International Journal of

Environmental Research
and Public Health

Review
Evidences from Clinical Trials in Down Syndrome:
Diet, Exercise and Body Composition
Rosa María Martínez-Espinosa 1,2 , Mariola D Molina Vila 2,3 and
Manuel Reig García-Galbis 2,4,5, *
1 Division of Biochemistry and Molecular Biology, Department of Agrochemistry and Biochemistry,
Faculty of Sciences, University of Alicante, 03690 Alicante, Spain; [email protected]
2 Applied Biochemistry Research Group AppBiochem, University of Alicante, 03690 Alicante, Spain;
[email protected]
3 Department of Mathematics, Faculty of Sciences, University of Alicante, 03690 Alicante, Spain
4 Department of Nutrition and Dietetics, Faculty of Health Sciences, University of Atacama,
Avda. Copayapu 2862, III Region, Copiapó 1530000, Chile
5 Noncommunicable Diseases Research Group, Atacama 1410000, Chile
* Correspondence: [email protected]; Tel.: +34-52-225-5647




Received: 29 April 2020; Accepted: 9 June 2020; Published: 16 June 2020


Abstract: Down syndrome (DS) is related to diseases like congenital heart disease, obstructive sleep
apnea, obesity and overweight. Studies focused on DS associated with obesity and overweight are still
scarce. The main objective of this work was to analyze the relationship between dietary intervention,
physical exercise and body composition, in DS with overweight and obesity. This review is based
on the PRISMA guidelines (Preferred Reporting Items for Systematic reviews and Meta-Analyses).
Selection criteria for this analysis were: publications between January 1997 and December 2019;
DS individuals with overweight and obesity; clinical trials using dietary intervention and physical
exercise paying attention to changes in body composition. Selected clinical trials were focused on
an exclusive intervention based on physical exercise. The anthropometric measures analyzed were
body fat, BMI, waist circumference, body weight and fat free mass. The main conclusion is that
prescribing structured physical exercise intervention may be related to a greater variation in body
composition. Despite limited number of clinical trials analyzed, it can be assumed that the reported
studies have not achieved optimal results and that the design of future clinical trials should be
improved. Some guidelines are proposed to contribute to the improvement of knowledge in this field.

Keywords: Down’s syndrome; obesity; overweight; diet; exercise and body composition

1. Introduction
Down Syndrome (DS) (OMIM#190685, Online Mendelian Inheritance in Man® , An Online Catalog
of Human Genes and Genetic Disorders) is a genetic disorder caused by a trisomy of chromosome 21
and is the most common genetic cause of intellectual disability (ID) [1]. DS is associated with significant
health problems as diseases such as congenital heart disease, obstructive sleep apnea, celiac disease
and endocrinopathologies. Endocrine disorders are usually characterized by thyroid disorders, low
bone mass, diabetes, short stature and propensity to be overweight/obese [1,2].
Life expectancy of people with DS has increased significantly from 12 years in 1949, to 60 years
in 2004, and it is expected to increase in the near future [1,2]. Unfortunately, the increase in life
expectancy is not parallel to the increase in the period of life with optimal health. Accelerated aging is
identified in the case of DS based on two aspects: a. Clinical-pathological characteristics of the subject;
b. Monitoring of molecular markers related to biological age and the aging process, highlighting the

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shortening of the telomeres [1]. Thus, several studies have connected the shortening of the telomeres
with obesity, and particularly with the increase of BMI and adiposity causing accelerated aging [3,4].
Currently, there is a higher prevalence of overweight in ID patients (≥18 years) compared to
those not affected by IDs, both in obesity (38.3% vs. 28%) and in morbid obesity (7.4% vs. 4.2%) [5].
Prevalence in overweight and obesity varied between 23–70% in DS patients (13.3–52.9 and 0–62.5%).
Thus, young people with DS have higher rates of overweight and obesity than young people
without DS [6].
The causes of the development of overweight and obesity in DS are: hypotonia (decreased
muscle tone), susceptibility to systemic inflammation, metabolic diseases and/or slow metabolism [7].
Usually, people affected by DS consume less healthy food, and show physical limitations, depression,
and lack of social and financial support. Besides, medications contribute to weight gain [8]. The key
challenge for this field of knowledge in incoming years will be to identify therapeutic intervention
strategies for weight loss that reduce body fat and systemic inflammation [6,9]. Therefore, there is
a need to increase evidence-based clinical knowledge, with the aim of improving existing care
programs [2,10,11].
Among the approaches used to monitor obesity and overweight, anthropometry reveals as one
of the most efficient, cheaper and less time consuming. Anthropometry is considered a branch of
biological anthropology; it is responsible for studying any physiological, psychological or anatomical
trait. It is a powerful tool for the evaluation of nutritional status in the clinical environment
and is used for general nutritional monitoring. Between the parameters measured, height and
weight measurements are simple and quick. Other more complex measures include skin folds and
circumferences, which require more professional training and involve different degrees of error [12].
To avoid errors or biases of these measurements, it is advisable to follow a protocol to measure
these anthropometric variables, for example: the methodology ISAK (International Society for the
Advancement of Cineanthropometry) [13–15].
In carrying out studies of an anthropometric nature, different methodologies have been developed
during the last decades that have given rise to the following three groups: (i) Direct (dissection of corpses
and neutron activation analysis); (ii) Indirect (hydrostatic densitometry; isotopic solution; total body
potassium; DXA, dual X-ray absorptiometry; CT, computed tomography; QMR, quantitative magnetic
resonance; ADP, air displacement plethysmography); (iii) Mixed or doubly indirect (Skin folds;
BIA, bioelectrical impedance analysis and ultrasound) [16]. The measurement methods in the
“Gold Standard” body composition to provide more information and to have greater accuracy are:
full-body computerized tomography, four-compartment models (fat mass, muscle mass, other tissues
and bone mass) and dual absorptiometry of X-rays. Here, accuracy is defined as the variation of
body composition between different measurements in the same subject [17]. However, the most used
methods in the clinical daily routine are: Skin folds; BIA and ultrasound [16,17].
Considering all the previous mentioned issues as well as the advantages of using anthropometric
parameters to monitor nutritional status and obesity, the low number of studies about obesity and
overweight in people with DS is striking. Consequently, this research is justified by the following facts:

1. DS individuals are characterized by high rates of overweight and obesity and low-quality life [1,6].
2. Obesity has negative health effects and lowers life expectancy [3,4].
3. Consumption of less healthy foods, lower levels of physical activity and medication are factors
that enhance weight gain in DS [8].
4. There is a need to increase evidence-based clinical knowledge [2,10,11].

Thus, the main objective of this systematic review was to analyze the effectiveness of described
interventions (based on dietary intervention and/or physical exercise) on the improvement of body
composition and anthropometric parameters in people suffering from DS with overweight and obesity.
As secondary objectives, the following have been identified: (i) To evaluate the methodological design
quality of the CONSORT 2010 guidelines; (ii) To indicate the anthropometric parameters and units of
Int. J. Environ. Res. Public Health 2020, 17, 4294 3 of 16

measurement that record changes in body composition, in subjects with DS, overweight and obesity; (iii)
Evaluation of body composition measuring instruments; (iv) To highlight dietary patterns and physical
exercises that cause significant changes in the clinical trials analyzed. At the time of writing this work,
the number of clinical studies performed involving the use of anthropometry to study DS individuals
is low and criteria used are disparate. It is therefore necessary to carry out a detailed review of the
methodology used, and the results achieved with a view to improving future interventions. From the
results obtained in this analysis some guidelines are proposed to contribute to the improvement of
knowledge in this field.

2. Methods

2.1. Search Strategy and Information Processing

This systematic review was conducted following the guidelines recommended by PRISMA
(Preferred Reporting Items for Systematic reviews and Meta-Analyses) as well as the recommendations
of the International Committee of Biomedical Journal Editors [18,19]. The information retrieval system
“the Boolean model” was used [20].
The databases used were: PubMed (search engine for free access to the MEDLINE database of
citations and abstracts of biomedical research articles); Scopus (bibliographic database containing
abstracts and citations for academic journal articles); Web of Science (online scientific information
service, provided by Thomson Reuters, integrated in ISI Web of Knowledge, WOK) (original articles
based on clinical trials). The keywords were: intellectual disability, Down syndrome, overweight,
obesity, diet and exercise. These keywords were obtained from the “MeSH database” (Medical Subject
Heading) and NLM (The National Library of Medicine). Controlled vocabulary thesaurus was used
for indexing articles for PubMed. The search strategies used are displayed in Table 1 and Figure 1.
In the “PubMed” database, the advanced form of search was used and the following options were
selected “title/abstract”, specific date and languages; in “Scopus” the option of “document search”,
“article title, abstract, keywords” and specific date; in “Web of Science”, the basic search was conducted
and the following options were selected: theme, specific date and “article”.
Other details like date or language of the publications were not specified, and the search was
conducted from January 1997 until December 2019. The open research questions at the beginning of
this research were: What were the results obtained in the included clinical trials on the base of their
design?; What are the anthropometric parameters and units of measurement registering changes in
body composition, in subjects with DS, overweight and obesity?; What are the dietary and physical
exercise patterns showing changes in body composition in the clinical trials analyzed?
Int. J. Environ. Res. Public Health 2020, 17, 4294 4 of 16

Table 1. Search strategies used to identify and to select clinical trials from January 1997 until December 2019.

PubMed Scopus Web of Science Summation

Identified/Included Identified/Included Identified/Included Identified/Included
“Down’s syndrome” OR “Down syndrome” OR “cognitive
disability” AND overweight OR obesity AND weight OR fat 21/4 47/7 85/6 153/17
AND “physical activity” OR exercise OR weightlifting
“Down’s syndrome” OR “Down syndrome” OR “cognitive
disability” AND overweight OR obesity AND weight OR fat AND
25/2 64/4 44/3 133/9
feeding OR nutrition OR “nutritional counselling” or diet OR
“dietary treatment”
“intellectual disability” or “Trisomy 21” AND overweight OR
obesity AND weight OR fat AND “physical activity” OR exercise 45/4 94/8 72/7 211/19
OR weightlifting
“intellectual disability” or “Trisomy 21” AND overweight OR
obesity AND weight OR fat AND feeding OR nutrition OR 33/2 86/4 56/6 175/12
“nutritional counselling” or diet OR “dietary treatment”
Summation
124/12 291/23 257/22 615/57
Identified/Included
Articles or clinical trials identified: complete list of articles retrieved from various databases (PubMed, Scopus and Web of Science), without having made the selection of the clinical trials
of interest. Articles or clinical trials included: articles that meet the selection criteria.
 Int. J. Environ. Res. Public Health 2020, 17, x FOR PEER REVIEW 1 of 17

Int. J. Environ. Res. Public Health 2020, 17, 4294 5 of 16

Records identified through Additional records identified

database searching through other sources
(n = 672) (n = 0)

Full‐text articles
Article deleted (n = 615)
excluded, with reasons:
1. 371
2. 131
3. 54
4. 25
5. 6
6. 19
7. 5
8. 2
Full‐text articles assessed for 9. 2
eligibility: (n = 57)

Items deleted by being

repeated (n = 43)

Elements eliminated due to not

having 100% of subjects with
Down syndrome in any of
their intervention groups

Studies included in (n = 8)

qualitative synthesis
(n = 6)

Figure Figure
1. Flow1. Flow chartin
chart in the
thescreening
screeningprocess for thefor
process selection of includedofclinical
the selection trials [18].
included Legend
clinical trials [18].
Legend exclusion criteria: 1. Subjects not related to the variation of body composition in excess
exclusion criteria: 1. Subjects not related to the variation of body composition in patients with patients with
weight; 2. Other intellectual or developmental disabilities that do not include Down syndrome; 3.
excess weight; 2. Other intellectual or developmental disabilities that do not include Down syndrome;
Reviews and / or meta‐analysis; 4. Interest in other pathologies (diabetes, hypertension, arthritis, heart
3. Reviews and/or meta-analysis; 4. Interest in other pathologies (diabetes, hypertension, arthritis,
failure, etc.); 5. Repeated articles; 6. Do not use dietary intervention or physical exercise as main treat‐
heart failure,
ments or etc.);
use 5.
theRepeated articles; 6. Dotreatment,
help of pharmacological not use dietary
surgery intervention or physical
or similar; 7. Animal exercise
intervention; 8. as main
treatments or useother
Languages the help
than of pharmacological
English and Spanish; 9.treatment, surgery
Clinical trials or similar;
involving children,7.adolescents
Animal intervention;
and
8. Languages
adults inother than intervention
the defined English and Spanish; 9. Clinical trials involving children, adolescents and
groups.
adults in the defined intervention groups.

2.2. Selection of the Articles Previously Identify

Each of the identified articles were independently analyzed by two researchers. PICOS strategy
was used to define the eligibility criteria for this revision (population, intervention, comparisons,
results and characteristics of clinical trials). Criteria included in the search strategy were: patients
with DS or Trisomy 21 [21], who had been diagnosed in overweight or obese clinical trials; in the
groups of children and adolescents, age will be less than or equal to 19 years [22], adults will be older
than 19 years; clinical trial published between 1997 and 2019 in scientific journals in Spanish and
English. These two languages were selected because they are two of three most spoken languages
worldwide [23,24]. Besides, those patients involved in the selected studies had undergone an ID and/or
physical exercise. Only the studies highlighting interest in the changes in body composition, through
the anthropometric parameters and units of measurement have been included (Tables 2 and 3) [25–30].
Int. J. Environ. Res. Public Health 2020, 17, 4294 6 of 16

Table 2. Clinical trials including children and adolescents suffering DS in which body composition was monitored (intervention in physical exercise).

Intervention Method Characteristics Anthropometric Parameters (Statistical Results) Variation in Body

Reference Sample/Groups/Characteristics
Location Study Design Studied/Comparative Statistical BW BF FFM BMI WC Composition
[25–27] Studied
Analysis of BC (kg/%) (kg/%) (kg/%) (kg/m2 /%) (cm/%) Mean

YES (kg) YES (%) YES (kg/m2 ) YES (cm) BW:

IG1: −0.7 kg
n = 41 (61% male) IG2: −0.1 kg
Comparative analysis: CG: + 0.5 kg
IG1, n = 16
IG2, n = 15 Within groups: BF:
South CG, n = 10 IG1 (group aerobic training) NS NS p < 0.05 p < 0.05 IG1: −0.2%
America IG2 (training group resistance) NS NS NS NS IG2: −0.5%
(The Age: CG (control group) NS p < 0.05 NS NS CG: 2.7%
[25] Clinical trial IG1: 15.7 ± 2.7 years NO
Federative
Republic of IG2: 16 ± 2.8 years Between groups BMI:
Brazil) CG: 14.4 ± 2.5 years IG1 vs. CG NS p < 0.05 NS NS IG1: −0.5 kg/m2
IG2 vs. CG NS p < 0.05 p < 0.05 NS IG2: −0.2 kg/m2
Duration: 3 months IG1 vs. IG2 NS NS p < 0.05 NS CG: 0 kg/m2

WC:
IG1: −1.1 cm
IG2: −0.1 cm
CG: 0.5 cm
n = 18 (55.5% male) YES (%) YES (kg/m2 ) YES (cm) BF: +0.18%
South
[26]
Age: 5–9 years Comparative analysis: BMI: −0.16 kg/m2
America Clinical trial NO NO
NS NS p < 0.01
(Chile)
Duration: 3 months WC: −3.07 cm
YES (kg) YES (kg/%) YES (kg/%) BW: −3.6 kg
n = 22 (100% male)
Europe Comparative analysis: p < 0.05 p < 0.05 NS BF: −5.5 kg/−5.8%
[27] Clinical trial NO NO
(Spain) Age: 16.2 ± 1.0 years
FFM: +1.8 kg/+5.8%
Duration: 3 months
Body composition (BC); Down syndrome (DS); intervention group (IG); intellectual disability (ID); percentage (%); body mass index (BMI); body fat (BF); body weight (BW); fat-free
mass (FFM); lean mass (LM); randomized clinical trial (RCT); waist circumference (WC); not significant (NS); the article includes the analysis of the parameter expressed in its correspondent
units (YES); the article does not include the analysis of the parameter (NO); not specified (NE); minutes (min); week (wk); day (d); kilocalorie (Kcal).
Int. J. Environ. Res. Public Health 2020, 17, 4294 7 of 16

Table 3. Clinical trials including adults suffering DS in which the variation of body composition was analyzed (intervention in physical exercise).

Intervention Method Characteristics Anthropometric Parameters (Statistical Results) Variation in Body

Reference Sample/Groups/Characteristics
Location Study Design Studied/Comparative Statistical BW BF FFM BMI WC Composition
[28–30] Studied
Analysis of BC (kg/%) (kg/%) (kg/%) (kg/m2 /%) (cm/%) Mean

YES (kg) YES (kg/%) YES (kg/m2 ) YES (cm) BW:

IG1: −2.3 kg
IG2: −1 kg
CG: +0.1 kg
Comparative analysis:
n = 42 (71.4% female) BF:
Within groups: IG1: −1.4 kg/−1.3%
Africa IG1: 13 IG1 (IT) IG2: −1.2 kg/−0.8%
(Republic of IG2: 13 IG2 (CAT) NE NE NE NE CG: +2.3 kg/−0.7%
[28] RCT CG: 16 CG NE NE NO NE NE
South
Africa) NE NE NE NE BMI:
Age: 33.8 ± 8.6 years Between groups IG1: −0.8 kg/m2
IG1 vs. CG IG2: −0.4 kg/m2
Duration: 3 months IG2 vs. CG p < 0.05 NS p < 0.05 NS CG: −0.3 kg/m2
IG1 vs. IG2 p < 0.05 NS NS NS
p < 0.05 NS p < 0.05 NS WC:
IG1: −0.4 cm
IG2: −1.3 cm
CG: −1.4 cm
YES (%) YES (kg/m2 ) YES (cm) BF: −3.9%
n = 20 (100% female)
Comparative statistical: BMI: −3.4 kg/m2
IG: 11
Europe CG: 9 Within groups: WC: −3.2 cm
[29] RCT NO NO
(Spain) IG p < 0.05 p < 0.05 p < 0.05
Age: 18–30 years CG NS NS NS
BMI: >30 kg/m2 Between groups p < 0.05 p < 0.05 p < 0.05

Duration: 2.5 months

YES (%) YES (cm) BF:
n = 20 (100% female) IG: −3.9%
Comparative analysis: CG: NE
IG: 11
Europe CG: 9 Within groups:
[30] RCT NO NO NO
(Spain) IG p < 0.05 p < 0.05 WC:
Age: 18–30 years CG NS NS IG: −3.2 cm
BMI: >30 kg/m2 Between groups p < 0.05 p < 0.05 CG: NE

Duration: 2.5 months

Down’s syndrome (DS); intervention group (IG); intellectual disability (ID); percentage (%); body mass index (BMI); body fat (BF); continuous aerobic training (CAT); fat-free mass (FFM);
lean mass (LM); body weight (BW); randomized clinical trial (RCT); waist circumference (WC); not significant (NS); the article includes the analysis of the parameter expressed in its
correspondent units (YES); the article does not include the analysis of the parameter (NO); not specified (NE); minutes (min); week (wk); day (d); kilocalorie (Kcal).
Int. J. Environ. Res. Public Health 2020, 17, 4294 8 of 16

The exclusion criteria were patients showing other pathologies (diabetes mellitus, polycystic
ovaries, etc.); clinical trials using pharmacology, gastric balloon and bariatric surgery; review articles and
meta-analysis. In the selection of included clinical trials, those studies involving sample groups of all
ages have been accepted to have a much broader view of the analysis. This has been a standard practice
in previous reviews [31,32]. Data were extracted from the following 5 domains [33] (Tables 2 and 3):

1. Population: characteristics of the population studied (country of origin, type of diagnostic criteria,
number, age and gender), inclusion and exclusion criteria.
2. Interventions: exclusive and multidisciplinary as therapeutic treatments.
3. Comparators: inclusion of clinical trials, control and intervention groups are identified.
In principle, only the intervention groups receive the therapeutic treatment that should cause
changes in body composition.
4. Results: they are identified as variation in body composition, presenting significant and not
significant variations.
5. Characteristics of clinical trials: authors, year of publication, type of clinical trial, duration of
intervention, instrument of analysis of body composition, type of intervention used (exclusive
or multidisciplinary) and body composition variation (measured with different anthropometric
parameters and units of measurement).

2.3. Extraction of Data, Synthesis of Results and Risk of Loss of Information

Three tables and two figures were designed to perform this review. As first step, all the identified
articles were listed including details about search engine and search strategy used. From these results,
the included clinical trials in this work were selected (Figure 1 and Table 1). Clinical trials were grouped
into several groups (Tables 2 and 3), based on age and type of intervention. Three versions of each
table were made. To minimize the risk of loss of information in the search of clinical trials, the term ID
was added (Table 1).
Tables 2 and 3 were designed to record the characteristics of interest of the included clinical trials.
The information collected was: author/s; study sample; duration of intervention; intervention/method;
the variation of the body composition (body mass index, BMI; body fat, BF; fat-free mass, FFM;
lean mass, LM; body weight, BW; waist circumference, WC) and the major changes in body composition.
To identify the variation of these parameters and units, a Yes/No code has been used: YES, means that
the article includes the analysis of the parameter expressed in its correspondent units and NO means
that the article does not include the analysis of the parameter. Thus, the most significant changes body
composition from each clinical trial was registered based on each parameter and unit (Tables 2 and 3).

2.4. Use of the CONSORT 2010 Methodology

In order to analyze the quality in the design of clinical trials included in this work involving the
highest variations in body composition, the CONSORT 2010 method has been used (assessment and
implementation guide on the most appropriate guidelines for the design of randomized trials) [34].

2.5. Evaluation of Body Composition Measuring Instruments

To evaluate how body composition has been measured, two groups have been established based on
the degree of information about the instrument or their accuracy: (i) The level of information presented
on the instruments used (model and its technical characteristics), as well as the monitoring of a protocol
for the measurement of body composition (Table 4) (ii) The accuracy of the instruments has been
assessed according to the scale of valuation indicated by Müller MJ and his colleagues [17] (p. 183).
Int. J. Environ. Res. Public Health 2020, 17, 4294 9 of 16

Table 4. Assessment of the level of information presented in the measurement of body composition.

Height Individual Assessment General Evaluation

Autor BW BF&FFM WC
(BMI) (Mean) (Mean)
Children and adolescents
[25] Moderate Moderate High Moderate Moderate (2.3)
[26] Moderate Moderate Moderate High Moderate (2.3) Moderate (2.4)
[27] Moderate High High APNM Moderate–High (2.7)
Adults
[28] High Moderate High High Moderate–High (2.8)
[29] Moderate Low Moderate Moderate Low–Moderate (1.8) Moderate (2.2)
[30] APNM Low Moderate High Moderate (2)
APNM: anthropometric parameter not measured; fat-free mass (FFM); body fat (BF); body weight (BW); randomized
clinical trial (RCT); waist circumference (WC).

For the first case, the following valuation scale is used (Table 4): (i) High (equivalent to three points,
and reporting the type of instrument used and the measurement protocol followed); (ii) Moderate
(equivalent to two points, and reporting the type of instrument used, but not the follow-up of any
protocol); iii) Low (equivalent to a point, in this case neither the instrument nor the protocol used is
indicated); (iv) Anthropometric parameter not measured (equivalent to zero points). The protocols
used had to show some similarity with those presented in the aforementioned revisions [13,14,35,36].

3. Results

3.1. Search Features and Types of Interventions Identified

Only 1% of the identified clinical trials have been included in this work to do the complete
analysis. The Scopus database and the third search strategy provided most of the included trials
(Figure 1 and Table 1).
Five clinical trials have been included in the study (6 papers, because Ordoñez and coworkers [a]
and Ordoñez and coworkers [b] referred to the same study, but both have been included because they
report some different parameters) (Tables 2 and 3) [29,30]. Three of the studies involve children and
adolescent populations (Table 2) and two of them work with adult patients (Table 3).
As a response to the second secondary objective, all of them were focused on an exclusive intervention
based on physical exercise and the anthropometric measures analyzed were BF (in kg or %, 100%),
BMI (in kg/m2 , 80%), WC (in cm, 80%), BW (in kg, 60%) and FFM (in kg or %, 20%). A period of
intervention between ten and twelve weeks was defined in all cases.

3.2. Instruments for Measuring Body Composition

As it is displayed in Table 4, there are no significant differences in the level of information about the
instruments used when evaluating children, adolescents and adults. Clinical trials that present more
complete information and with less error/measurement bias (because they have followed a specific
protocol) are those developed by Ordoñez and co-workers and Boer and co-workers [27,28].
For the evaluation of the instruments that measured fat mass, and in some cases fat-free mass,
the precision scale indicated by Müller and colleagues was used, where the greatest precision was
related to the smallest variation between the results when the measurement of body composition
in a subject is repeated, and the lowest accuracy in the opposite case [17] (p. 183). Thus, the
following groups were obtained: (i) The clinical trials of Seron, Boer and two of Ordoñez were
the most accurate [25,28–30]; (ii) The other clinical trials used instruments of less precision [26,27].
The instruments used for measuring body fat were: (i) Bod Pod® plethysmography equipment, body
composition was calculated based on the equation of Siri (Life Measurement Inc., Concord, CA,
Int. J. Environ. Res. Public Health 2020, 17, 4294 10 of 16

USA) [25]; (ii) The percentage of fat mass was estimated through the summation of the four folds
(triceps, biceps, subscapular and suprailiac regions) on the right side using the caliper de Lange
and as the standard of reference to West’s rate and Deurenberg [26]; (iii) Percentage of fat mass was
calculated from measurements according to the equation Durnin-Womersley using a Holtain lipometer
(Holtain Ltd., Crymych, Dyfed, Wales, UK). [27]; (iv) Body composition was assessed by bioelectrical
impedance analysis (Bodystat 1500 MDD, Douglas, Isle of Man, UK) [28]; (v) The percentage of fat
mass was measured by bioelectrical impedance analysis (Tanita TBF521 bioelectrical) [29]; (vi) Fat-mass
percentage was assessed by bioelectrical impedance analysis (Tanita TBF521) [30].
Considering the evaluations carried out, the third secondary objective is answered: most clinical
trials about DS show a moderate level of information (it is not indicated whether or not a protocol has
been followed in making measurements) and most instruments used to measure body fat and fat-free
mass show a high level of accuracy.

3.3. Evaluation of the Design of Clinical Trials

In order to analyze the quality of the design of controlled clinical trials included in this work
involving the highest variations in body composition (Seron and coworkers, Boer and coworkers and
Ordoñez and coworkers) [25,28–30]. The CONSORT 2010 method has been used (assessment and
implementation guide on the most appropriate guidelines for the design of randomized trials) [34].
Negative results should be considered for items that have not been performed or have been incompletely
performed. Positive results are those in which the items were fulfilled entirely. Items related to the
randomization process were eliminated for the analysis of the non-randomized trial [25].
As a response to the first secondary objective, positive results have been reported from half of the
clinical trial analyzed. However, in no case, the percentage of positive responses was greater than 65%.

3.4. Changes in Body Composition in Down Syndrome: Children and Adolescents

The three trials focused on children and adolescents were reported from Brazil, Chile and
Spain, respectively [25–27]. Seron and coworkers, presented a quasi-experimental study in which
the 41 patients (15.7 ± 2.7 years old) were assigned to two intervention groups plus a control group
(n = 16, n = 15 and n = 10, respectively). The patients grouped in the intervention groups underwent
two different types of training: aerobic (intensity of 50–70% of heart rate reserve 3 times per week)
and resistance (12 maximum repetitions 2 times per week). The anthropometric measures analyzed
were BW, BF, BMI and WC. Regarding to BW and BF, significant differences were not observed within
the intervention groups nor between them. However, the differences were significant with respect
to the control group and the two groups in BF but not in BW. The largest changes in BW occurred in
the first group (0.7 kg), while in BF in the second one (0.5%). In BMI and WC, significant differences
were observed within the first group (with changes of 0.5 kg/m2 and 1.1 cm, respectively), but not in
the other one. Regarding BMI, there were significant differences in the second intervention group
with respect to the other two groups, but these differences were already significant in the baseline
values (Table 2).
The other two articles presented interventions related to physical exercise in a single
group of patients. Mosso and coworkers, reported an intervention in a group of 18 children
between 5 and 9 years old. The intervention consisted in the application of a physical exercise program
with different aerobic and resistance activities. The anthropometric measurements analyzed were BF,
BMI and WC. BF increased and only significant differences in WC were obtained, with changes of
around 3.07 cm. Ordoñez and coworkers applied a physical exercise intervention on a group of 22 male
adolescents with a mean age of 16.2 ± 1.0 years. The training included exercises in water and land
three times per week. The anthropometric measurements analyzed were BF and FFM (in kg and %)
and BW. There were significant differences in BW and BF (changes of 3.6 kg in BW and 5.5 and 5.8% in
BF) [27] (Table 2).
Int. J. Environ. Res. Public Health 2020, 17, x FOR PEER REVIEW

with a mean age of 16.2 ± 1.0 years. The training included exercises in water and land three times per
week. The anthropometric measurements analyzed were BF and FFM (in kg and %) and BW. There
Int. J. Environ. Res. Public Health 2020, 17, 4294 11 of 16
were significant differences in BW and BF (changes of 3.6 kg in BW and 5.5 and 5.8% in BF) [27] (Table
2).
Regardingto
Regarding toBW
BW(kg) (kg)and
andBFBF(kg
(kgand
and%),
%),Ordoñez
Ordoñezandandcoworkers
coworkersreported
reportedthe
thegreatest
greatestchanges
changes
in three months in a group from baseline, and the greatest variation was 3.6 kg,
in three months in a group from baseline, and the greatest variation was 3.6 kg, 5.5 kg and 5.8%, 5.5 kg and 5.8%,
respectively[27].
respectively [27].ItItisisimportant
importanttotohighlight
highlightthat
thatthe
thenumber
numberof ofstudies
studieshere
hereincluded
includedthat
thatfollow
follow
inclusion and
inclusion and exclusion criteria
criteria was
was small.
small. Consequently,
Consequently,these
thesecomparisons
comparisons maybe
maybeareare
notnot
significant
signifi‐
and and
cant conclusive
conclusiveenough
enough (Table 2 and2 Figure
(Table 2). 2).
and Figure

Within-groupdifferences
Figure2.2.Within‐group
Figure differences(with
(with95%
95%confidence
confidenceinterval)
interval)in
inchildren
childrenand
andadolescents
adolescents trials.
trials.

Consideringthe
Considering thenumber
numberofofclinical
clinicaltrials
trialsanalyzed,
analyzed,the
thefourth
fourthsecondary
secondaryobjective
objectiveisisanswered.
answered.
The main finding regarding BMI (kg/m 2 ) is that Seron and co-authors reported the greatest
The main finding regarding BMI (kg/m ) is that Seron and co‐authors reported the greatest changes
2
changes in threeand
months and the greatestwas
variation was 0.5 kg/m 2 [25]; with respect to WC (cm),
in three months the greatest variation 0.5 kg/m 2 [25]; with respect to WC (cm), Mosso and
Mosso and coworkers, reported the greatest changes in three months and
coworkers, reported the greatest changes in three months and the greatest variation the greatest
wasvariation was
3.07 cm [26]
3.07 cm [26]
(Table 2). (Table 2).

3.5. Changes in Body Composition in Down Syndrome: Adults

3.5. Changes in Body Composition in Down Syndrome: Adults
Regarding to trials focused on adults, Boer and coworkers, described an experimental study
Regarding to trials focused on adults, Boer and coworkers, described an experimental study lo‐
located in the Republic of South Africa, in which the 42 patients (33.8 ± 8.6 years old, and 71.4% of
cated in the Republic of South Africa, in which the 42 patients (33.8 ± 8.6 years old, and 71.4% of
female) were assigned to two interventions and a control group (n = 13, n = 13 and n = 16, respectively).
female) were assigned to two interventions and a control group (n = 13, n = 13 and n = 16, respectively).
The patients in the intervention groups underwent two different types of training: interval training (IT)
The patients in the intervention groups underwent two different types of training: interval training
versus continuous aerobic training (CAT). The anthropometric measures analyzed were BW, BF, BMI
(IT) versus continuous aerobic training (CAT). The anthropometric measures analyzed were BW, BF,
and WC. The significance of the differences within each group was not reported, but the differences
BMI and WC. The significance of the differences within each group was not reported, but the differ‐
between groups are not significant in BF and WC. On the contrary, in BW there are significant differences
ences between groups are not significant in BF and WC. On the contrary, in BW there are significant
in the comparisons between the three groups, obtaining the greatest changes in the IT group (2.3 kg).
differences in the comparisons between the three groups, obtaining the greatest changes in the IT
In BMI no significant differences were observed between CAT groups and the control group, but
group (2.3 kg). In BMI no significant differences were observed between CAT groups and the control
between IT and the other two groups being the drop in this group of 0.8 kg/m2 (Table 3). 2
group, but between IT and the other two groups being the drop in this group of 0.8 kg/m (Table 3).
The other trial was reported by Ordoñez and coworkers, in which 21 females (between 18 and
The other trial was reported by Ordoñez and coworkers, in which 21 females (between 18 and
30 years old) were randomly assigned to the intervention group (n = 11) participating in an aerobic
30 years old) were randomly assigned to the intervention group (n = 11) participating in an aerobic
training of three sessions per week, whilst the other 10 were assigned to a control group. The trial was
training of three sessions per week, whilst the other 10 were assigned to a control group. The trial
conducted in Spain and the anthropometric measures analyzed were BF, BMI and WC. All measures
showed significant changes in the intervention group, but the differences between the groups were
Int. J. Environ. Res. Public Health 2020, 17, 4294 12 of 16

not reported. Changes in the measures in the intervention group were 3.9%, 3.4 kg/m2 and 3.2 cm,
respectively [29,30] (Table 3).
Considering the number of clinical trials analyzed, the fourth secondary objective is answered:
regarding to BF (kg), Boer and coworkers, reported the greatest changes in three months and the
greatest variation was 1.4 kg [28]; with respect to BF (%), BMI (kg/m2 ) and WC (cm), Ordoñez and
coworkers, reported the greatest changes in two and a half months and the greatest variations were
3.9%, 3.4 kg/m2 and 3.2 cm, respectively [29]. Due to the small number of studies analyzed regarding
this issue (2 works on DS in adults) the conclusions to be obtained may not be accurate and significant
enough (Table 3).

4. Discussion
Down syndrome is the most commonly occurring genetic chromosomal disorder and its estimated
incidence is between 1 in 1000 to 1 in 1100 live births worldwide, according to the World Health
Organization [37]. People suffering from DS are more likely to be overweight or obese than the general
population [6]. Despite this, the number of studies (even clinical trials) on DS in connection with
overweight or obesity is significantly low compared to other diseases. The lack of knowledge on this
field justified from the very beginning this systematic review, which has been difficult to conduct
because of the low number of clinical trials identified on this topic. Consequently, it has not been
possible to address accurately the main objective. However, in view of the scarcity of knowledge in
this area, it was decided to carry out this work, not only to identify what has been described so far,
but also to highlight the need to deepen this field of research, from both levels basic and applied.
Thus, three main limitations have been identified in this review: (i) Small number of studies based on
clinical trials; (ii) Absence of clinical trials with dietary intervention; and (iii) Absence of studies based
on multidisciplinary interventions.
In order to analyze the information described so far on DS and overweight or obesity, the first
approach was to evaluate the degree of information described in each study on the anthropometric
measures carried out and the type of instrument used for the measurement. Regarding the level of
information presented by each clinical trial on the measurements of body composition, it can be seen
that in most clinical trials they are not following specific, standardized protocols for their measurement
(Table 4) [13,14,35,36]. This information is of concern in clinical trials measuring body fat by measuring
skin folds, because it is a method whose accuracy is lower due to errors resulting from measurement
without a specific protocol [17] (p. 183). Among the instruments analyzed, the measuring tape and the
skin fold register are sensitive measurement methods with variability in accuracy. It should therefore
be stressed that in the future it is essential to use protocols for the different measurement techniques
applied in order to ensure that the measures are reliable and reproducible [14–16]. In this sense, it is of
special importance to identify two aspects: (i) The validity, precision and nature of the parameters
that are monitored to estimate the body composition (without losing sight of both the daily and
inter-individual variation); (ii) The variation of results according to the protocols of study used and
the dynamics of weight changes (before, during and after the intervention) [38]. As a reflection, it is
advisable to convey that despite the existence of more precise methods, it is possible to use any of the
named methods if a protocol is used to decrease the variation in precision. In this way, changes in
obesity can be monitored in response to the investment of time and money required for the monitoring.
In this review it has been found that the strategies that allowed greater changes in body composition,
in children and adolescents were those base on planned physical exercise, considering the intensity,
the duration, the number of repetitions, days per week and with programming by macrocycles, are the
techniques that cause the greatest variation in body composition. The gradual increase of load in time
and intensity is a technique that was also considered in two studies [25,26]. In the case of adults, the
best results were observed when planned physical exercise was prescribed taking into consideration
the intensity, duration, number of repetitions and days per week, including the continuous aerobic
exercise [28,29]. In the absence of more evidences, the guidelines for dietary intervention and physical
Int. J. Environ. Res. Public Health 2020, 17, 4294 13 of 16

exercise in children, adolescents and adults with overweight or obesity without DS remain the main
references to follow [39–42]. When prescribing physical exercise, it is recommended to use guidelines
reporting positive results. These guidelines should follow the recommendations given in this review
and by the American College of Sports Medicine (including degrees of evidence and greater accuracy
in prescribing physical exercise) [43,44] (pp. 460, 1336).
In general terms, it can be concluded that there is a shortage of research personnel focused on this
area of knowledge, as well as deficiencies in the means and infrastructures available for these studies.
Therefore, research in this field, training of clinical staff in specific aspects of DD, and high-quality
clinical care for subjects with this syndrome should be enhanced [10,45].
Regarding to the design of clinical assays involving DS individuals, it is worth mentioning that
guidelines like CONSORT 2010 should be used [34] (p. 31), and studies involving individuals only
suffering from DS has to be conducted [46] (pp. 137–140), so that dietary and multidisciplinary
intervention is used to promote change in body composition. At the time of writing this review, most of
the studies involved patients showing more diseases apart from DS, which makes difficult to establish
correlations between changes of the measured parameters and exclusively DS.
As cited in the introduction and in Section 3.2, different type of instruments are used to measure key
anthropometric parameters. Most instruments used to measure body fat and fat-free mass show a high
level of accuracy in the analyzed studies, however, no clear protocols used to take the measurements are
referred, which is a significant limitation of these reported studies. Apart from these instruments, the
use of accelerometers as a precision method for evaluating physical activity is also suggested [47,48].
Among the issues to be considered in the design of further studies involving DS and obesity or
overweight, the following should be included: cardiorespiratory fitness and analysis at molecular
level. Cardiorespiratory fitness as a feasible method in subjects with DS without congenital heart
disease. This approach is also useful to measure the level of physical condition in order to perform
a safe physical activity [49]. Cardiorespiratory fitness is defined as the ability of the circulatory,
respiratory and muscular systems to deliver oxygen during sustained physical activity. Records found
in individuals with intellectual disabilities indicate a low level; levels in children, adolescents and
men with intellectual disabilities are already low and decrease further with increasing age [50,51].
Regarding to the analysis at molecular level, it is important to mention that not only the shortening of
the telomeres [1], but also other molecular targets like molecules sustaining systemic inflammation,
hormones or peptides like leptin and adiponectin have to be considering to monitor obesity and
overweight in DS. Recently it has been described that leptin is at higher concentration in young subjects
with DS and adiponectin is higher in older subjects [52]. So, it is possible to establish correlations
between leptin and adiponectin over time in DS as a tool to monitor weigh changes in people suffering
from DS.
If all these objectives could be explored in the short term reaching positive results, it would
be possible to assume that the monitoring of the variation of body composition through dietary
intervention and physical exercise, could be an area of knowledge that contributes to the slowing down
of aging in subjects with DS [1–4], allowing also the decrease of the high prevalence of overweight and
obesity [6].

5. Conclusions
Down syndrome (DS) with overweight and obesity constitutes a field of knowledge in which
research should continue with the aim of analyzing relationship between dietary intervention, physical
exercise and body composition variation. From the results of this systematic review, it can be concluded
that the studies carried out to date have not achieved optimal results and that the design of future
clinical trials should be improved. Only reinforcing the knowledge related to this topic will improve
daily clinical practice in sports sciences, nutrition and dietetics as well as in public health will improve.
An increase in body composition variation will help to reduce the side effects of overweight and obesity,
leading to a reduction in healthcare costs.
Int. J. Environ. Res. Public Health 2020, 17, 4294 14 of 16

Author Contributions: R.M.M.-E.: selection of the information of interest in the tables; information analysis using
the PRISMA methodology; writing, translation and revision of the manuscript. M.D.M.V.: selection of information
of interest displayed in the tables; information analysis using the PRISMA methodology; analysis of clinical
trials included by the CONSORT 2010 guide; writing, translation and revision of the manuscript. M.R.G.-G.:
collaborated in the selection of the included clinical trials; elaboration and design of the tables and the flow
diagram; analysis of clinical trials included by the CONSORT 2010 guide; information analysis using the PRISMA
methodology; writing of the manuscript draft and revision of the manuscript. All authors have read and agreed to
the published version of the manuscript.
Funding: This research has been partially funded by VIGROB-309 (University of Alicante).
Acknowledgments: Enrique Albert Pérez for contributions discussing the main results.
Conflicts of Interest: The authors report no conflict of interest.

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