Research in Developmental Disabilities 57 (2016) 181–192

Contents lists available at ScienceDirect

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
b
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

a r t i c l e i n f o a b s t r a c t

Article history: Background: Children with Down syndrome (DS) are more likely to be overweight or obese
Received 25 February 2016 than the general population of youth without DS.
Received in revised form 9 June 2016 Aims: To review the prevalence of overweight and obesity and their determinants in youth
Accepted 26 June 2016
with DS. The health consequences and the effectiveness of interventions were also exam-
Number of reviews completed is 2 ined.
Methods and procedures: A search using MEDLINE, Embase, Web of Science, Scopus, CINAHL,
Keywords: PsycINFO, SPORTDiscus, LILACS, and COCHRANE was conducted. From a total of 4280 stud-
Overweight ies, we included 45 original research articles published between 1988 and 2015.
Obesity
Outcomes and results: The combined prevalence of overweight and obesity varied between
Youths
studies from 23% to 70%. Youth with DS had higher rates of overweight and obesity than
Down syndrome
youths without DS. Likely determinants of obesity included increased leptin, decreased rest-
ing energy expenditure, comorbidities, unfavorable diet, and low physical activity levels.
Obesity was positively associated with obstructive sleep apnea, dyslipidemia, hyperinsu-
linemia, 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

What this paper adds? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
2. 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: fbertapelli@gmail.com (F. Bertapelli), ken.pitetti@wichita.edu (K. Pitetti), sagiovlasitis@colled.msstate.edu (S. Agiovlasitis),
gilguer@fcm.unicamp.br (G. Guerra-Junior).

http://dx.doi.org/10.1016/j.ridd.2016.06.018
0891-4222/© 2016 Elsevier Ltd. All rights reserved.
182 F. Bertapelli et al. / Research in Developmental Disabilities 57 (2016) 181–192

2.2. Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

3. 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

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, Pi-
Sunyer, & 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.
 F. Bertapelli et al. / Research in Developmental Disabilities 57 (2016) 181–192 183

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 com-
position; 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, case-
control, 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 cut-
points (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 Gameren-
Oosterom 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.
184 F. Bertapelli et al. / Research in Developmental Disabilities 57 (2016) 181–192

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 Age (years) Sex Sample size Diseases Classification Indicator of Indicator of Overweight (%) Obesity (%) Combined
method overweight obesity obesity and
overweight (%)
Cronk et al. (1988) USA 0–18 Both 730 Included Fels, NHANES BMI ≥ p85 15–50%
Myrelid et al. (2002) Sweden 0–18 Both 354 Included BMI > 25 kg/m2 Girls: 36; Boys:
31i
Fonseca et al. (2005) Brazil 10–18 Both 15 Excluded CDC BMI ≥ p85 < p95 BMI ≥ p95 13.3 26.7 40
Marques et al. Brazil 10–19 Both 30 Excluded NCHS/WHO 26.7 6.6 33.3
(2007)

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

Grammatikopoulou Greece 2–18 Both 34 CDC BMI > 1 and <2 BMI ≥ 2 SD 52.9d 14.7d 67.6
et al. (2008) SD
Gonzalez-Aguero Spain 12–19 Both 31 IOTF Girls: 50; Boys: None
et al. (2010) 21.1
Van Netherlands 2–18 Both 659 Included IOTF Girls: 32; Boys: Girls: 5.1; Boys: Girls: 37.1;
Gameren-Oosterom 25.5 4.2 Boys: 29.7
et al. (2012)
Yahia et al. (2012) Egypt 2–10 Both 36 Excluded CDC BMI ≥ p95 Girls: 27.8;
Boys: 36.1f
Samarkandy et al. Saudi Arabia 5–12 Both 108 Included CDC BMI ≥ p85 < p95 BMI ≥ p95 20.4* 23.1* 43.5
(2012)
Esposito et al. (2012) USA 8–16 Both 104 Excluded CDC 45.5
AbdAllah et al. Saudi Arabia 6–18 Both 30 Excluded CDC BMI ≥ p85 < p95 BMI ≥ p95 53#
(2013)
Hill et al. (2013) USA 3–10 Both 28 Excluded CDC BMI ≥ p95 25*
Pau et al. (2013) Italy 3–18 Both 118 Myrelid BMI ≥ p95 Girls: 21.2;
Boys: 28.8g
Seron et al. (2014) Brazil 15.7 ± 2.7 Both 41 Excluded CDC BMI ≥ p85 < p95 BMI ≥ p95 Girls: 6.2; Boys: Girls: 62.5; Girls: 62.5;
40 Boys: 24 Boys: 64
Austeng et al. (2014) Norway 8 Both 29 IOTF 62.1j
Su et al. (2014) China 0–14 Both 73a Included IOTF, Leung Girls: 12; Boys:
26
Aburawi et al. (2015) UAE 2–16 Both 656b Excludedc IOTF 14.2e 8.8e 23
Galli et al. (2015) Italy 5–18 Both 78 Excluded Myrelid et al. BMI ≥ p95 51.3h
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).

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.
 F. Bertapelli et al. / Research in Developmental Disabilities 57 (2016) 181–192 187

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 comorbidi-
ties, 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 Gameren-
Oosterom 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
188 F. Bertapelli et al. / Research in Developmental Disabilities 57 (2016) 181–192

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 chil-
dren 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
 F. Bertapelli et al. / Research in Developmental Disabilities 57 (2016) 181–192 189

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 quasi-
experimental 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 family-
based 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;
190 F. Bertapelli et al. / Research in Developmental Disabilities 57 (2016) 181–192

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 interven-
tions 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 examina-
tions 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. If a global task force were formed, it would provide leadership, setting a research agenda and informing
evidence-based world-wide policies for obesity prevention and control in youth with DS.

Acknowledgements

This study was supported by the CAPES foundation (BEX 3546/15-2), Ministry of Education of Brazil. The authors acknowl-
edge Dr. Alejandro González-Agüero of the Aberystwyth University (United Kingdom), who provided helpful suggestions to
improve the draft manuscript. They also acknowledge Mrs. Ana Paula de Moraes for her assistance with literature searches.

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