A National e-Health Program for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence in Greece

Obesity in childhood and adolescence represents one of the most challenging public health problems of the 21st century owing to its epidemic proportions worldwide and the associated significant morbidity, mortality and public health costs. In Greece, the prevalence of overweight and obesity in childhood and adolescence exceeds 30–35%. To address the increasing prevalence of overweight and obesity in children and adolescents in our country, we developed the ‘National e-Health Program for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence’, which provides specific and detailed guidance to all primary health care physicians about the personalized management of children and adolescents with overweight or obesity. In the present study we evaluated 2400 children and adolescents [mean age ± SEM: 10.10 ± 0.09 years.; Males: 1088, Females: 1312; Obesity (n = 1370, 57.1%), Overweight (n = 674, 28.1%), normal BMI (n = 356, 14.8%)], who followed the personalized multi-disciplinary management plan specified by the ‘National e-Health Program for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence’, and were studied prospectively for 1 year. We demonstrated that at the end of the first year, the prevalence of obesity decreased by 32.1%, the prevalence of overweight decreased by 26.7%, and the cardiometabolic risk factors improved significantly. These findings indicate that our National e-Health Program is effective at reducing the prevalence of overweight and obesity in childhood and adolescence after one year of intervention in the largest sample size reported to date.


Introduction
Obesity represents one of the most challenging public health problems of the 21st century owing to both its epidemic proportions worldwide and the associated significant morbidity and mortality [1]. present and past medical history, the family history, the clinical examination findings (including the anthropometric parameters and arterial blood pressure) and the patient's signed consent form [13,15]. The electronic database system (EDS) then automatically calculates the BMI from the data on height and weight and informs the physician whether the patient has normal or increased BMI. In addition, the corresponding growth chart for BMI appears on the computer screen. Subsequently, the EDS selects the most appropriate therapeutic algorithm file (TAF), according to the patient's age, gender, BMI and all other information (including information on diet and exercise) entered in the system. Therefore, the TAF provides a comprehensive and personalized multidisciplinary management plan for the prevention and/or management of overweight and obesity for the patient. The TAF indicates what the initial advice to the patient and his/her family should be; when the physician should reassess the patient; how he/she will manage the patient if there is adequate response to the therapeutic interventions or if there is no response to the therapeutic interventions despite compliance with those; when he/she will perform laboratory investigations and which ones; when he/she will refer the patient to a pediatric dietician or psychologist; and when he/she will refer the patient to a pediatric endocrinologist or a specialist center with expertise in the management of overweight and obesity [13,15].
To the best of our knowledge, our 'National e-Health Program for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence' is the first web-based e-Health application in Greece developed to be used by health professionals. It is accessible by the following URL: https: //app.childhood-obesity.gr/ and has been awarded the BRONZE Award in the category "e-Health/H1.1 Digital Applications for Integrated Patient care" by the Healthcare Business Awards in 2016.
The aim of the present study was to evaluate the effectiveness of the interventions suggested by this electronic system in reducing the prevalence of obesity and overweight, and to present the progress of a large number of children and adolescents who have followed the personalized multi-disciplinary management plan specified by the 'National e-Health Program for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence'.

Patients
Two thousand four hundred (n = 2400) children and adolescents, aged 2-18 years, (mean age ± SEM: 10.10 ± 0.09 years; 1088 males, 1312 females) attending our Out-patient Clinic for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence were studied prospectively for one year. Subjects were classified as having obesity, overweight or normal BMI according to the International Obesity Task Force (IOTF) cut-off points [16]. The clinical characteristics of all subjects are summarized in Table 1. The study was approved by the local Committee on the Ethics of Human Research. (Approval Number: EB-PASCH-MoM: 28/11/2013, Re: 10290-14/05/2013). Written informed consent was obtained in all cases by a parent/guardian, and assent was given by children older than 7 years.

Methods
All participants were admitted to the Endocrine Unit early in the morning on the day of the study, and a detailed medical history and clinical examination, including pubertal assessment and standard anthropometric measurements (weight, height, waist circumference, hip circumference) were obtained by a single trained observer. Body weight was measured in light clothing and without shoes using the same scale for all subjects (Seca GmbH & Co. KG., Hamburg, Germany). Standing height was also measured without shoes using a stadiometer (Holtain Limited, Crymych-Dyfed, UK). Waist and hip circumferences were measured according to WHO STEPS protocol using the same stretch-resistant tape (Seca GmbH & Co. KG., Hamburg, Germany) with the subject on standing position. More specifically, waist circumference was measured in the horizontal plane midway between the lowest rib and the iliac crest at the end of a normal expiration. Hip circumference was measured in the horizontal plane at the Nutrients 2020, 12, 2858 4 of 15 level of maximum circumference of hips and buttocks. On both occasions, the tape did not compress the skin and was parallel to the floor. Blood pressure was determined by a sphygmomanometer (Comfort 20/40, Visomat, Parapharm, Metamorphosi, Attiki, Greece) and with an appropriate cuff according to the age of the subject [14].
A blood sample for baseline hematological, biochemical and endocrinologic investigations was drawn at 8:00 h following a 12-h fast. Samples were centrifuged and separated immediately after collection and were stored at −80 • C until assayed.

Assessment and Interventions
At initial assessment, all subjects were evaluated by a Pediatrician and Pediatric Dietitian for their daily eating habits, and a 24-h recall of their diet was performed based on the USDA method [17]. The dietitian recorded the number of meals and snacks, the usual food choices, the person responsible for the preparation of meals, the amount of liquids (water, milk, juices and other beverages) consumed, as well as the frequency and amount of junk food and sweet consumption. Subsequently, children and their parents were informed about the complications of obesity and the need for the whole family to adopt a healthier lifestyle. Also, they were guided about changes in their nutritional habits. They were given advice on a healthy diet according to "My Plate" standard, a visualized approach of the USDA 2010 guidelines [18], which included three main meals (breakfast, lunch and dinner) and two snacks (fruits, vegetables) at mid-morning and mid-afternoon. The importance of breakfast consumption was emphasized because of its association with better cognitive performance at school, as well as with better achievement and maintenance of normal weight. The appropriate food portions were determined according to the guidelines proposed by the National Nutrition Guide for Infants, Children and Adolescents [19]. The aim was to recommend a personalized plan of healthy diet, which would also take into consideration the child's preferences on food consumption (and therefore not be perceived as boring or difficult), as well as the food availability and preparation while the child is at school or at home.
In addition, a professional fitness Personal Trainer evaluated children and adolescents in relation to their activities and hobbies throughout the week, suggested a personalized exercise program, and encouraged the whole family to avoid a sedentary lifestyle and to follow a physical activity of their choice on a daily basis for 30-45 min, such as walking, jogging, dancing, cycling [20]. The Personal Trainer discussed the child's interests with the family in order to identify suitable sport activities. The aim was to recommend a personalized physical activity plan, which would not be perceived as compulsory, boring or difficult, but rather as a highly enjoyable and entertaining activity. The assessment of the Personal Trainer was repeated each month and recorded all information about physical activity and exercise.
Finally, subjects referred for psychological evaluation were assessed by a Pediatric Clinical Psychologist, who evaluated the family dynamics and provided psychological support to children and their parents. In cases where more severe psychopathology was evident, patients were referred to a mental health service.
All subjects included in the study complied with the advice given on diet and exercise, as reported by them and their families. Patients who required psychological or psychiatric input were excluded from the study. Subjects with obesity were followed-up at least every month, with overweight every two months and with normal-BMI every three months. It should be emphasized that all information and guidance on life-style interventions were given in person, when our patients attended our Out-patient Clinic, and were the same with those provided by the National e-Health Program for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence. At each subsequent appointment, the Pediatrician re-evaluated the anthropometric measurements and the goals set in previous sessions were discussed in detail with the Pediatric Dietitian and the Personal Trainer, as well as the possible difficulties faced by children in achieving their optimal BMI. Detailed hematologic, Nutrients 2020, 12, 2858 5 of 15 biochemical and endocrinologic investigations were performed at the beginning and at the end of the study.

Assays
Standard hematologic investigations were determined using the ADVIA 2110i analyzer (Roche Diagnostics GmbH, Mannheim, Germany). The concentrations of glucose, total cholesterol, triglycerides and high-density lipoprotein cholesterol (HDL) were determined using the ADVIA 1800 Siemens analyzer (Siemens Healthcare Diagnostics, Tarrytown, NY, USA). Apolipoprotein A1, B (ApoA1, ApoB) and lipoprotein (a) concentrations were determined by means of latex particle-enhanced immunonephelometric assays on the BN ProSpec nephelometer (Dade Behring, Siemens Healthcare Diagnostics, Liederbach, Germany). Insulin was measured using automated electro-chemiluminescense immunoassays (Analyzer Cobas e411, Roche Diagnostics GmbH). Insulin-like growth factor-I and insulin-like growth factor binding protein-3 were measured using automated chemiluminescence immunoassays on an IMMULITE 2000 immunoassay system (Siemens Healthcare Diagnostics Products Ltd., Frimley, Camberley, UK). Total 25-hydroxyvitamin D was measured using an automated electrochemiluminescence immunoassay on the Modular Analytics E170 analyzer. Hemoglobin A1C (HbA1C) was determined using reversed-phase cation exchange high-performance liquid chromatography on an automated glycohemoglobin analyzer HA-8160 (Arkray, Kyoto, Japan).

Statistical Analyses
The results are presented as mean value ± standard error of the mean (SEM) for continuous variables and frequencies (%) for categorical variables. Normality was tested by using graphical methods (i.e., histograms and Q-Q plots) and homogeneity of variance was tested with the Levene's test. Differences in the distribution of continuous variables between the three categories of BMI (obesity, overweight and normal BMI) were assessed using the ANOVA F test. The Bonferroni rule was applied to each of the multiple comparisons for adjustment for a significance level of 5%. The comparison of pre-and post-intervention results within each category of BMI was calculated by a paired samples t test for normally distributed variables. The associations between skewed variables and groups of participants were evaluated by the Mann-Whitney U test, the Kruskal-Wallis H test or Wilcoxon's signed rank test. The associations between categorical variables were analyzed using Pearson's χ2 or the Monte Carlo test. A series of two-sample z tests of proportions was conducted to determine whether there were significant differences between groups. Data were analyzed using the SPSS statistical package version 24.0 (SPSS Inc., Chicago, IL, USA).

Results
The study sample consisted of 2400 children and adolescents (mean age ± SEM: 10.10 ± 0.09 years.; 1088 males, 1312 females), who were studied prospectively for 1 year. Subjects were classified as having obesity (n = 1370, 57.1%), overweight (n = 674, 28.1%) or normal BMI (n = 356, 14.8%) according to the International Obesity Task Force cut-off points [15]. The clinical characteristics of all subjects at baseline are shown in Table 1.
At initial evaluation, the percentage of subjects with obesity was 57.1%, overweight 28.1% and normal-BMI 14.8% ( Figure 1A). A significantly higher number of boys had obesity compared with girls (66.3% vs. 49.5%, p < 0.0001), while a higher number of girls had overweight compared with boys (30.7% vs. 25%, p < 0.0001) ( Figure 1B). There was no significant difference in BMI category between prepubertal and pubertal children. The clinical characteristics of all subjects at baseline are shown in Table 1 and after one year of intervention in Table 2. Children and adolescents with obesity had significantly higher systolic (SBP) and diastolic (DBP) blood pressure, waist circumference, hip circumference, waist-to-height ratio and waist-to-hip ratio than their overweight and normal-BMI counterparts. In addition, a strong positive correlation was observed between children's BMI and their parents' BMI, indicating that parents with overweight or obesity were more likely to have children  (Tables 1 and 2). Table 3 presents the biochemical and endocrinologic parameters. Subjects with obesity had significantly higher concentrations of fasting plasma glucose and serum insulin, HbA1C, triglycerides, LDL-cholesterol, uric acid and ApoB, and significantly lower concentrations of HDL-cholesterol and ApoA1 than their overweight and normal-BMI counterparts ( Table 3). Table 4 presents only the subjects who had a lipid profile indicative of dyslipidemia at baseline, while Table 8 presents the improvement that was demonstrated in terms of dyslipidemia one year after implementation of our interventions. The subgroup of subjects who had dyslipidemia was determined according to the American College of Cardiology criteria for dyslipidemia [21].       Following one year of intervention, the proportion of obese subjects decreased significantly by 15.8% (57.1% vs. 41,3%, p < 0.0001), while the proportion of overweight and normal-BMI subjects increased significantly by 10.1% and 5.7%, respectively (28.1% vs. 38.2%, 14.8% vs. 20.5%, p < 0.0001 all) (Figure 2A). Similar changes were observed in both boys and girls ( Figure 2B,C, respectively). Parameters that are associated with cardiovascular risk factors, such as lipid profile, plasma glucose, serum insulin and HbA1C concentrations were evaluated at baseline and one year after the interventions in subjects with obesity (Table 5), overweight (Table 6) and normal BMI (Table 7). When the progress of subjects was evaluated after one year of implementation of the multi-disciplinary management interventions, the proportion of subjects with obesity decreased by 32.1% while the proportion of subjects with overweight decreased by 26.7% ( Figure 3A,B). The majority of children and adolescents with normal BMI maintained their normal BMI till the end of our study, and only a small percentage of 8.5% developed overweight ( Figure 3C). The cardiometabolic risk indices improved significantly, as indicated by the improvement in the lipid profile and the criteria for dyslipidemia (Table 8). More specifically, we divided our population of children and adolescents into different subgroups, who fulfilled the criteria for dyslipidemia according to American College of Cardiology guidelines [21], and studied them at the beginning and the end of the study. We demonstrated that one year after implementation of our interventions, total cholesterol, LDL, triglycerides and ApoB decreased significantly, while HDL increased significantly, most likely as a result of the reduction in BMI (Table 8).

Discussion
In the present study we evaluated 2400 children and adolescents attending our Out-patient Clinic for the Prevention and Management of Overweight and Obesity. The majority of these subjects had obesity (57.1%) or overweight (28.1%), while only a small proportion had normal BMI (14.8%). All subjects followed the personalized multi-disciplinary management plan specified by the 'National e-Health Program for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence' and were assessed at the end of the first year of their participation in this program. We demonstrated that at the end of the first year the proportion of subjects with obesity decreased by 32.1%, the proportion of subjects with overweight decreased by 26.7%, and the cardiometabolic risk factors improved significantly. These findings indicate that our National e-Health Program is effective at reducing the prevalence of overweight and obesity in childhood and adolescence after one year of intervention in the largest sample size reported to date.
In addition to the observed improvement in BMI, a significant improvement was also observed in cardiovascular risk factors, such as lipid profile, plasma glucose, serum insulin and HbA1C concentrations. In particular, the concentrations of HDL-cholesterol and the anti-inflammatory cytokine, adiponectin, increased significantly, while the concentrations of LDL-cholesterol, Apo-B and HbA1C decreased significantly as a result of the reduction in BMI. These encouraging results demonstrate the importance of such a coordinated effort within the context of a multi-disciplinary intervention program in the effective management of overweight and obesity in childhood and adolescence, as well as the prevention of atherosclerotic cardiovascular disease later in life. The increased adipose tissue and its associated dyslipidemia and hypertension are the underlying pathogenetic factors in the development of endothelial dysfunction, increased fat deposition in the aortic linear muscle, increased arterial wall thickness and abnormalities in the coronary arteries, already present in childhood and adolescence [22,23]. Indeed, less than 1% of adults who did not have risk factors in childhood eventually developed carotid plaque in adulthood [24]. In addition, the cardiovascular risk is directly related to circulating atherogenic factors, i.e., lipoproteins that interact and invade the vessel wall, and is determined by the balance between proathrogens (ApoB) and antiplatelet-antiatherogenic agents (ApoA1) [25]. Therefore, this study allowed us to document the cardiovascular risk factors associated with dyslipidemia in a large sample of children and adolescents, as well as the significant improvement that was observed as a result of complying with the interventions specified by our National e-Health Program.
Furthermore, we confirmed the expected higher SBP and DBP of children and adolescents with obesity compared to their overweight and normal-BMI counterparts. Obesity is one of the most important factors in the development of primary (idiopathic) hypertension in childhood. Hypertension, in turn, is associated with left ventricular hypertrophy and early cardiovascular disease [26,27]. Therefore, adequately addressing the epidemic of obesity in childhood and adolescence is of major importance in reducing systemic inflammation [28,29] and atherosclerotic cardiovascular disease in adulthood. Maintaining normal BMI and adopting a healthy lifestyle have been the main goals of our program that seem to have been largely achieved.
Addressing the obesity epidemic should include measures that take into consideration genetic, epigenetic and environmental factors [30]. In addition to genetic factors, the life-style of the parents influences the weight of their children. Longitudinal studies showed that parental obesity is strongly associated with childhood obesity, and this effect is more pronounced in adolescence [31,32]. Furthermore, consumption of a high-fat diet by the parents even prior to conception may result in increased weight gain of the child [23,33]. Therefore, it is important to determine the various genetic, epigenetic or environmental factors that affect weight gain [31,[34][35][36].
In summary, the "National e-Health Program for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence", is a unique and innovative e-Health application that provides a comprehensive, personalized, multidisciplinary intervention program to combat overweight and obesity in childhood and adolescence in Greece. Evaluation of this program in 2400 children and adolescents indicated that it is effective at reducing the prevalence of overweight and obesity in childhood and adolescence, and at improving the cardiometabolic risk factors after one year of intervention.