delivered intermittently throughout the school day. Physical education classes per school day (45 minutes each)

Faude et al., 2010

11/11

Kriemler et al., 2010

297/205

Overweight children School children

Three times per week (1 hour each) football training Five physical education lessons per week

Li et al., 2010

2329/2371

School children

Jansen et al., 2011

1240/1382

School children

Thivel et al., 2011

229/228

Lean and obese school children

Walther et al., 2011

141/91

School children

Two daily 10-min physical activity sessions conducted in the break between classes. Physical education classes and afterschool activities are not replaced. Three physical education classes per week plus additional sport and play activities outside school hours (voluntary). Two physical education classes per week plus 2 times additional exercise classes (2 times, 60 minutes each = 120 minutes per week) Five times a week, one hour of regulated sport exercise, including 15 minutes of endurance training.

frequency/intensity of regular curriculum physical education classes, the pooled effect was 0.08 kg/m2 (95% CI − 0.14, 0.30), I2 0%. The other studies described isolated and highly heterogeneous interventions, such as only football training or regular physical education classes [−0.11 kg/m2 (95% CI −0.32, 0.09), I2 0%].

Evaluated outcomes

Body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides 1 school year Body mass index

Traditional health education Regular physical education classes

6 months

Body mass index

3 years

Body mass index

Two physical education classes per week (45 minutes each) Established standard sports program Three physical education lessons per week

1 school year Total cholesterol, triglycerides

No intervention. (Regular physical education classes and after-school activities)

6 months

Body mass index

12 months

Body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol 1 school year Body mass index

Two education classes

8 months

Body mass index

Two physical education classes per week

6 months

Body mass index

Two times a week, one hour of current sport activity

2 school years

Systolic blood pressure, Diastolic blood pressure

Blood pressure Three studies (Kriemler et al., 2010; Vandongen et al., 1995; Walther et al., 2011) (n = 1037) evaluated SBP and DBP (Fig. 3). In the study by Vandongen et al, baseline levels of SBP were 105.2 mmHg (95% CI 104–105.5) and DBP were 61.8 mmHg (95% 61.3–62.2). In the study by

Table 2 Risk of bias of included studies. Study, year

Adequate sequence generation

Allocation concealment

Blinding of investigator

Blinding of participant

Blinding of assessors

Blinding of outcome assessors

Intentionto-treat analysis

Description of losses and exclusions

Vandongen et al., 1995 Barbeau et al., 2007; Weintraub et al., 2008 Donnelly et al., 2009 Walther et al., 2009 Faude et al., 2010 Kriemler et al., 2010 Li et al., 2010 Jansen et al., 2011 Thivel et al., 2011 Walther et al., 2011

Not reported Not reported Yes Not reported Not reported Yes Yes Yes Yes Not reported Not reported

Not reported Unclear Unclear Unclear Unclear Not reported Adequate Not reported Not reported Not reported Adequate

Not reported Not reported No No No Not reported No Not reported No Not reported No

Not reported Not reported No No No Not reported No Not reported No Yes No

Yes Not reported No Yes Yes Not reported Yes Not reported No Not reported No

Unclear Not reported Not reported Not reported Not reported Not reported Not reported Not reported No Not reported Not reported

No Yes Yes Not reported Yes No Yes No Yes Yes No

Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes

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Fig. 2. Absolute changes in body mass index (BMI, kg/m2) for physical activity intervention vs. controls. Legend: CI: confidence interval; SD: standard deviation. Weights are from randomeffects analysis.

Kriemler et al., mean SBP and DBP were 104 ± 9 mmHg and 62 ± 8 in the intervention group and 103 ± 8 mmHg and 61 ± 7 in the control group, respectively. In the study by Walther et al., mean SBP and DBP were 102 ± 11.2 mmHg and 69.5 ± 9.69 in the intervention group and 103 ± 10.1 mmHg and 70.7 ± 8.09 in the control group, respectively. Physical activity interventions were associated with reductions on SBP and DBP when compared to less intensive physical activity interventions or no intervention [SBP: −1.25 mmHg (95%CI −2.47, −0.02), I2 0%; DBP: −1.34 mmHg (95%CI −2.57, −0.11), I2 41%] (Fig. 3). Lipid profile Total cholesterol and triglycerides Two studies (Vandongen et al., 1995; Walther et al., 2009) (n = 464) evaluated TC. In the study by Vandongen et al, baseline levels of TC were 4.24 mmol/L (95% CI 4.18–4.29). In the study by Walther et al., mean TC was 4.20 ± 0.63 mmol/L in the intervention group and 4.26 ± 0.70 in the control group. Physical activity interventions were associated with TC increase when compared to less intensive or no intervention [0.14 mmol/L (95%CI 0.01, 0.27), I2 0%] (Fig. 4). Triglycerides were evaluated in two (Kriemler et al., 2010; Walther et al., 2009) studies (n = 663). In the study by Kriemler et al., mean TG levels were 0.6 ± 0.25 mmol/L in the intervention group and 0.64 ± 0.29 mmol/L in the control group. In the study by Walther et al., mean TG was 1.10 ± 0.46 mmol/L in the intervention group and 1.10 ± 0.51 mmol/L in the control group. Physical activity interventions

were associated with reductions on TG when compared to less intensive physical activity interventions or no intervention [−0.09 mmol/L (95% CI −0.14, −0.04), I2 0%] (Fig. 4). Type of intervention We performed a sensitivity analysis in order to evaluate possible differences in studies that comprised physical activity as the only intervention and studies that included minimal nutritional interventions; there were no significant differences when studies with minimal nutritional interventions were withdrawn. (Donnelly et al., 2009; Faude et al., 2010; Kriemler et al., 2010; Li et al., 2010; Thivel et al., 2011; Vandongen et al., 1995). Discussion This systematic review with meta-analysis showed that physical activity and exercise-training interventions performed for at least 6 months are not associated with reductions on BMI in children, but are associated with reductions on blood pressure and triglycerides when compared to less intensive or no intervention. To the best of our knowledge, this is the first systematic review with meta-analysis that combines different cardiovascular risk factors in children as outcomes, evaluating physical activity interventions to improve cardiovascular health in 6–12-year-old school children. In the present review, RCTs that included BMI as an outcome showed non-significant results, since all confidence intervals failed to show any

Fig. 3. Absolute changes in systolic and diastolic blood pressure (mmHg) for physical activity intervention vs. controls. Legend: CI: confidence interval; SD: standard deviation. Weights are from random-effects analysis.

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Fig. 4. Absolute changes in total cholesterol and triglycerides (mmol/L) for physical activity intervention vs. controls. Legend: CI: confidence interval; SD: standard deviation. Weights are from random-effects analysis.

beneficial effect. These results may be due to the small difference between intervention and control groups, since control groups in all trials received regular physical education classes, and interventions consisted of added sessions of exercise that did not differ much in quality or quantity from the regular physical education classes. Moreover, mechanisms by how dietary changes and physical training promote metabolic improvements are common in some respects, but different in others (Ferrier et al., 2004). Because of this, it is expected that these interventions applied together would result in greater metabolic effects, as previously shown for glucose control amelioration in diabetic patients (Umpierre et al., 2011). This highlights the need for a combined recommendation of these lifestyle interventions. It is also important to consider that BMI may not be the best parameter to measure the effect of these interventions in children. Increases in BMI are normally expected with time in this age group, increasing the difficulty of comparisons over time. Additionally, BMI may not reflect the complex effect of interventions on body composition and increase in lean mass. In a recent systematic review, educational interventions were effective to reduce obesity, blood pressure and waist circumference in obese or overweight children, but not to prevent these risk factors in nonselected populations of schoolchildren that include both overweight and eutrophic children (Sbruzzi et al., 2013). Studies of exercise training and physical activity in children should focus on other outcomes, such as lifestyle modifications and improvement of blood pressure and lipid profile, to portray more comprehensively the complex effects of the intervention. The lack of effect of physical activity on BMI was similarly observed in other meta-analysis in different contexts (Harris et al., 2009; McGovern et al., 2008). However, the last Cochrane Collaboration Systematic Review's update, that included other types of studies besides RCTs and non structured physical activity showed that these interventions in children for 6–12 years old can reduce BMI (Waters et al., 2011). Interestingly, exercise training and physical activity reduced blood pressure levels in children and adolescents, consistent with observational studies that showed that blood pressure levels were inversely associated with the amount of physical activity in this age group (Hallal et al., 2011; Maximova et al., 2009). As blood pressure reduction associated with exercise seems to be related with increased cardiorespiratory fitness, and low cardiorespiratory fitness is a strong and independent predictor of cardiovascular and all-cause mortality in adults (Wei et al., 1999), it is tempting to speculate this would also be true in children. Also in accordance with data obtained in adults, as several trials have reported a very important role of blood pressure lowering on cardiovascular events reduction (Verdecchia et al., 2010), this could also be expected in children and adolescents. Considering that each two mmHg of diastolic blood pressure reduction in adults can lower

the likelihood of having any cardiovascular outcome in 12%, we could hypothesize that reductions around 1 mmHg in healthy children would provide a potential impact in adult blood pressure and future cardiovascular events (Verdecchia et al., 2010), considering the long period of cumulative exposition. As we already mentioned, there is observational evidence linking the presence of these risk factors in childhood with an increased risk of atherosclerosis in adult life. That said, there are no intervention studies showing that the reduction of these factors, especially at already normal levels, have any impact. Longterm randomized clinical trials of physical activity interventions for decades, compared to sedentary controls to evaluate adult outcomes, would be impractical, if not unethical. We must also consider that the establishment of healthy habits in childhood may be a desiderable outcome per se, regardless of changes in biological parameters during this period. Since there is reasonable evidence that these habits track into adulthood (Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents and National Heart, Lung, and Blood Institute, 2011), they would then be responsible for favorable outcomes. In the present study, physical activity promoted a reduction of TG, but an increase in TC. Another systematic review with meta-analysis focusing in aerobic exercise and lipid profile in youth showed similar results (Kelley and Kelley, 2007). Cholesterol curves for normal children show that TC peaks at the age of 9–10 years, being approximately 15 mg/dL higher than in younger children and adolescents. On the other hand, TG does not show the same peak in preadolescents (Skinner et al., 2011). The association of exercise training and physical activity with lower TG levels may be a result of more ample lifestyle modifications caused by exercise, with accompanying healthier eating habits (Downs et al., 2007). Studies included in this meta-analysis did not employ any specific dietary intervention to reduce TC. Additionally, there was no data on high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels, making the interpretation of the increase in TC difficult. This may be a possible explanation for the “worst” lipid profile concerning TC associated with a better profile of TG in the present analyses. Considering this, and that exercise training in early life can influence lipid levels in mid-adulthood (Magnussen et al., 2011), exercise training and physical activity in children and adolescents can also be considered beneficial for lipid levels. Since TG is an independent cardiovascular risk factor for ischemic heart diseases in adults, the improvement observed could have a positive impact on cardiovascular health prevention (Jeppesen et al., 1998). Although recent guidelines (Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents and National Heart, Lung, and Blood Institute, 2011) suggest

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pharmacologic treatment for children with no familiar disorders who fail to reduce their lipid levels with lifestyle interventions, this should be considered with caution, because the long-term risk-benefit of this kind of treatment remains unclear (Psaty and Rivara, 2011). Additionally, diet and/or physical activity recommendations usually are associated with lower harm when compared with the pharmacologic approach and can determine a healthier behavior for the entire life. A limitation of this systematic review and meta-analysis is that most of the studies retrieved were of low methodological quality. Studies inadequately reported the allocation concealment and blinding of outcome assessors. Non-pharmacological studies that involve physical activity interventions have several limitations compared to drug RCTs. These limitations can involve learning curves, standardization of interventions, lack of blinding, and cointervention. The lack of blinding could be considered a major limitation of RCTs included in this systematic review, but, as discussed above, this is an inherent limitation of nonpharmacological studies. Moreover, it must also be mentioned that interventions were very heterogeneous. This could be an advantage, allowing the comparison of different components, but dose-response studies are still needed, including a variety of interventions with standardize approach regarding type, intensity, frequency and duration for future research. Sensitivity analyses were limited because of the low number of studies for each outcome. These biases may have influenced results in favor of interventions, but since these interventions are of low risk and cost, the results may be worth considering despite the low level of evidence. On the other hand, this systematic review and meta-analysis has methodological strengths worth citing. First, we selected key words and conducted the strategy search to get the most sensitive citation selection. Second, only studies that met stricter criteria, such as RCT design, time of intervention longer than 6 months and BMI, blood pressure, and lipid profile outcomes were included. Third, the overall references screening and the inclusion/exclusion paper criteria were carried on with no language restrictions. Lastly, low heterogeneity was identified in the performed meta-analysis, except for diastolic blood pressure, that showed moderate heterogeneity.

Conclusion Exercise training and physical activity intervention programs longer than 6 months are associated with a better cardiovascular risk factor profile in children, notably blood pressure and triglycerides reduction as compared to less intensive interventions. New approaches, including trials with greater exercise intensity, standardized interventions, comprehensive strategies and dose-response studies are needed to extend these results to other cardiovascular risk factors, such as obesity and hypercholesterolemia, and to evaluate their effects in the prevention of cardiovascular diseases in future adults.

Acknowledgments This study received financial support from the Brazilian Ministry of Science and Technology, Ministry of Health and the Brazilian Research Council (Ministério da Ciência e Tecnologia, Ministério da Saúde, Conselho Nacional de Desenvolvimento Científico e Tecnológico – MCT/CNPq/CT-Saúde/MS/SCTIE/DECIT – no. 067/2009), Rio Grande do Sul Research Foundation (Fundação de Apoio à Pesquisa do Estado do Rio Grande do Sul – FAPERGS) and Institute of Cardiology Research Foundation (Fundo de Apoio do Instituto de Cardiologia/FUC à Ciência e Cultura – FAPICC). Sandra Mari Barbiero and Graciele Sbruzzi received doctoral research scholarships from National Council for Scientific and Technological Development, Ministry of Science and Technology (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq). Claudia Ciceri Cesa received doctoral research scholarships from CAPES Foundation, Ministry of Education of Brazil (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES) and a grant by Brazilian Cardiology Society (Sociedade Brasileira de Cardiologia).

Appendix I PubMed Search Strategy #1 Search obesity OR overweight #2 Search Child Nutrition Disorders OR child$ OR school OR student$ #3 Search (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized controlled trials[mh] OR random allocation [mh] OR double-blind method[mh] OR single-blind method[mh] OR clinical trial[pt] OR clinical trials[mh] OR (“clinical trial”[tw]) OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw] OR tripl*[tw]) AND (mask* [tw] OR blind*[tw])) OR (“latin square”[tw]) OR placebos[mh] OR placebo*[tw] OR random*[tw] OR research design[mh:noexp] OR comparative studies[mh] OR evaluation studies[mh] OR follow-up studies[mh] OR prospective studies[mh] OR cross-over studies[mh] OR control* [tw] OR prospectiv*[tw] OR volunteer*[tw]) NOT (animal[mh] NOT human[mh]) #4 Search drug therapy OR surgery OR review OR letter OR editorial #5 Search exercise OR exercise therapy OR Exercise Movement Techniques OR motor activit$ OR sports OR Physical Education and Training OR physical fitness #6 Search (#5 AND #1 AND #2 AND #3) NOT #4

Appendix II

List of abbreviations RCT randomized clinical trial BMI body mass index SBP systolic blood pressure DBP diastolic blood pressure TC total cholesterol TG triglycerides HDL high-density lipoprotein LDL low-density lipoprotein CIs confidence intervals

Conflict of interest statement The authors declare that there are no conflicts of interest.

Fig. AII.1. Funnel plot: published papers describing body mass index as an outcome. Legend: x axis: mean difference; y axis: standard error of mean difference.

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Fig. AII.2. Funnel plot: Published papers describing systolic blood pressure and diastolic blood pressure as an outcome. Legend: x axis: mean difference; y axis: standard error of mean difference.

Fig. AII.3. Funnel plot: Published papers describing total cholesterol and triglycerides as an outcome. Legend: x axis: mean difference; y axis: standard error of mean difference.

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