Hemoglobin and Hematocrit Levels are Positively Associated with Blood Pressure in Children and Adolescents Aged 10 to 18 Years: The Korea National Health and Nutrition Examination Surveys 2007–2017.

Objective: To investigate investigated the association of hemoglobin (Hb) concentration, hematocrit (Hct) and blood pressure (BP) in children and adolescents. Methods: The study population consisted of a total 7,950 subjects (4,229 boys, 3,721 girls) aged 10 to 18 years who participated in the Korea National Health and Nutrition Examination Surveys conducted between 2007 and 2017. Results: The prevalence of hypertension is estimated about 19.19% (21.51% for boys and 16.5% for girls). The prevalence of obesity is estimated about 9.59% (10.5% for boys and 8.6% for girls). Hb and Hct level tended to increase with the degree of obesity and blood pressure. The systolic BP (SBP) and diastolic BP (DBP) have positively correlated with Hb and Hct levels in both sex. In the multiple regression analysis, the Hb and Hct presented positive association with SBP and DBP after adjustment for for age, BMI SDS, alcohol consumption, smoking physical activity, rural residence, household income, diagnosis of T2DM, hypertension, and dyslipidemia. Conclusion: Hemoglobin and hematocrit levels were positively associated with SBP and DBP, in children and adolescent, aged 10- 18 year. alcohol consumption, smoking, physical activity, rural residence, household income, diagnosis of T2DM, hypertension, and dyslipidemia.


Introduction
High blood pressure is an important risk factors for cardiovascular disease(1) and the leading causes of global burden of disease (2,3). High BP in childhood often develops in to hypertension (HTN) in adulthood, as childhood BP predicts adult BP (4)(5)(6)(7). It is a growing health problem that is often overlooked (8,9).
In children younger than 13 years, elevated blood pressure is de ned as blood pressure in the 90th percentile or higher for age, height, and sex, and hypertension is de ned as blood pressure in the 95th percentile or higher (10). In adolescents 13 years and older, elevated blood pressure is de ned as blood pressure of 120 to 129mm Hg systolic and less than 80mm Hg diastolic, and hypertension is de ned as blood pressure of 130/80mm Hg or higher (10). HTN in childhood may contribute to premature atherosclerosis and the early development of cardiovascular disease (CVD). Therefore, identifying the prevalence of HTN and determining the potential risk factors in children and adolescents, would be useful for understanding the pathophysiology and improving the treatment and prevention of hypertension. Obesity is knowns as risk factors of childhood HTN (11), pediatric HTN is increasing along with worldwide epidemics of obesity. Chronic kidney disease, sleep disorder is attributed development of HTN (12,13). Family history of HTN or CVD, male sex, low birth weight, and maternal smoking during pregnancy are additional risk factors, whereas children who were breastfed have a reduced risk of HTN (14,15). Also, the risk of HTN varies according to race and ethnicity, Hispanic and black children are known to have a greater risk (16).
Abnormalities in blood viscosity have been implicated in a number of cardiovascular disease (17). Hemoglobin (Hb) is the most important determinant of whole blood viscosity (18), and high hemoglobin level would be a potential risk factor to increase the BP. Several studies have reported that Hb concentrations increased in humans with HTN. However, only a limited number of large-population studies have shown an association between Hb concentration and BP (19)(20)(21)(22). Also, population study conducted in childhood was rare. Therefore, the current study investigated the prevalence of HTN and obesity, and the association of Hb, Hct and blood pressure in children and adolescents.

Results
A total 7,950 subject participated in nal analysis. Among them, 4,229 were boys (53.19%) and 3,721 were girls. The subjects categorized into 3 groups according to BMI, 3,343 of the boys were normal weight (79.0%), 443 were overweight (10.5%), and 443 was obesity(10.5%). 3,059 of the girls were normal weight (82.2%), 342 were overweight (9.2%), and 320 were obesity (8.6%). Table 1 presents the clinical characteristics of the study population. The SDS of height and waist circumference were signi cantly higher for boys than for girls. SBP, DBP, and serum glucose concentrations were higher for boys, and concentrations of TC, TG, HDL-C, and LDL-C were higher for girls. Alcohol drinker and smoker were more common in boys, and physical activity was greater in boys.  Mean Hb and Hct according to sex, BMI group and presence of hypertension are shown in Table 2, Fig. 1(c) and 1(d). In boys, when analyzed in all groups according to the BMI, Hb and Hct were signi cantly higher in cases of HTN than in cases of normal BP ( p < 0.001). In girls with NW group, Hb and Hct were signi cantly higher in HTN group than normal BP group ( p < 0.001, respectively). In girls with OW group, Hb was signi cantly higher in HTN group ( p < 0.05), but Hct was not(p = 0.083). In girls with OB group, Hb and Hct level showed a high tendency in HTN group, but there was no statistically signi cant difference (p = 0.295 and p = 0.054, Hb and Hct level in girls with OB, respectively ). HTN was de ned as i) systolic blood pressure (SBP) or diastolic blood pressure (DBP) ≥ the 95th percentile value for age, sex, and height or ii) SBP ≥ 130 mmHg or DBP ≥ 80 mmHg Table 3 presented the correlation between hemoglobin, and hematocrit and blood pressure in all subjects. Hb and Hct level were positively correlated with SBP, DBP in boys and girls. After adjustment for age in all participants, Hb and Hct were positively correlated with SBP, DBP in both sex, too.

Discussion
The current study presented the prevalence of obesity and hypertension, and a positive associated between Hb, hematocrit level and blood pressure, in children and adolescent. To our knowledge, this is the rst study that investigated the association between hemoglobin and hematocrit level, and systolic and diastolic blood pressure in a large Korean children and adolescents, aged 10-18 years. Our study population was representative of the Korean children and adolescents because the KNHANES is an o cial, nationwide database that re ects geographic and demographic differences in Korea.
Recently, the prevalence of overweight and obesity has increased rapidly in children and adolescents. Obesity is a multifactorial disease, caused by genetic, biological, environmental, behavioral, psychological factor (23).
Childhood obesity leads to adult obesity (24,25), and increased the risk of cardiovascular disease and mortality in adulthood (26). Severe obesity in children associated with an increased prevalence of cardiometabolic risk factor, including low HDL cholesterol, high SBP and DBP, high TG level, and high glycated hemoglobin level (27).
The prevalence of overweight and obesity was reported more than 10 % in developing countries and even higher (20%) in developed countries (28). Reports on the prevalence of childhood obesity in Korea vary from data to data, but it has increased over time, too. In 2013, the prevalence of overweight and obesity in children age < 20 years was 21.2 in boys and 13.2 in girls, and the prevalence of obesity was 4.8 in boys and 3.1 in girls (28). In our study, the overall prevalence of obesity and overweight was 21% in boys, and 17.8 % in girls, and the prevalence of obesity was 10.5% in boys and 9.2% in girls, aged 10-18 yeas, from 2007 to 2017. Our study did not analyzed the annual prevalence of obesity and overweight. And the difference in prevalence was caused by the age difference between subjects and the method of analysis.
The prevalence of elevated blood pressure and hypertension in children is reported around 6% and 3%, respectively (9,29). In obese adolescents, the combinded prevalence increases to around 30% (29). Cho  The results of our study showed that the prevalence of obesity and HTN was higher in boys than girls, and the prevalence of HTN was higher in the obesity and overweight group than normal weight group, in both sex. Hb and Hct level tended to increase with the degree of obesity and blood pressure in both sex, but there were sexual divergence. In boys and girls, Hb and Hct increased in hypertension than normal BP. In boys, Hb and Hct level were signi cantly increased in OB group, than NW and OW group. On the other hand, in girls, Hb and Hct were no difference according to obesity. This indirectly suggest that Hb and Hct are closely related to blood pressure than obesity.
Several studies have investigated the association between Hb concentration, Hct and BP, however, most of study performed in adult (19)(20)(21)(22). Previous studies presented that Hb concentration increased in humans with Hb concentration ≥ 11.0 g/dL, increased by 2.6 mm Hg with every 1mmol/l increase in the Hb concentration.
DBP increased by 3.2 mm Hg with every 1mmol/L increase in the Hb concentrationin both men and women in Korean adult population (aged ≥ 20 yeas) (22). In our study, the regression coe cients was relatively lower than the previous study. SBP increased by 1.3mmHg in boys, and 0.5mmHg in girls with every 1g/dL increase in the Hb level, DBP increased by 1.1 mmHg in boys, and 0.8 mmHg in girls with every 1g/dL in the Hb level. In our study, subjects were 10-18 years old, younger than in previous studies, and the unit of Hb was used as g/dL, instead of mmol/L, so the regression coe cient seem so be smaller. It is estimated that the difference in study design, ethnicity and characteristics of the study subject caused the difference in the results.
Göbel et al found signi cant correlations between mean arterial blood pressure and red blood cell count, Hct, and Hb concentration in healthy subjects. They suggested that Hct plays a role in determining the viscosity of the blood, and that it may be involved as a rheological factor controlling blood pressure (21). Our study did not collect data of red blood cell count, but indicates that Hct and Hb level are involved with blood pressure determination, although the mechanisms for an elevated BP with increasing Hb and Hct level are not entirely known. Previous stud presented higher Hct levels were associated with a higher incidence of hypertension (34).
Increased Hct level associated with increased blood viscosity, and that increased viscosity is a determinant of vascular resistance, and it is expected to contribute to blood pressure (35,36). The fact that polycythemia vera is often associated with cardiovascular disease supported this theory as plausible (37). Moreover, Kawamoto reported that Hb is strongly related to arterial stiffness, which, in turn, increases SBP and DBP (38). Therefore, they suggested a slightly low Hb level was bene cially associated with arterial stiffness in women. Because Hb is a scavenger of nitric oxide (NO), produced in the endothelial cells (39). NO act as vasodilator and to prevent atherosclerosis development and its complications (40). Increased levels of free Hb induce vasoconstriction due to NO scavenging and consequently, an elevation of BP.
The current study has some limitations. First, since our study is a cross sectional study, it is inherently di cult to draw conclusion about any causal relationship between level of Hb or Hct and BP. Second, it is possible to approximate the prevalence of hypertension, but it is di cult to understand the actual prevalence of HTN, because white coat HTN was not excluded. Finally, the cause of the sexual difference in the relationship between Hb or Hct and blood pressure was not fully elucidated. Periodic menstrual bleeding in girls might have in uenced the difference of results. However we have no data about pubertal status, diagnosis of anemia and menstrual loss in the present study. Subsequent prospective studies are needed to clarify the mechanisms by which blood pressure increase with increasing Hb and Hct level, and to determine the cause of sexual difference.
In conclusion, Hb and Hct levels were positively associated with SBP and DBP in Korean children and adolescent, aged 10-18 year. Both Hb and Hct levels are involved with blood pressure, and their increase could be a potential risk factor for increasing blood pressure. In particular, obesity could have a synergistic effect A total of 89,630 individuals were included. Of these subjects, 7,950 participants aged 10 to 18 years were included in the preliminary analysis. All subjects and their parents were interviewed at home after providing informed consent and underwent various examinations, including blood sampling (42). Those with incomplete records regarding the physical examination, including anthropometric measurements, blood pressure, and laboratory tests, including the lipid pro le, were excluded. Those who had high TGs ≥ 400 mg/dL were also excluded (n = 16  (43). The subjects were categorized into 3 groups according to BMI: normal weight (NW, BMI was <85th percentile), overweight (OW, BMI was ≥85th percentile and <95th percentile), and obesity (OB,BMI was ≥95th percentile).
Hypertension was de ned as sex-, age-, and height-speci c SBP or DBP equal to or greater than the 95th percentile based on the 2017 Korean reference (43) or SBP ≥130 mmHg or DBP ≥80 mmHg.
Lifestyle-related behaviors, such as alcohol consumption, smoking, household income, and residence, were assessed by means of a questionnaire. Information about alcohol consumption (drinkers vs. nondrinkers) and smoking status (smokers vs. nonsmokers) was collected with a self-administered questionnaire from subjects aged 12 years and older (42). Physical activity was used to divide subjects into two groups (yes or no), and subjects were included in the 'yes' group if they performed intense physical activity ≥20 min/day and ≥3 days/week, if they performed moderate physical activity ≥30 min/day and ≥5 days/week, or if they walked ≥30 min/day and ≥5 days/week.
Questionnaires on household income and area of residence (urban vs. rural) were administered by trained interviewers. Diagnosis of HTN, diabetes and dyslipidemia were also included in the questionnaire.
Statistical analyses R, version 3.5.1 (The R Foundation for Statistical Computing, Austria), was used for statistical analysis.
Continuous variables are expressed as mean and SD. Categorical variables are presented as number and the percentages (%). A 2-tailed t-test was performed to identify differences in clinical parameters between the boys and girls, whereas categorical variables were compared using the χ 2 test. To determine statistical signi cance, analysis of variance (ANOVA) was used for hemoglobin and hematocrit according to obesity groups. The Pearson's correlation coe cient analysis was performed to evaluate the correlation between Hb, Hct and blood pressure. Multiple linear regression was performed to investigate the relation between hemoglobin and hematocrit and blood pressure. Probability values less than .05 were considered statistically signi cant.