HHS Public Access Author manuscript Author Manuscript
Circulation. Author manuscript; available in PMC 2017 January 26. Published in final edited form as: Circulation. 2016 January 26; 133(4): 398–408. doi:10.1161/CIRCULATIONAHA.115.017936.
Establishing International Blood Pressure References Among Non-Overweight Children and Adolescents Aged 6–17 Years
Author Manuscript
Bo Xi, PhD1,*, Xin’nan Zong, MS2,*, Roya Kelishadi, MD3,*, Young Mi Hong, MD4,*, Anuradha Khadilkar, MD5,*, Lyn M. Steffen, PhD6,*, Tadeusz Nawarycz, PhD7,*, Małgorzata Krzywińska-Wiewiorowska, MD, PhD8,*, Hajer Aounallah-Skhiri, MD9,*, Pascal Bovet, MD10,*, Arnaud Chiolero, MD, PhD10,*, Haiyan Pan, PhD11,*, Mieczysław Litwin, MD, PhD12, Bee Koon Poh, MD13, Rita Y.T. Sung, MD14, Hung-Kwan So, PhD14, Peter Schwandt, MD, PhD15, Gerda-Maria Haas, MPH15, Hannelore K. Neuhauser, MD16, Lachezar Marinov, MD, PhD17, Sonya V Galcheva, MD18, Mohammad Esmaeil Motlagh, MD19, Hae Soon Kim, MD4, Vaman Khadilkar, MRCP5, Alicja Krzyżaniak, MD, PhD8, Habiba Ben Romdhane, MD20, Ramin Heshmat, MD, PhD21, Shashi Chiplonkar, PhD5, Barbara Stawińska-Witoszyńska, MD, PhD8, Jalila El Ati, PhD22, Mostafa Qorbani, PhD23, Neha Kajale, MS5, Pierre Traissac, MS24, Lidia Ostrowska-Nawarycz, MD7, Gelayol Ardalan, MD3, Lavanya Parthasarathy, MS5, Min Zhao, PhD25, and Tao Zhang, PhD26 on behalf of the International Child Blood Pressure References Establishment Consortium 1Department
Author Manuscript Author Manuscript
of Epidemiology, School of Public Health, Shandong University, Jinan, China of Growth and Development, Capital Institute of Pediatrics, Beijing, China 3Department of Pediatrics, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran 4Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea 5Growth and Endocrine Unit, Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, India 6Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 7Department of Biophysics, Chair of Experimental and Clinical Physiology, Medical University of Lodz, Lodz, Poland 8Department of Epidemiology, Poznan University of Medical Sciences, Poznan, Poland 9National Institute of Public Health (INSP), Tunis, Tunisia 10Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland 11Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical College, Dongguan, China 12Department of Nephrology and Arterial Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland 13Nutritional Sciences Programme, School of Healthcare Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia 14Department of Pediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 15Atherosclerosis Prevention Institute, Munich-Nuremberg, Germany 16Department of Epidemiology and Health Monitoring, Robert Koch Institute, Berlin, Germany and DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany 17Department of Pediatrics & Medical genetics,Varna 2Department
Correspondence: Bo Xi, MD, Department of Epidemiology, School of Public Health, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong, 250012, China, Phone: 86-531-88382141, Fax: 86-531-88382141, [email protected] or [email protected]. *contributed equally Disclosures: None.
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Medical University, Varna, Bulgaria 18Department of Pediatrics and Medical Genetics, University Hospital “St. Marina”, Varna, Bulgaria 19Department of Pediatrics, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 20Cardiovascular Epidemiology and Prevention, Research Laboratory; Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia 21Department of Epidemiology, Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran 22SURVEN (Nutrition Surveillance and Epidemiology Unit), National Institute of Nutrition and Food Technology, Tunis, Tunisia 23Department of Community Medicine, Alborz University of Medical Sciences, Karaj, Iran 24IRD (Institut de Recherche pour le Développement), UMR NUTRIPASS IRD-UM-SupAgro, Montpellier, France 25Department of Nutrition and Food Hygiene, School of Public Health, Shandong University, Jinan, China 26Department of Biostatistics, School of Public Health, Shandong University, Jinan, China
Author Manuscript
Abstract Background—Several distributions of country-specific blood pressure (BP) percentiles by sex, age and height for children and adolescents have been established worldwide. However, there are no globally unified BP references for defining elevated BP in children and adolescents, which limit international comparisons of prevalence of pediatric elevated BP. We aimed to establish international BP references for children and adolescents using seven nationally representative data (China, India, Iran, Korea, Poland, Tunisia and USA).
Author Manuscript
Methods and Results—Data on BP for 52,636 non-overweight children and adolescents aged 6–19 years were obtained from seven large nationally representative cross-sectional surveys in China, India, Iran, Korea, Poland, Tunisia, and USA. BP values were obtained with certified mercury sphygmomanometers in all seven countries, using standard procedures for BP measurement. Smoothed BP percentiles (50th, 90th, 95th and 99th) by age and height were estimated using the Generalized Additive Model for Location Scale and Shape (GAMLSS) model. BP values were similar between males and females until the age of 13 years and were higher in males than females thereafter. Compared to BP level of the 90th and 95th percentiles of the U.S. Fourth Report at median height, systolic BP of the corresponding percentiles of these international references was lower while diastolic BP was similar. Conclusions—These international BP references will be a useful tool for international comparison of the prevalence of elevated BP in children and adolescents and may help identify hypertensive youths in diverse populations.
Author Manuscript
Keywords Blood pressure; Hypertension; Percentiles; Children; Adolescents
Introduction Elevated blood pressure (BP) in children and adolescents is a public health concern worldwide,1 notably because of obesity epidemic and high salt intake.2 Elevated BP in children and adolescents is associated with target organ damage3. In addition, elevated BP in
Circulation. Author manuscript; available in PMC 2017 January 26.
Xi et al.
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childhood moderately tracks into adulthood4 which in turn increases the risk of subclinical atherosclerosis among adults.5 Hence, decreasing the level of BP in children and adolescents could help reduce the risk of elevated BP related diseases in both childhood and adulthood. BP measurement in children above 3 years of age in the course of routine healthcare is currently recommended by several prominent medical organizations in Europe and the U.S.6–8 Screening programs require that elevated BP is well defined in children and adolescents. In adult populations, the definition of hypertension is based on the relation between BP and subsequent development of CVD, renal or other related events. However, since it is difficult to assess events related to elevated BP in children and adolescents because of generally long time lag between exposure and outcomes,9 elevated BP in children and adolescents is usually defined based on the distribution of BP in a reference population. It is generally considered that children and adolescents have elevated BP if their BP values are in the upper range of the distribution (e.g., hypertension if BP above the 95th percentile). 6, 10 In 2004, the US Fourth Report recommended that pre-hypertension and hypertension should be defined based on the age-, sex- and height- specific 90th and 95th BP percentiles in the US youths, using data collected between 1973 and 2000 6. These US references are widely used in US and European countries.2, 5, 7 However, there are several limitations for the establishment of BP percentiles from the Fourth Report, such as included overweight youths, data collection spanned a large time period, and used data with the first BP reading only. Of note, several studies confirmed that the inclusion of overweight/obese children would, as expected, raise the cut-off points for elevated BP.11–15 Although several country-specific BP percentiles for children and adolescents have been established worldwide,11–17 there is no globally unified BP reference for defining elevated BP in children and adolescents, which limits international comparisons of the prevalence of pediatric elevated BP between countries and regions.
Author Manuscript Author Manuscript
In this study, we aimed to develop international BP percentiles by sex-, age-, and height among 52,636 non-overweight children and adolescents aged 6–19 years who had standardized BP measurements with a mercury sphygmomanometer, using nationally representative datasets from seven countries (China18, India19, Iran20, 21, Korea22, Poland23, Tunisia24 and USA2). In addition, we compared BP percentiles in our study with values from the U.S. Fourth Report and the updated US references by sex and age at median height (according to the WHO growth charts 25).
Methods Study population
Author Manuscript
Data on BP for 52,636 non-overweight children and adolescents aged 6–19 years were obtained from seven large nationally representative cross-sectional surveys in China, India, Iran, Korea, Poland, Tunisia and USA (Table 1). The characteristics of the participants in each survey have been described in detail elsewhere.2, 18–24 The prevalence of overweight and obesity in the whole sample of each survey is shown in Supplemental Table 1. Overweight and obese status was assessed based on age- and sex-specific BMI percentiles as recommended by the International Obesity Task Force.26 Since the inclusion of overweight or obese subjects would raise the threshold for normal BP, we excluded overweight/obese
Circulation. Author manuscript; available in PMC 2017 January 26.
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children from the reference population. After exclusion of 13,598 overweight/obese children, the final data included a total of 52,636 children and adolescents aged 6–19 years, with the sample sizes of the seven surveys ranging from 2,416 to 14,844. Three (India, Poland and Tunisia) of the seven national datasets were based on a single cross-sectional survey while data from China, Iran, Korea and USA included pooled samples from several continuous cross-sectional surveys. All participants were healthy with no genetic diseases and acute or serious chronic diseases. Written informed consent had been obtained from parents and/or children and adolescents in each national survey. Each survey had been approved by their respective Institutional Ethics Review Board. Measurements
Author Manuscript Author Manuscript
In all seven counties, BP values were obtained with certified mercury sphygmomanometers by trained examiners following the standard protocol recommended by the AHA.27 In brief, after at least 5 minutes of rest, BP was obtained on the right arm of the seated children with the elbow at the level of the right atrium, using an appropriately sized cuff. The feet of children were on a platform during BP measurement. SBP was determined by the onset of the first Korotkoff sound (i.e., appearance of tones) and DBP was determined by the fifth Korotkoff sound (i.e., total disappearance of tones). BP was measured up to three times on one occasion, at several min intervals. Children with DBP values equal to zero mmHg were excluded in all datasets before the data analysis. For five countries (China, India, Korea, Poland and USA), participants had three separate BP values were included, and the mean of the last two readings was used for our analysis; for the other two countries (Iran and Tunisia), only two readings were available and the averaged BP value was used for our analysis. Weight and height were recorded for each individual in light clothing without shoes. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Statistical analysis
Author Manuscript
The datasets from each country were weighted according to population size (when analyzing the individual countries, we weighted the included studies by study size; then the data from countries were combined by weighted population size) 28. We estimated SBP and DBP centile curves for non-overweight children and adolescents by age, sex and height using the Generalized Additive Model for Location Scale and Shape (GAMLSS) model for the BoxCox power exponential (BCPE) or Box-Cox t (BCT) distribution with cubic spline smoothing.29 Both distributions have four parameters including μ, σ, ν, and τ which represent location (median), scale (approximate coefficient of variation), skewness (power transformation to symmetry) and kurtosis (degrees of freedom or power exponential parameter), respectively. Data analyses were performed using the GAMLSS 4.3-1 library running under R 3.1.2.30 Goodness of fit of the models was assessed by the Bayesian Information Criterion and by Q-Q plots31. The final best models were based on the BCT distribution for SBP in males and females and on the BCPE distribution for DBP in males and females, in consideration of the additive effects of the functions of age and height as well as their multiplicative effects on SBP and DBP under two distributions. With regard to SBP, log(μ) for males and females were modeled as a smooth function of age (df=0.8) and a linear function of height for males and as a linear function of age and height for females. Circulation. Author manuscript; available in PMC 2017 January 26.
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With regard to DBP, log(μ) for males and females were modeled as a linear function of age and height for males and as a linear function of age and a smooth function of height (df=0.2) for females. For both SBP and DBP, log(σ) was considered as a linear function of age and ν and log(τ) as a constant for both sexes. Smoothed country-specific median SBP and DBP curves for age and height were modeled simultaneously to examine the average difference in SBP/DBP between seven countries at median height derived from seven pooled data.28 The reference values of SBP and DBP percentiles (50th, 90th, 95th and 99th) were computed by the age and height percentiles recommended by the WHO25 (5th, 10th, 25th, 50th, 75th, 90th and 95th) for boys and girls, separately. The SBP and DBP percentile values (50th, 90th, 95th and 99th) in our study were compared with the percentile values reported in the U.S. Fourth Report6 as well as with the updated U.S. BP reference values after excluding overweight/ obese children (https://sites.google.com/a/channing.harvard.edu/bernardrosner/pediatricblood-press) 11 at median height (as recommended by the WHO25).
Author Manuscript
Results A total of 52,636 non-overweight children and adolescents aged 6–19 years were included in the final data analysis. As shown in Table 1, children aged 6–9 years in China, India, Iran and Poland had similar mean values of weight, height and BMI; children aged 10–14 years in USA and Korea had higher values than in China, India, Iran and Poland; adolescents aged 15–19 years had similar BMI values in all seven countries but adolescents in USA, Poland and Korea had higher height than in the other four countries. However, because each country collected data in different years, comparisons should be made with caution.
Author Manuscript
Supplemental Figure 1 shows the median SBP and DBP at median height (derived from mixed data of the seven countries by GAMLSS) by age and sex for non-overweight children and adolescents aged 6–19 years in the seven nationally representative datasets. The median BP curves show similar shapes, although some differences exist, for both sexes, between the studies especially for median DBP curves. Overall, for median SBP, Poland had the highest values for both sexes at a given age, while Korea, Iran and China had the lowest values. For median DBP, India had the highest values for both sexes, while USA had the lowest values. Finally, the international BP percentiles were obtained after weighting the fitted countryspecific distributions according to population size since the trends of BP curves by age were similar in all the datasets.
Author Manuscript
Tables 2 and 3 show the smoothed BP percentiles (50th, 90th, 95th, 99th) for non-overweight children and adolescents by age and height. Height in centimeters for each age represents the 5th, 10th, 25th, 50th, 75th, 90th, 95th percentiles as recommended by the WHO.25 SBP and DBP values were similar in males and females until 13 years of age, while males had higher BP values than females at age 14 years and older. In addition, BP values increased with height percentiles (from 5th percentile to 95th percentile) at a given age for both sexes. We then compared our BP percentiles with the U.S. percentiles from the Fourth Report by sex and age at median height (according to the WHO growth charts 25) (Figure 1).The 90th and 95th percentiles of SBP were lower in our data than those in the U.S. while the 90th and 95th percentiles of DBP were similar. For example, differences for the 95th percentile of
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SBP (our BP values minus the U.S. values) by age ranged from −5 to −2 mmHg in males and −4 to −1 mmHg in females. In addition, we compared the difference in the 90th and 95th BP percentile between our references and the updated U.S. references (a re-analysis of the US Fourth Report data after excluding overweight/obese children) at median height (WHO) (Figure 2). The 90th and 95th percentile values of SBP were similar until age of 13 years and they were lower in our international values than in the updated U.S. references at age 14 years and older (by age ranging from −3 to −1 mmHg for both percentiles). For the 90th and 95th percentiles of DBP, our international values were somewhat higher than values in the updated U.S. references (by age ranging from 1 to 2 mmHg for both percentiles).
Discussion Author Manuscript
To our knowledge, this is the first study to present BP percentiles by sex, age, and height using mixed data consisting of ≥ 50,000 youths with non-overweight from seven countries. Compared to the percentiles of the U.S. Fourth Report at median height, the 90th and 95th percentiles of our international references were lower for SBP but similar for DBP. Consistent with cut-offs for elevated BP categories in children and adolescents in other guidelines,6 we suggest that BP percentile values from our study could be used to define pre high BP (SBP/DBP ≥ 90th percentile and
Circulation. Author manuscript; available in PMC 2017 January 26. Published in final edited form as: Circulation. 2016 January 26; 133(4): 398–408. doi:10.1161/CIRCULATIONAHA.115.017936.
Establishing International Blood Pressure References Among Non-Overweight Children and Adolescents Aged 6–17 Years
Author Manuscript
Bo Xi, PhD1,*, Xin’nan Zong, MS2,*, Roya Kelishadi, MD3,*, Young Mi Hong, MD4,*, Anuradha Khadilkar, MD5,*, Lyn M. Steffen, PhD6,*, Tadeusz Nawarycz, PhD7,*, Małgorzata Krzywińska-Wiewiorowska, MD, PhD8,*, Hajer Aounallah-Skhiri, MD9,*, Pascal Bovet, MD10,*, Arnaud Chiolero, MD, PhD10,*, Haiyan Pan, PhD11,*, Mieczysław Litwin, MD, PhD12, Bee Koon Poh, MD13, Rita Y.T. Sung, MD14, Hung-Kwan So, PhD14, Peter Schwandt, MD, PhD15, Gerda-Maria Haas, MPH15, Hannelore K. Neuhauser, MD16, Lachezar Marinov, MD, PhD17, Sonya V Galcheva, MD18, Mohammad Esmaeil Motlagh, MD19, Hae Soon Kim, MD4, Vaman Khadilkar, MRCP5, Alicja Krzyżaniak, MD, PhD8, Habiba Ben Romdhane, MD20, Ramin Heshmat, MD, PhD21, Shashi Chiplonkar, PhD5, Barbara Stawińska-Witoszyńska, MD, PhD8, Jalila El Ati, PhD22, Mostafa Qorbani, PhD23, Neha Kajale, MS5, Pierre Traissac, MS24, Lidia Ostrowska-Nawarycz, MD7, Gelayol Ardalan, MD3, Lavanya Parthasarathy, MS5, Min Zhao, PhD25, and Tao Zhang, PhD26 on behalf of the International Child Blood Pressure References Establishment Consortium 1Department
Author Manuscript Author Manuscript
of Epidemiology, School of Public Health, Shandong University, Jinan, China of Growth and Development, Capital Institute of Pediatrics, Beijing, China 3Department of Pediatrics, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran 4Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea 5Growth and Endocrine Unit, Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, India 6Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 7Department of Biophysics, Chair of Experimental and Clinical Physiology, Medical University of Lodz, Lodz, Poland 8Department of Epidemiology, Poznan University of Medical Sciences, Poznan, Poland 9National Institute of Public Health (INSP), Tunis, Tunisia 10Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland 11Department of Epidemiology and Health Statistics, School of Public Health, Guangdong Medical College, Dongguan, China 12Department of Nephrology and Arterial Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland 13Nutritional Sciences Programme, School of Healthcare Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia 14Department of Pediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 15Atherosclerosis Prevention Institute, Munich-Nuremberg, Germany 16Department of Epidemiology and Health Monitoring, Robert Koch Institute, Berlin, Germany and DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany 17Department of Pediatrics & Medical genetics,Varna 2Department
Correspondence: Bo Xi, MD, Department of Epidemiology, School of Public Health, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong, 250012, China, Phone: 86-531-88382141, Fax: 86-531-88382141, [email protected] or [email protected]. *contributed equally Disclosures: None.
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Medical University, Varna, Bulgaria 18Department of Pediatrics and Medical Genetics, University Hospital “St. Marina”, Varna, Bulgaria 19Department of Pediatrics, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 20Cardiovascular Epidemiology and Prevention, Research Laboratory; Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia 21Department of Epidemiology, Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran 22SURVEN (Nutrition Surveillance and Epidemiology Unit), National Institute of Nutrition and Food Technology, Tunis, Tunisia 23Department of Community Medicine, Alborz University of Medical Sciences, Karaj, Iran 24IRD (Institut de Recherche pour le Développement), UMR NUTRIPASS IRD-UM-SupAgro, Montpellier, France 25Department of Nutrition and Food Hygiene, School of Public Health, Shandong University, Jinan, China 26Department of Biostatistics, School of Public Health, Shandong University, Jinan, China
Author Manuscript
Abstract Background—Several distributions of country-specific blood pressure (BP) percentiles by sex, age and height for children and adolescents have been established worldwide. However, there are no globally unified BP references for defining elevated BP in children and adolescents, which limit international comparisons of prevalence of pediatric elevated BP. We aimed to establish international BP references for children and adolescents using seven nationally representative data (China, India, Iran, Korea, Poland, Tunisia and USA).
Author Manuscript
Methods and Results—Data on BP for 52,636 non-overweight children and adolescents aged 6–19 years were obtained from seven large nationally representative cross-sectional surveys in China, India, Iran, Korea, Poland, Tunisia, and USA. BP values were obtained with certified mercury sphygmomanometers in all seven countries, using standard procedures for BP measurement. Smoothed BP percentiles (50th, 90th, 95th and 99th) by age and height were estimated using the Generalized Additive Model for Location Scale and Shape (GAMLSS) model. BP values were similar between males and females until the age of 13 years and were higher in males than females thereafter. Compared to BP level of the 90th and 95th percentiles of the U.S. Fourth Report at median height, systolic BP of the corresponding percentiles of these international references was lower while diastolic BP was similar. Conclusions—These international BP references will be a useful tool for international comparison of the prevalence of elevated BP in children and adolescents and may help identify hypertensive youths in diverse populations.
Author Manuscript
Keywords Blood pressure; Hypertension; Percentiles; Children; Adolescents
Introduction Elevated blood pressure (BP) in children and adolescents is a public health concern worldwide,1 notably because of obesity epidemic and high salt intake.2 Elevated BP in children and adolescents is associated with target organ damage3. In addition, elevated BP in
Circulation. Author manuscript; available in PMC 2017 January 26.
Xi et al.
Page 3
Author Manuscript
childhood moderately tracks into adulthood4 which in turn increases the risk of subclinical atherosclerosis among adults.5 Hence, decreasing the level of BP in children and adolescents could help reduce the risk of elevated BP related diseases in both childhood and adulthood. BP measurement in children above 3 years of age in the course of routine healthcare is currently recommended by several prominent medical organizations in Europe and the U.S.6–8 Screening programs require that elevated BP is well defined in children and adolescents. In adult populations, the definition of hypertension is based on the relation between BP and subsequent development of CVD, renal or other related events. However, since it is difficult to assess events related to elevated BP in children and adolescents because of generally long time lag between exposure and outcomes,9 elevated BP in children and adolescents is usually defined based on the distribution of BP in a reference population. It is generally considered that children and adolescents have elevated BP if their BP values are in the upper range of the distribution (e.g., hypertension if BP above the 95th percentile). 6, 10 In 2004, the US Fourth Report recommended that pre-hypertension and hypertension should be defined based on the age-, sex- and height- specific 90th and 95th BP percentiles in the US youths, using data collected between 1973 and 2000 6. These US references are widely used in US and European countries.2, 5, 7 However, there are several limitations for the establishment of BP percentiles from the Fourth Report, such as included overweight youths, data collection spanned a large time period, and used data with the first BP reading only. Of note, several studies confirmed that the inclusion of overweight/obese children would, as expected, raise the cut-off points for elevated BP.11–15 Although several country-specific BP percentiles for children and adolescents have been established worldwide,11–17 there is no globally unified BP reference for defining elevated BP in children and adolescents, which limits international comparisons of the prevalence of pediatric elevated BP between countries and regions.
Author Manuscript Author Manuscript
In this study, we aimed to develop international BP percentiles by sex-, age-, and height among 52,636 non-overweight children and adolescents aged 6–19 years who had standardized BP measurements with a mercury sphygmomanometer, using nationally representative datasets from seven countries (China18, India19, Iran20, 21, Korea22, Poland23, Tunisia24 and USA2). In addition, we compared BP percentiles in our study with values from the U.S. Fourth Report and the updated US references by sex and age at median height (according to the WHO growth charts 25).
Methods Study population
Author Manuscript
Data on BP for 52,636 non-overweight children and adolescents aged 6–19 years were obtained from seven large nationally representative cross-sectional surveys in China, India, Iran, Korea, Poland, Tunisia and USA (Table 1). The characteristics of the participants in each survey have been described in detail elsewhere.2, 18–24 The prevalence of overweight and obesity in the whole sample of each survey is shown in Supplemental Table 1. Overweight and obese status was assessed based on age- and sex-specific BMI percentiles as recommended by the International Obesity Task Force.26 Since the inclusion of overweight or obese subjects would raise the threshold for normal BP, we excluded overweight/obese
Circulation. Author manuscript; available in PMC 2017 January 26.
Xi et al.
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children from the reference population. After exclusion of 13,598 overweight/obese children, the final data included a total of 52,636 children and adolescents aged 6–19 years, with the sample sizes of the seven surveys ranging from 2,416 to 14,844. Three (India, Poland and Tunisia) of the seven national datasets were based on a single cross-sectional survey while data from China, Iran, Korea and USA included pooled samples from several continuous cross-sectional surveys. All participants were healthy with no genetic diseases and acute or serious chronic diseases. Written informed consent had been obtained from parents and/or children and adolescents in each national survey. Each survey had been approved by their respective Institutional Ethics Review Board. Measurements
Author Manuscript Author Manuscript
In all seven counties, BP values were obtained with certified mercury sphygmomanometers by trained examiners following the standard protocol recommended by the AHA.27 In brief, after at least 5 minutes of rest, BP was obtained on the right arm of the seated children with the elbow at the level of the right atrium, using an appropriately sized cuff. The feet of children were on a platform during BP measurement. SBP was determined by the onset of the first Korotkoff sound (i.e., appearance of tones) and DBP was determined by the fifth Korotkoff sound (i.e., total disappearance of tones). BP was measured up to three times on one occasion, at several min intervals. Children with DBP values equal to zero mmHg were excluded in all datasets before the data analysis. For five countries (China, India, Korea, Poland and USA), participants had three separate BP values were included, and the mean of the last two readings was used for our analysis; for the other two countries (Iran and Tunisia), only two readings were available and the averaged BP value was used for our analysis. Weight and height were recorded for each individual in light clothing without shoes. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Statistical analysis
Author Manuscript
The datasets from each country were weighted according to population size (when analyzing the individual countries, we weighted the included studies by study size; then the data from countries were combined by weighted population size) 28. We estimated SBP and DBP centile curves for non-overweight children and adolescents by age, sex and height using the Generalized Additive Model for Location Scale and Shape (GAMLSS) model for the BoxCox power exponential (BCPE) or Box-Cox t (BCT) distribution with cubic spline smoothing.29 Both distributions have four parameters including μ, σ, ν, and τ which represent location (median), scale (approximate coefficient of variation), skewness (power transformation to symmetry) and kurtosis (degrees of freedom or power exponential parameter), respectively. Data analyses were performed using the GAMLSS 4.3-1 library running under R 3.1.2.30 Goodness of fit of the models was assessed by the Bayesian Information Criterion and by Q-Q plots31. The final best models were based on the BCT distribution for SBP in males and females and on the BCPE distribution for DBP in males and females, in consideration of the additive effects of the functions of age and height as well as their multiplicative effects on SBP and DBP under two distributions. With regard to SBP, log(μ) for males and females were modeled as a smooth function of age (df=0.8) and a linear function of height for males and as a linear function of age and height for females. Circulation. Author manuscript; available in PMC 2017 January 26.
Xi et al.
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With regard to DBP, log(μ) for males and females were modeled as a linear function of age and height for males and as a linear function of age and a smooth function of height (df=0.2) for females. For both SBP and DBP, log(σ) was considered as a linear function of age and ν and log(τ) as a constant for both sexes. Smoothed country-specific median SBP and DBP curves for age and height were modeled simultaneously to examine the average difference in SBP/DBP between seven countries at median height derived from seven pooled data.28 The reference values of SBP and DBP percentiles (50th, 90th, 95th and 99th) were computed by the age and height percentiles recommended by the WHO25 (5th, 10th, 25th, 50th, 75th, 90th and 95th) for boys and girls, separately. The SBP and DBP percentile values (50th, 90th, 95th and 99th) in our study were compared with the percentile values reported in the U.S. Fourth Report6 as well as with the updated U.S. BP reference values after excluding overweight/ obese children (https://sites.google.com/a/channing.harvard.edu/bernardrosner/pediatricblood-press) 11 at median height (as recommended by the WHO25).
Author Manuscript
Results A total of 52,636 non-overweight children and adolescents aged 6–19 years were included in the final data analysis. As shown in Table 1, children aged 6–9 years in China, India, Iran and Poland had similar mean values of weight, height and BMI; children aged 10–14 years in USA and Korea had higher values than in China, India, Iran and Poland; adolescents aged 15–19 years had similar BMI values in all seven countries but adolescents in USA, Poland and Korea had higher height than in the other four countries. However, because each country collected data in different years, comparisons should be made with caution.
Author Manuscript
Supplemental Figure 1 shows the median SBP and DBP at median height (derived from mixed data of the seven countries by GAMLSS) by age and sex for non-overweight children and adolescents aged 6–19 years in the seven nationally representative datasets. The median BP curves show similar shapes, although some differences exist, for both sexes, between the studies especially for median DBP curves. Overall, for median SBP, Poland had the highest values for both sexes at a given age, while Korea, Iran and China had the lowest values. For median DBP, India had the highest values for both sexes, while USA had the lowest values. Finally, the international BP percentiles were obtained after weighting the fitted countryspecific distributions according to population size since the trends of BP curves by age were similar in all the datasets.
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Tables 2 and 3 show the smoothed BP percentiles (50th, 90th, 95th, 99th) for non-overweight children and adolescents by age and height. Height in centimeters for each age represents the 5th, 10th, 25th, 50th, 75th, 90th, 95th percentiles as recommended by the WHO.25 SBP and DBP values were similar in males and females until 13 years of age, while males had higher BP values than females at age 14 years and older. In addition, BP values increased with height percentiles (from 5th percentile to 95th percentile) at a given age for both sexes. We then compared our BP percentiles with the U.S. percentiles from the Fourth Report by sex and age at median height (according to the WHO growth charts 25) (Figure 1).The 90th and 95th percentiles of SBP were lower in our data than those in the U.S. while the 90th and 95th percentiles of DBP were similar. For example, differences for the 95th percentile of
Circulation. Author manuscript; available in PMC 2017 January 26.
Xi et al.
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SBP (our BP values minus the U.S. values) by age ranged from −5 to −2 mmHg in males and −4 to −1 mmHg in females. In addition, we compared the difference in the 90th and 95th BP percentile between our references and the updated U.S. references (a re-analysis of the US Fourth Report data after excluding overweight/obese children) at median height (WHO) (Figure 2). The 90th and 95th percentile values of SBP were similar until age of 13 years and they were lower in our international values than in the updated U.S. references at age 14 years and older (by age ranging from −3 to −1 mmHg for both percentiles). For the 90th and 95th percentiles of DBP, our international values were somewhat higher than values in the updated U.S. references (by age ranging from 1 to 2 mmHg for both percentiles).
Discussion Author Manuscript
To our knowledge, this is the first study to present BP percentiles by sex, age, and height using mixed data consisting of ≥ 50,000 youths with non-overweight from seven countries. Compared to the percentiles of the U.S. Fourth Report at median height, the 90th and 95th percentiles of our international references were lower for SBP but similar for DBP. Consistent with cut-offs for elevated BP categories in children and adolescents in other guidelines,6 we suggest that BP percentile values from our study could be used to define pre high BP (SBP/DBP ≥ 90th percentile and
