Overweight and obesity in children and adolescents with Down syndrome—prevalence, determinants, consequences, and interventions: A literature review

Research in Developmental Disabilities 57 (2016) 181–192

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Research in Developmental Disabilities

Review article

Overweight and obesity in children and adolescents with Down syndrome—prevalence, determinants, consequences, and interventions: A literature review Fabio Bertapelli a,b,∗ , Ken Pitetti c , Stamatis Agiovlasitis d , Gil Guerra-Junior b,e a

CAPES Foundation, Ministry of Education of Brazil, Brasília, DF 70040-020, Brazil Growth and Development Lab, Center for Investigation in Pediatrics, Faculty of Medical Sciences, University of Campinas, Campinas, SP 13083-887, Brazil c Department of Physical Therapy, College of Health Professions, Wichita State University, Wichita, KS 67260-0043, USA d Department of Kinesiology, Mississippi State University, Mississippi State, Starkville, MS 39762, USA e Department of Pediatrics, Faculty of Medical Sciences, University of Campinas, Campinas, SP 13083-970, Brazil b

a r t i c l e

i n f o

Article history: Received 25 February 2016 Received in revised form 9 June 2016 Accepted 26 June 2016 Number of reviews completed is 2 Keywords: Overweight Obesity Youths Down syndrome

a b s t r a c t Background: Children with Down syndrome (DS) are more likely to be overweight or obese than the general population of youth without DS. Aims: To review the prevalence of overweight and obesity and their determinants in youth with DS. The health consequences and the effectiveness of interventions were also examined. Methods and procedures: A search using MEDLINE, Embase, Web of Science, Scopus, CINAHL, PsycINFO, SPORTDiscus, LILACS, and COCHRANE was conducted. From a total of 4280 studies, we included 45 original research articles published between 1988 and 2015. Outcomes and results: The combined prevalence of overweight and obesity varied between studies from 23% to 70%. Youth with DS had higher rates of overweight and obesity than youths without DS. Likely determinants of obesity included increased leptin, decreased resting energy expenditure, comorbidities, unfavorable diet, and low physical activity levels. Obesity was positively associated with obstructive sleep apnea, dyslipidemia, hyperinsulinemia, and gait disorder. Interventions for obesity prevention and control were primarily based on exercise-based programs, and were insufficient to achieve weight or fat loss. Conclusions and implications: Population-based research is needed to identify risk factors and support multi-factorial strategies for reducing overweight and obesity in children and adolescents with DS. © 2016 Elsevier Ltd. All rights reserved.

Contents

1. 2.

What this paper adds? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 2.1. Search strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

∗ Corresponding author at: Growth and Development Lab, Center for Investigation in Pediatrics, Faculty of Medical Sciences, University of Campinas, SP 13083-887, Brazil. E-mail addresses: [email protected] (F. Bertapelli), [email protected] (K. Pitetti), [email protected] (S. Agiovlasitis), [email protected] (G. Guerra-Junior). http://dx.doi.org/10.1016/j.ridd.2016.06.018 0891-4222/© 2016 Elsevier Ltd. All rights reserved.

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2.2. Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 3.1. Prevalence of overweight and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 3.2. Gender differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 3.3. Age differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 4. Determinants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 4.1. Leptin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 4.2. Resting energy expenditure (REE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 4.3. Physical activity (PA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 4.4. Dietary patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 4.5. Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 5. Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 5.1. Obstructive sleep apnea (OSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 5.2. Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 5.3. Hyperinsulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 5.4. Orthopedic and gait abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 5.5. Cardiorespiratory fitness (CRF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 6. Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 7. Limitations of the review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 8. Implications for future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 9. Implications for clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 3.

What this paper adds? A number of systematic reviews about childhood obesity have been developed. However, no systematic literature review has been conducted for youth with Down syndrome (DS). This review summarizes a large body of research on obesity and overweight in children and adolescents with DS. Overall, findings demonstrate that youth with DS have higher rates of overweight and obesity than youth without Down syndrome. This study also provides evidence on risk factors for obesity in youth with DS, as well as on the effectiveness of interventions. These findings may be useful in setting a research agenda and informing evidence-based world-wide policies for obesity prevention and control in youth with DS.

1. Introduction Down syndrome (DS) is the most common chromosomal disorder with prevalence estimates ranging from 6.1 to 13.1 per 10,000 people (de Graaf et al., 2011; Presson et al., 2013). Life expectancy among persons with DS has substantially increased during the last century (de Graaf et al., 2011). This increasing life expectancy may be linked to expansion of governmental and non-governmental initiatives, as well as improvements in medical care and services for persons with DS (Day, Strauss, Shavelle, & Reynolds, 2005; Glasson et al., 2002; Yang, Rasmussen, & Friedman, 2002). Despite these improvements, challenges still exist for implementing health care services for children and adolescents with DS worldwide. Those challenges are linked health conditions associated with DS. These conditions include congenital heart defects, hearing and vision dysfunctions, thyroid disease, gastrointestinal disorders, cognitive impairments, obstructive sleep apnea, and muscle hypotonia (Bull, 2011; Roizen et al., 2014). Recent guidelines by the American Academy of Pediatrics and the U.S. Government for addressing public health research and health care highlighted another risk to the health profiles of persons with DS, obesity (Bull, 2011; Rasmussen, Whitehead, Collier, & Frias, 2008). Childhood obesity has increased substantially worldwide (de Onis, Blossner, & Borghi, 2010). The etiology and health risks of childhood obesity in youth without disabilities continue to be an active area of research. Several recent reviews have examined obesity in children and adolescents with developmental disabilities (Hendrix, Prins, & Dekkers, 2014; Liou, PiSunyer, & Laferrere, 2005; Maiano, Normand, Aime, & Begarie, 2014), specifically targeting children with physical disabilities, coordination disorder, and intellectual disability. However, no systematic state-of-the-science literature review has been conducted specifically for youth with DS. As it will become evident from the present review, many reports suggest that youth with DS may have even higher risk for obesity than youth in the general population. It is therefore important to review the existing knowledge-base and offer a representation of the state of the science on the topic of obesity in youth with DS. Such effort may steer future research and inform initiatives for reducing obesity in this vulnerable population of youth. The purpose of this literature review was to examine (a) the prevalence of overweight and obesity in youth with DS from birth to age 20 years; (b) if differences exist in weight status between youth DS and youth without DS; (c) the determinants or risk factors for obesity; (d) the immediate and long term impact of obesity; and (e) the effectiveness of interventions for prevention or treatment of obesity in youth DS.

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2. Study selection 2.1. Search strategies A search using MEDLINE, Embase, Web of Science, Scopus, CINAHL, PsycINFO, SPORTDiscus, LILACS, and COCHRANE was conducted up to October 2015 on the following Medical Subject Headings (MeSH): Down syndrome; Down’s syndrome; Downs syndrome; trisomy 21; chromosome 21; obesity; overweight; weight; body mass index (BMI); body fat; body composition; and skinfold thickness. The reference lists of eligible articles were also examined. Two independent reviewers conducted the search through title and abstracts, and full articles were analyzed for potential eligibility and data abstraction. 2.2. Eligibility criteria The eligibility criteria for including studies in the present review were: (a) studies that included children and adolescents with DS aged 0–20 years; (b) original research with a prospective or retrospective cohort, cross-sectional, longitudinal, casecontrol, or randomized controlled trial design administered in hospital, specialized pediatric outpatient clinics, or community settings (e.g. recreational center or school); (c) studies that reported prevalence of overweight and obesity based on BMI cutpoints (e.g. BMI above the 85th percentile and below the 95th percentile for overweight, or BMI at or above the 95th percentile for obesity); (d) primary or secondary outcomes related to causes and contributing factors for overweight or obesity (e.g. sex, age, leptin profile, resting energy expenditure, comorbidities, dietary patterns, physical activity, sedentary behavior, psychological factors, or education and skills), and consequences of obesity (e.g. high blood pressure, high cholesterol, impaired glucose tolerance, insulin resistance, type 2 diabetes, sleep apnea, asthma, musculoskeletal and gait abnormalities); and (e) intervention strategies targeting physical activity, nutrition, behavioral/education, weight or body fat-loss. This review was restricted to studies published in English, Spanish, or Portuguese. We also included in the current review studies that focused on gender-specific differences in mean BMI and studies that compared the mean BMI between subjects with and without DS. We did not exclude studies that targeted youth with DS with medical conditions such as congenital heart diseases, hypothyroidism, celiac disease, diabetes, or leukemia. However, we excluded studies that did not report the criteria for defining overweight or obesity. We also excluded studies that used parent-reported height, weight or BMI. Finally, we did not exclude studies based on sample size. The search identified 6290 studies. Exclusion of studies occurred in three phases: (I) duplicated records (n = 2010); (II) records that did not apply any key question on overweight or obesity in persons with DS (n = 4144); (III) articles that did not meet eligibility criteria (n = 91). After the eligibility, 45 studies were included (Fig. 1). 3. Results 3.1. Prevalence of overweight and obesity Overweight and obesity have high prevalence in youth with DS (Table 1). Combined overweight and obesity prevalence was 23–70% (overweight: 13.3–52.9%; obesity: 0–62.5%). Four studies compared the prevalence of overweight or obesity between youth with DS and youth without disabilities (AbdAllah, Raffa, Alaidaroos, Obaid, & Abuznada, 2013; Hill et al., 2013; Samarkandy, Mohamed, & Al-Hamdan, 2012; Van Gameren-Oosterom et al., 2012). Two of these studies found significantly higher prevalence of obesity in youth with DS (BMI-for-age ≥95th percentile) when compared to unaffected siblings (Hill et al., 2013; Samarkandy et al., 2012). Another study found increased rates of overweight and obesity in 659 youth with DS than in youth from the general population (Van Gameren-Oosterom et al., 2012). Additional insight into overweight and obesity in youth with DS can be offered by research comparing mean BMI between youth with and without DS. Eight of eleven studies found higher BMI in youth with than without DS (Hill et al., 2013; Magge, O’Neill, Shults, Stallings, & Stettler, 2008; Marques et al., 2007; O’Neill, Shults, Stallings, & Stettler, 2005; Pau, Galli, Crivellini, & Albertini, 2012; Samarkandy et al., 2012; Wee et al., 2015; Whitt-Glover, O’Neill, & Stettler, 2006) (Fig. 2). Taken together, these data suggest that youth with DS are more likely to be overweight or obese than the general population of youth. 3.2. Gender differences Two large retrospective population-based studies from the Netherlands and Sweden offer information regarding gender differences in overweight and obesity among youth with DS (Myrelid, Gustafsson, Ollars, & Anneren, 2002; Van GamerenOosterom et al., 2012). The combined cross-sectional and longitudinal data from these two studies suggested a higher prevalence of overweight in females (Myrelid et al., 2002; Van Gameren-Oosterom et al., 2012), but no statistical analyses between genders were performed. Among five cross-sectional studies reporting BMI in boys and girls with DS (AbdAllah et al., 2013; Chad, Jobling, & Frail, 1990; Gonzalez-Aguero, Ara, Moreno, Vicente-Rodriguez, & Casajus, 2011; Gonzalez-Aguero, Vicente-Rodriguez, Moreno, & Casajus, 2010; Loveday, Thompson, & Mitchell, 2012), one found significantly higher BMI in the girls (Gonzalez-Aguero, Vicente-Rodriguez, et al., 2011) (Fig. 3). Collectively, these findings are suggestive of higher body weight status in girls than boys with DS, but gender has not been established as a risk factor for obesity among youth with DS.

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Fig. 1. Flow chart of study selection.

Fig. 2. Comparisons of body mass index (BMI) between youth with and without Down syndrome (DS and non-DS, respectively). Values within bars are means. P-values are over bars. NS = not significant difference (p > 0.05). Letters over p-values show references: A = O’Neill et al. (2005); B = Hill et al. (2013); C = Whitt-Glover et al. (2006); D = Magge et al. (2008); E = Luke et al. (1994); F = Samarkandy et al. (2012); G = Pau et al. (2012); H = AbdAllah et al. (2013); I = Wee et al. (2015); J = Gonzalez-Aguero, Ara, et al. (2011); K = Marques et al. (2007).

Table 1 Prevalence of overweight and obesity in youth with DS. Author, year

Country

Sex

Sample size

Diseases

Classification method

Indicator of overweight

Cronk et al. (1988) USA Myrelid et al. (2002) Sweden

0–18 0–18

Both Both

730 354

Included Included

Fels, NHANES

BMI ≥ p85 BMI > 25 kg/m2

15–50%

Fonseca et al. (2005) Marques et al. (2007) Grammatikopoulou et al. (2008) Gonzalez-Aguero et al. (2010) Van Gameren-Oosterom et al. (2012) Yahia et al. (2012)

Brazil Brazil

10–18 10–19

Both Both

15 30

Excluded Excluded

CDC NCHS/WHO

BMI ≥ p85 < p95 BMI ≥ p95

13.3 26.7

26.7 6.6

Girls: 36; Boys: 31i 40 33.3

Greece

2–18

Both

34

CDC

BMI > 1 and <2 SD

52.9d

14.7d

67.6

Spain

12–19

Both

31

Netherlands

2–18

Both

659

Included

IOTF

Girls: 50; Boys: 21.1 Girls: 32; Boys: 25.5

Girls: 5.1; Boys: Girls: 37.1; 4.2 Boys: 29.7

Egypt

2–10

Both

36

Excluded

CDC

BMI ≥ p95

Samarkandy et al. (2012) Esposito et al. (2012) AbdAllah et al. (2013) Hill et al. (2013) Pau et al. (2013)

Saudi Arabia

5–12

Both

108

Included

CDC

BMI ≥ p85 < p95 BMI ≥ p95

20.4*

Girls: 27.8; Boys: 36.1f 23.1*

USA Saudi Arabia

8–16 6–18

Both Both

104 30

Excluded Excluded

CDC CDC

BMI ≥ p85 < p95 BMI ≥ p95

USA Italy

3–10 3–18

Both Both

28 118

Excluded

CDC Myrelid

Seron et al. (2014)

Brazil

15.7 ± 2.7

Both

41

Excluded

CDC

8 0–14

Both Both

29 73a

Included

IOTF IOTF, Leung

Both Both

656b

Excludedc

78

Excluded

Austeng et al. (2014) Norway Su et al. (2014) China Aburawi et al. (2015) UAE Galli et al. (2015) Italy

2–16 5–18

Indicator of obesity

BMI ≥ 2 SD

IOTF

IOTF Myrelid et al.

BMI ≥ p95 BMI ≥ p95 BMI ≥ p85 < p95 BMI ≥ p95

Overweight (%)

Combined obesity and overweight (%)

None

43.5 45.5 53#

25* Girls: 21.2; Boys: 28.8g Girls: 6.2; Boys: Girls: 62.5; 40 Boys: 24 Girls: 12; Boys: 26 14.2e

BMI ≥ p95

Obesity (%)

8.8e 51.3h

Girls: 62.5; Boys: 64 62.1j

23

CDC, Centers for Disease Control and Prevention; NCHS/WHO, National Center for Health Statistics/World Health Organization; IOTF, International Obesity Task Force; BMI, Body Mass Index; p85, 85th percentile; p95, 95th percentile; W/H, weight-for-height; SD, Standard deviation. a Number of measurements used to determine the overweight at the 14 years (girls: 30; boys: 43). b Number of measurements used to determine the prevalence of overweight and obesity (we extracted the data from Table 6). c Subjects with hypothyroidism on thyroxin treatment were included. d Children aged 2–9 years (overweight: 36.4%, Obesity: None), and adolescents aged 10–18 years (overweight: 60.9%, Obesity: 21.7%). e Prevalence (%) was calculated in this review on the data reported by the authors (we extracted the data from Table 6). f Prevalence (%) was calculated in this review on the data reported by the authors (obese: 10 girls and 13 boys). g Prevalence (%) was calculated in this review on the data reported by the authors (obese: 25 girls and 34 boys). h Prevalence (%) was calculated in this review on the data reported by the authors (n = 40). i Prevalence (%) was analyzed in youth with DS at 18 years of age. j Prevalence (%) was calculated in this review on the data reported by the authors (n = 18). # No significant difference between children with DS and those without DS. * Significantly different between children with DS and those without DS (p < 0.05).

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Age (years)

185

186

F. Bertapelli et al. / Research in Developmental Disabilities 57 (2016) 181–192

Fig. 3. Comparisons of body mass index (BMI) between male and female youths with Down syndrome (DS). * p < 0.05; NS = not significant difference (p > 0.05); Letters in parentheses over bars show references: A =Loveday et al. (2012); B =AbdAllah et al. (2013); C =Chad et al. (1990); D = Gonzalez-Aguero, Ara, et al. (2011); E = Gonzalez-Aguero et al. (2010).

3.3. Age differences Studies have attempted to identify the critical age period for the development of overweight and obesity in youth with DS. Three population-based studies with combined cross-sectional and longitudinal BMI data of youth aged 1 month to 18 years showed that higher rates of overweight and obesity tended to occur in youth with DS from 2 years of age (Aburawi, Nagelkerke, Deeb, Abdulla, & Abdulrazzaq, 2015; Cronk et al., 1988; Van Gameren-Oosterom et al., 2012). Based on the large retrospective cohort, Alexander et al. (2016) found that the incidence of obesity was elevated at all ages in individuals with DS with an incidence rate of 6.8 (95% CI: 4.1–11.3) in those aged 3–6 years and older. A cross-sectional study of 785 children with DS aged 0–5 years observed an increase of BMI in children more than 2 years of age (Al Husain, 2003). Another cross-sectional study reported higher BMI in adolescents aged 10–18 years than children aged 2–9 years (BMI z-score of 1.45 ± 0.71 and 0.06 ± 1.45, respectively) (Grammatikopoulou et al., 2008). In summary, these findings demonstrate the overweight and obesity rates increase after age 2 years in children with DS, but critical periods for becoming overweight or obese during childhood and adolescence have not been clearly identified. Identifying critical periods would be helpful to parents, guardians, and clinicians for implementation of dietary and activity interventions.

4. Determinants In an attempt to explain the epidemic of childhood obesity, several hypotheses have been proposed, involving a myriad of biological and environmental factors. In children with DS, progress has been made in identifying the factors that increase their risk for obesity. The following sections provide an overview of potential risk factors.

4.1. Leptin Leptin is a hormone produced by the adipose tissue. It helps regulate energy balance by inhibiting hunger, and has been labeled as the “satiety hormone”. Studies demonstrate higher serum leptin levels in obese subjects, generally thought to be the outcome of increased leptin resistance, although causation has not been entirely established (Klok, Jakobsdottir, & Drent, 2007; Oswal & Yeo, 2010; Scarpace & Zhang, 2007, 2009). In children with DS, Magge et al. (2008) reported higher leptin levels than siblings without DS after adjustment for age, sex, race, and ethnicity (difference, 5.8 ng/mL; 95% CI, 2.4–9.3); the difference persisted even after an additional adjustment for %BF (difference, 2.7 ng/mL; 95% CI, 0.08–5.40), suggesting that leptin in youth with DS may be elevated for reasons other than body composition. In contrast, Yahia et al. (2012) found that leptin levels were not significantly different between obese children with DS and obese children without DS (median, 18 ng/mL; range 11–36 vs. 18.25 ng/mL; range 10.4–45.7); nor were differences found between non-obese children with DS and non-obese children without DS (median, 3 ng/mL; range 1.8–10 vs. 3 ng/mL, range 1.9–7.0). However, the same study (Yahia et al., 2012) reported that obese children with DS showed higher leptin than non-obese children with DS. El Gebali, Zaky, Agwa, & Mohamed (2014) found higher leptin levels in children with than without DS (20.3 ± 8.1 ng/mL vs. 5.2 ± 2.05 ng/mL), and both BMI and%BF were higher in those with DS. What becomes clear from these findings is the presence of high leptin levels in youth with DS. The mechanism of leptin resistance may be in play when considering that high levels of leptin and obesity seem to coincide in youth with DS.

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4.2. Resting energy expenditure (REE) High prevalence of obesity have led researchers to hypothesize that lower REE could partially explain the increased risk of obesity in youth with DS. Hill et al. (2013) found that children with DS aged 3–10 years had lower REE adjusted for fat free mass (difference, −78 kcal/day; 95% CI, −133 to −27) compared to siblings without DS; the difference persisted even after an additional adjustment for fat mass, sex, and race (difference, −49 kcal/day; 95% CI, −94 to −4). However, the same study (Hill et al., 2013) found that REE was not associated with fat mass changes over three years. Luke, Roizen, Sutton, and Schoeller (1994) found similar results to Hill et al. (2013) although follow-up duration was shorter (1–year). In contrast, a cross-sectional study showed a moderate correlation between%BF and REE in youths with DS aged 10–14 years (Chad et al., 1990). In summary, the existing data consistently suggest that children with DS have lower REE than children without DS; however, low REE has not been directly established as a causative factor for obesity in these youths. 4.3. Physical activity (PA) PA impacts the energy balance and, if low, it can potentially contribute to overweight or obesity in youth with DS, as it has been suggested for youth without disabilities (Remmers et al., 2014; Trinh, Campbell, Ukoumunne, Gerner, & Wake, 2013). It appears that youth with DS have lower PA levels than youth without DS (Pitetti, Baynard, & Agiovlasitis, 2013). It has also been proposed that PA may decline with age in youth with DS (Pitetti et al., 2013). These factors could potentially contribute to the high obesity rates in youth with DS, especially as they grow. However, only few studies have examined the direct relationship between PA and weight status in these youths. A cross-sectional study found that PA had weak relationships with BMI and%BF in 104 U.S. children with DS aged 8–16 years (Esposito, MacDonald, Hornyak, & Ulrich, 2012). Another cross-sectional study, (Izquierdo-Gomez, Villagra, Fernhall, Veiga, & UP&DOWN study group, 2015) showed that, in 100 Spanish youths with DS (11–20 years), PA levels were not associated with BMI and%BF. Whitt-Glover et al., 2006 suggested that further research with larger samples is needed to examine the influence of vigorous PA on BMI levels in youth with DS. Studies in children without DS have suggested that PA has small impact on fat loss (Wareham, 2007; Wilks, Besson, Lindroos, & Ekelund, 2011); however, this could be to methodological problems such as cross-sectional designs, low statistical power, and accuracy of techniques in estimating PA and adiposity (Riddoch et al., 2009). Nevertheless, the low PA levels of youth with DS suggest that PA could be an important component of interventions for improving their body composition profiles. 4.4. Dietary patterns Research has documented the relationship between obesity and consumption of energy-rich and nutrient-poor food products in the general childhood population (Lobstein et al., 2015). This issue has not been examined thoroughly in youth with DS. One study found a significant positive correlation of energy intake with triceps skinfold, but not with body weight among 13 black children with DS aged 2–6 years (Unonu & Johnson, 1992). This study also reported some micronutrient deficiencies; most notably, vitamin B-6, folate, iron, magnesium, zinc, and calcium. Somewhat contrastingly, another study among only 10 youth with DS found that those who were not obese were more likely to have deficiencies in micronutrient intakes than those who were obese (Luke, Sutton, Schoeller, & Roizen, 1996). Deficiencies in vitamins and minerals may be due to excessive consumption of energy-rich, micronutrient poor, and refined foods. In children without disabilities, evidence indicates large consumption of energy-dense and low-nutrient foods (e.g., sweet bakery products and sugar-sweetened beverages) (Grimes, Szymlek-Gay, Campbell, & Nicklas, 2015; Keast, Fulgoni, Nicklas, & O’Neil, 2013). These findings provide evidence that youth with DS may have low-nutrient intake, but a relationship between energy-dense and low-nutrient food intakes and weight status has not been established. Other important risk factors for childhood obesity are parenting, child feeding practices, and children’s eating (Birch & Ventura, 2009). A cross-sectional study assessed parental perceptions and practices related to feeding (e.g., perceived child overweight, responsibility, concern, restriction, pressure, and monitoring) and their associations with weight status in youth with DS and siblings aged 3–10 years (O’Neill et al., 2005). When adjusted for BMI, parents were more concerned about the body weight status of their children with DS than those without DS. Perceived child weight and concern were positively associated to the child’s weight status, and pressure to eat was inversely associated to the child’s weight status. However, the potential impact of parental practices such as coercion for eating (e.g., rewards for eating), choices (e.g., what, when, and how much to eat) and perceptions of the child’s weight status on the development of obesity in youth with DS is an unexplored issue. 4.5. Comorbidities Some studies have examined whether the increased risk of overweight in children with DS is associated with comorbidities, especially thyroid disorders and heart defects. One study found no significant differences in overweight rates between healthy children with DS and those with hypothyroidism, congenital heart defects, and other disorders (Van GamerenOosterom et al., 2012). In another study (Kowalczyk, Pukajlo, Malczewska, Krol-Chwastek, & Barg, 2013), DS children with hypothyroidism showed decreases in BMI after L-thyroxine treatment, and those with heart defects had higher BMI than children with DS without defects. In the general population, evidence supports that body weight may be influenced by

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thyroid function (Bjergved et al., 2014; Fox et al., 2008; Svare, Nilsen, Bjoro, Asvold, & Langhammer, 2011), and congenital heart defects (Pinto et al., 2007; Tamayo, Manlhiot, Patterson, Lalani, & McCrindle, 2015), but the data are not conclusive for youth with DS. 5. Consequences Obesity is associated with many health conditions in youth without disabilities. The relationship of obesity with health disorders is difficult to establish in youth with DS because of numerous medical problems attributed to DS. However, some hypotheses may link the weight status of youth with DS with adverse health outcomes, including obstructive sleep apnea, dyslipidemia, hyperinsulinemia, orthopedics and biomechanics complications, and impaired cardiorespiratory fitness. 5.1. Obstructive sleep apnea (OSA) Individuals with DS are more likely to have severe OSA than the general population (Lal, White, Joseph, van Bakergem, & LaRosa, 2015). Three studies reported that OSA was associated with weight status (Dyken, Lin-Dyken, Poulton, Zimmerman, & Sedars, 2003; Ng et al., 2006; Shires et al., 2010), whereas another study did not observe an association (Austeng et al., 2014). Dyken et al. (2003) showed that, in nineteen youth with DS (3–18 years), BMI was significantly associated with apnea index (r = 0.62) and arterial oxygen saturation level (r = −0.55). Ng et al. (2006) found that, among 22 DS children with and without habitual snoring, 31.2% were obese and apnea-hypopnea index was significantly related with weight-for-age. In a study of children with DS aged 9 ± 4 years, those with OSA had a significantly higher mean BMI Z-score than those without OSA (2.09 ± 0.84 vs. 1.4 ± 0.40) (Shires et al., 2010). Some studies have supported the hypothesis that physical conditions may predispose persons with DS to OSA because of their smaller upper airway, midfacial hypoplasia, adenoid hypertrophy, lingual tonsillar hypertrophy, and micrognathia or muscular hypotonia (Lal et al., 2015; Ng et al., 2006). These factors should be considered in studies examining the relationship between obesity and OSA in youth with DS. In summary, the existing data suggest that obesity may potentially contribute to OSA in youth with DS. 5.2. Dyslipidemia Obese children are more likely to have dyslipidemia than normal weight children (Friedemann et al., 2012). In children with DS, cross-sectional studies examined the relationship of weight status with total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG). In the study by Ordonez-Munoz, Rosety-Rodriguez, Rosety-Rodriguez, and Rosety-Plaza (2005) higher BMI and waist-to-hip ratio were significantly correlated with higher TC, lower levels of HDL and higher levels of TG in Spanish adolescents with DS aged 16 ± 1 years. The second study by Adelekan, Magge, Shults, Stallings, and Stettler (2012) reported that healthy children with DS aged 4–10 years had abnormal lipid profiles independent of weight status when compared to siblings. These children had significantly higher TC, LDL, TG and lower HDL after adjustment for race, gender, age, ethnicity, and BMI. In summary, although these findings show children with DS to have less favorable lipid profiles, obesity has not been clearly established as a risk factor for dyslipidemia in this population. 5.3. Hyperinsulinemia It has also been suggested that obese youth with DS have increased risk of hyperinsulinemia. A cross-sectional study in 15 Brazilian aged 10–18 y found that overweight and obese participants had higher insulin and homeostatic model assessment (HOMA) than those of normal weight (Fonseca, Amaral, Ribeiro, Beserra, & Guimaraes, 2005). The second study found that obese children with DS had higher median values of insulin and HOMA compared to non-obese children with DS, but also compared to obese children without DS (Yahia et al., 2012). It is difficult to infer whether obesity is an antecedent or outcome of hyperinsulinemia in youth with DS. Physiologically, a bidirectional relationship is possible (Tremblay, Boulé, Doucet, & Woods, 2005), but there are presently no data that can clarify which direction predominates in youth with DS. However, most research in youth views obesity as an antecedent to hyperinsulinemia (Friedemann et al., 2012)—obesity contributes to insulin resistance which, in turn, may lead to hyperinsulinemia (Shanik et al., 2008). It is reasonable to suggest that the same applies to youth with DS. 5.4. Orthopedic and gait abnormalities Children with DS have inherent orthopedic alterations (e.g., flat feet) possibly resulting from hypotonia and ligamentous laxity (Pau et al., 2012). Studies have examined the additional impact of obesity on biomechanics complications in children with DS. A cross-sectional study assessed the relationship between obesity and plantar pressure distribution in 118 Italian youth with DS aged 3–18 years, and reported that obese children with DS showed significantly larger contact areas (girls only) and higher plantar pressures in the forefoot and the midfoot (girls and boys) than non-obese children with DS (Pau, Galli, Crivellini, & Albertini, 2013). Another Italian study performed a biomechanical analysis of gait in 40 obese and 38 non-obese DS aged 5–18 years (Galli, Cimolin, Rigoldi, Condoluci, & Albertini, 2015). Obese in that study had longer stance

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duration and less dorsiflexion during the swing phase than non-obese. In summary, the available data suggest that obesity in youth with DS has an impact on gait patterns in addition to that of DS alone. 5.5. Cardiorespiratory fitness (CRF) It is widely accepted that individuals with DS have very low peak oxygen consumption (VO2peak ) (Baynard, Pitetti, Guerra, Unnithan, & Fernhall, 2008; Fernhall et al., 2001; Mendonca, Pereira, & Fernhall, 2010; Pitetti et al., 2013)—the gold standard for CRF. A review suggested that this may be partially due to—inherent in DS—autonomic difficulties in achieving a high peak heart rate (HRpeak ) (Fernhall, Mendonca, & Baynard, 2013). This review indicated that the low VO2peak of individuals with DS is independent of age and sex, and postulated that obesity is a weak risk factor for low CRF (Fernhall et al., 2013). Two recent studies examined the relationship between obesity and CRF in children with DS. A retrospective study found lower HRpeak and VO2peak in youth with DS compared to youth with and without intellectual disability aged <18 years, but obesity was not associated with HRpeak or VO2peak (Wee et al., 2015). Another study showed that, in 111 adolescents with DS aged 11–20 years, fatness had no clear effect on CRF (Izquierdo-Gomez et al., 2016). Thus, the limited existing knowledge base supports the notion that CRF is low in youths with DS and that obesity is not a strong risk factor for impaired CRF in these youths. 6. Interventions Interventions to promote loss of body fat and weight in youth with DS include randomized controlled trials and quasiexperimental research focusing on PA training and parent support programs in clinical or community settings. Overall, changes in body fat were inconsistent, with no significant change in%BF from baseline (Gonzalez-Aguero, Matute-Llorente, Gomez-Cabello, Casajus, & Vicente-Rodriguez, 2013; Gonzalez-Aguero, Vicente-Rodriguez, et al., 2011; Seron, Silva, & Greguol, 2014). In contrast, a randomized trial of 61 healthy youth with DS aged 8–15 years did find decreased%BF after a 12-month intervention (Ulrich, Burghardt, Lloyd, Tiernan, & Hornyak, 2011). Another study carried out in 22 adolescents with DS reported decreases in%BF after 12-weeks of exercise training (Ordonez, Rosety, & Rosety-Rodriguez, 2006). A familybased randomized controlled trial examined the effects of two different interventions (nutrition and activity education plus behavioral vs. nutrition and activity education intervention group) in healthy young people with DS aged 13–26 years (Curtin et al., 2013). At 6 months, the nutrition and activity education plus behavioral intervention group had significantly higher reduction in body weight. Although that study included young adults above the upper age limit set for the present review (>20 years-old), it was considered here because it is only family-based intervention on weight loss that included adolescents with DS. Overall, there is considerable heterogeneity across studies in design and interventions, limiting the generalization of findings. Nevertheless, the available data show that weight loss can be promoted with multi-factorial interventions that include PA in youth with DS. 7. Limitations of the review The following limitations of this review should be considered. First, our review was restricted to studies published in English, Spanish, or Portuguese, which may possibly lead to publication bias. Second, we could not effectively compare results between studies due to various methodological differences, such as designs and reported outcomes. Third, we were unable to effectively assess the prevalence of overweight and obesity because only few studies had large sample sizes. Fourth, most studies classified overweight and obesity with BMI cut-points developed for the general population of youth. It is not known if these cut-points are appropriate for youth with DS who appear to have different body proportions. Fifth, the conclusions from our review only provide a picture of the obesity and their determinants, consequences, or effectiveness of interventions in youth with DS. Most studies used a cross-sectional design and did not control for important confounding factors such as age, sex, socioeconomic status, or early life factors, reducing the possibility for detecting causal relationships between obesity and its associated factors. Finally, most past research on interventions for obesity in youth with DS has been limited to exercise-based interventions. 8. Implications for future research Future studies should examine specific BMI cut-points for overweight and obesity in youth with DS. Population-based studies on the relationships among weight, height, BMI, fat mass, fat-free mass, and percentage body fat in youth with DS would also be of interest, given that this population shows growth restriction (Aburawi et al., 2015). Based on the present review, likely contributors to weight gain in youth with DS include: 1) increased leptin; 2) decreased resting energy expenditure; 3) lower physical activity levels; 4) unfavorable dietary patterns; and 5) comorbidities. Additional factors that could be examined are low birthweight, underheight, unfavorable breastfeeding, and intellectual disability; factors are known to contribute to the development of obesity in youth without DS. It is also important to evaluate more thoroughly the health impact of obesity in youth with DS. Health outcomes that have been examined in youth without DS include increased left ventricular mass, greater arterial stiffness, endothelial dysfunction, elevated C-reactive protein, high blood pressure, incident asthma, low neurocognitive functioning, psychological disorders, and low health-related quality of life;

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these outcomes could also be examined in youth with DS. Researchers should attempt to develop and test multi-factorial interventions for alleviating obesity in youth with DS. Past research in youth with DS has been limited to exercises-based interventions. To control and prevent obesity in the general childhood population, researchers have increasingly called for multi-factorial strategies involving the family, home, school, and community environments. Multi-factorial interventions may be an important next step for reducing obesity in youth with DS. The challenge would be in implementing interventions that achieve long-term weight reductions in these youth. 9. Implications for clinical practice To our knowledge, this systematic review is the first to focus on prevalence, determinants, consequences, and interventions of overweight and obesity in children and adolescents with DS. Although many research issues need to be resolved and therefore no definitive conclusions can be made at this point, the findings from the current study have clinical implications for understanding, preventing, and treating overweight and obesity in children and adolescents with DS. This systematic review demonstrated that youth with DS have high prevalence of overweight and obesity that presents a risk to their health. For these reasons, routine evaluation of the body weight of children with DS as early as 2 or 3 years of age is recommended. If overweight or obesity is confirmed, additional screening based on health history, and physical and laboratory examinations should be performed for evaluating the potential causes and health consequences as well as for designing appropriate interventions. Comprehensive lifestyle intervention programs that include diet, physical activity, and behavior therapy may allow parents and health professionals to promote optimal weight in youth with DS. Importantly, there is a need to develop prevention strategies against obesity in youth with DS. 10. Conclusions In conclusion, children and adolescents with DS appear to have higher levels of overweight and obesity compared to the general population of youth. Likely determinants of obesity among youth with DS include increased leptin, decreased resting energy expenditure, lower PA levels, unfavorable dietary patterns, and comorbidities. Obesity in children and adolescents with DS appears to increase their risks for dyslipidemia, hyperinsulinemia, obstructive sleep apnea, and gait disorders. Interventions for obesity prevention and control limited to exercise-based programs seem insufficient to achieve weight or fat loss. Population-based research is needed to support multi-factorial strategies for reducing overweight and obesity in youth with DS. 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