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a Lifespan Health Research Center, Department of Community Health
c Department of Pediatrics, Wright State University Boonshoft School of Medicine, Dayton, Ohio
b National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
d Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
e Department of Pediatrics, University of Colorado, School of Medicine, Denver, Colorado
| ABSTRACT |
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METHODS. We analyzed serial data for 240 men and 253 women in the Fels Longitudinal Study. We derived age- and gender-specific childhood blood pressures that predict hypertension and the metabolic syndrome in adulthood, and we validated these criterion values in a larger sample.
RESULTS. Blood pressure diverged between adults with and without the metabolic syndrome beginning at age 5 for boys and age 8 for girls. The odds ratios for developing hypertension at
30 years of age ranged from 1.1 for 14- to 18-year-old boys to 3.8 for 5- to 7-year-old boys and from 2.7 for 8- to 13-year-old girls to 4.5 for 5- to 7-year-old girls, if their blood pressure exceeded criterion values at a single examination in childhood. The corresponding odds ratios for the metabolic syndrome, with or without hypertension, ranged from 1.2 for 14- to 18-year-old boys to 2.6 for 8- to 13-year-old boys and from 1.5 for 14- to 18-year-old girls to 3.1 for 5- to 7-year-old girls. The relative risk of adult hypertension ranged from 1.5 to 3.8 for boys and from 1.5 to 4.7 for girls, and that of the metabolic syndrome ranged from 1.1 to 1.8 for boys and from 1.2 to 5.6 for girls. These relative risks varied directly with the number of examinations at which systolic blood pressure exceeded criterion values.
CONCLUSION. Children with systolic blood pressures above the criterion values established in this longitudinal study are at increased risk of hypertension and the metabolic syndrome later in life.
Key Words: childhood blood pressure adult hypertension metabolic syndrome
Abbreviations: NCEPNational Cholesterol Education Program ATP IIIAdult Treatment Panel III NHANESNational Health and Nutrition Examination Survey EBPelevated blood pressure ROCreceiver operating characteristic HDLhigh-density lipoprotein
The cluster of dyslipidemia, hypertension, and glucose intolerance defines the metabolic syndrome1 in adults and predicts the development of type 2 diabetes and cardiovascular disease.24 The third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) redefines this syndrome by including waist circumference as a proxy measure for visceral fat accumulation.5 The ATP III further defines the metabolic syndrome in adults as a cluster of 3, 4, or 5 risk factors that exceed criterion values, that is, waist circumference of >102 cm for men or >88 cm for women; systolic blood pressure of >130 mm Hg and/or diastolic blood pressure of >85 mm Hg; fasting plasma triglyceride level of >150 mg/dL; fasting plasma high-density lipoprotein (HDL) cholesterol level of <40 mg/dL for men or <50 mg/dL for women; and fasting plasma glucose level of >110 mg/dL.6 In 2003, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus recommended lowering the criterion for impaired fasting plasma glucose levels to 100 mg/dL.7 There are 16 possible clusters of the 5 risk factors combined in 3, 4, or 5 ways, including 10 triads, 5 tetrads, and 1 pentad. Four of these triads and 1 tetrad do not include elevated blood pressure (EBP). Among the participants in the Fels Longitudinal Study who meet the ATP III criteria for diagnosis of the metabolic syndrome, the most commonly encountered diagnostic triad for both men and women, namely, increased waist circumference, low fasting plasma HDL cholesterol level, and elevated fasting plasma triglyceride level, does not include EBP.
Currently, there is no agreement regarding the definition of the metabolic syndrome in children or adolescents. Several investigators have selected various criterion values to estimate the prevalence of the metabolic syndrome in children and adolescents, on the basis of absolute values of fasting plasma triglyceride levels, fasting plasma HDL cholesterol levels, and fasting plasma glucose levels, coupled with age- and gender-specific
90th percentile values for waist circumference and blood pressure from National Health and Nutrition Examination Survey (NHANES) III.810 However, it is more informative to link the adult metabolic syndrome directly to childhood risk factors in the same individuals, to establish criterion values according to age and gender that are associated with metabolic and cardiovascular health later in life.
Significant tracking of obesity and blood pressure from childhood into adulthood has been observed,1113 and the onset of obesity and hypertension often begins in childhood.14 However, little is known about the accuracy of age- and gender-specific cutoff values for blood pressure in childhood for predicting hypertension (defined as systolic blood pressure of >130 mm Hg and/or diastolic blood pressure of >85 mm Hg) and the metabolic syndrome later in life, because of the paucity of serial data collected for the same individuals over several decades. Lacking such serial data, earlier studies were not capable of ascertaining the age in childhood when values for risk factors diverge between subjects who develop hypertension or the metabolic syndrome in adulthood and those who do not.
The present study identifies the earliest age of divergence of blood pressure in childhood among adults with the metabolic syndrome and age- and gender-matched adults without the metabolic syndrome. The present study also establishes age- and gender-specific criterion values of childhood blood pressure for predicting hypertension and the metabolic syndrome later in life and validates the predictiveness of these childhood criterion values independent of the effects of age when the metabolic syndrome was first diagnosed and independent of childhood BMI.
| METHODS |
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20 years of age at the time of analysis. The 493 participants included 240 men and 253 women who have been monitored since birth and have had serial blood pressure readings recorded from age 2 into adulthood.15 Childhood measurements for these participants included weight; height; skinfold thicknesses; waist, arm, and leg circumferences; and blood pressure. These data were recorded during examinations at birth, at 1, 3, 6, 9, and 12 months, every 6 months to 18 years, and every 2 years thereafter. Additional measurements were added to the examination protocol when these participants turned 8 years of age, including hydrodensitometry, dual-energy x-ray absorptiometry, fasting plasma lipid and lipoprotein measurements, fasting plasma glucose measurement, and fasting plasma insulin measurement. Approximately 8% of Fels Longitudinal Study participants have been lost to follow-up monitoring, but their anthropometric, metabolic, and cardiovascular data at the last visit did not differ from those of the 92% who remain in the study. There are 2 parts to this study. Part 1 is a retrospective cohort study of a discovery sample of 149 subjects (90 men and 59 women; 50 ± 15 years and 49 ± 16 years of age, respectively) within the Fels Longitudinal Study population who met the NCEP ATP III criteria for the metabolic syndrome and 149 randomly selected men and women within the Fels Longitudinal Study population, matched for age and gender, who did not meet the ATP III criteria for the metabolic syndrome.
Of the 149 subjects with the metabolic syndrome 24 were excluded because they were missing data for birth weight. Of the 149 subjects without the metabolic syndrome, 11 were excluded because they also were missing data for birth weight. The remaining subjects included 125 with the metabolic syndrome (75 men and 50 women) and 138 without the metabolic syndrome (83 men and 55 women). The 263 subjects had been examined an average of 37 times each during their years of participation in the Fels Longitudinal Study. Data from these 263 subjects were used to identify the age in childhood when blood pressure diverges between adults with and without the metabolic syndrome and to establish age- and gender-specific criterion values for blood pressures in childhood that predict the metabolic syndrome in adulthood.
In part 2, we validated the accuracy of the age- and gender-specific criterion values for blood pressure in childhood that we derived in part 1 in predicting hypertension and the metabolic syndrome later in life. We reviewed childhood blood pressure data in the validation sample of all 493 subjects to determine whether their blood pressures at any time in childhood exceeded the age- and gender-specific criterion values established in part 1. We then ascertained the prevalence of hypertension and the metabolic syndrome, with or without hypertension, in the 493 subjects. We found that 118 of the 240 men and 86 of the 253 women had hypertension and 89 of the 240 men and 80 of the 253 women had the metabolic syndrome, with or without hypertension.
A flowchart depicting the origin of the discovery sample in part 1 is shown in Fig 1. The validation sample in part 2 included all 493 subjects in the original total sample.
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Birth weights were obtained from hospital records. We assessed bone age, with the Fels Longitudinal Study method, from hand-wrist radiographs obtained at each annual visit.16 Relative bone age (bone age minus chronological age) was used as a proxy for biological maturity. A positive relative bone age indicates accelerated maturity, which may hasten the appearance of risk factors in childhood for the metabolic syndrome later in life. All procedures were approved by the institutional review board of Wright State University, and all participants provided written consent to join the Fels Longitudinal Study.
Statistical Analyses
Part 1: Discovery Sample Analysis
A random-effects model was used to analyze the complete set of serial data simultaneously.17 The model imputed missing values and included measurements made at various time intervals, as well as time-varying covariates, such as relative bone age, and nontime-varying covariates, such as birth weight. The random-effects model can be expressed as yijk = µ +
i + ßj +
ij +
ijxijk +
ijk,where yijk is the dependent variable (ie, serial childhood blood pressure), i denotes the group variable (adults with metabolic syndrome versus adults with nonmetabolic syndrome), j denotes the subject, k denotes the within-subject factor (age), xijk represents the covariates of birth weight and relative bone age,
ijk is an error term, and
ij is the age at which the dependent variable differs significantly between the groups with and without the metabolic syndrome.
Annual age- and gender-specific least-squares means and SEs were estimated from the fitted random-effects models for blood pressure with adjustment for relative bone age and birth weight. The age- and gender-specific least-squares means were chosen as criterion values for blood pressures in childhood that were associated with hypertension and the metabolic syndrome in adulthood.
Part 2: Validation Sample Analysis
Because blood pressure increases with age during childhood and adolescence in a curvilinear, rather than in a linear, manner, we divided the childhood systolic blood pressure data for the 493 subjects in the validation sample into 3 age intervals (57 years, 813 years, and 1418 years of age). These 3 age intervals were chosen to reflect age-blood pressure interactions during the prepubertal, pubertal, and postpubertal years. We used logistic regression analysis to relate the first appearance of hypertension or the metabolic syndrome, with or without hypertension, at
30 years of age to 3 childhood predictors, that is, BMI; EBP, defined as a single mean elevated systolic blood pressure that exceeded age- and gender-specific criteria established in part 1 at any examination within 1 of the 3 age intervals; and recurring EBP, expressed as the proportion of examinations within an age interval in childhood at which systolic blood pressure exceeded criterion values established in part 1. Logistic models were used for the 2 dependent variables, that is, adulthood hypertension and the metabolic syndrome, with or without hypertension. We analyzed the effects of childhood EBP on hypertension and the metabolic syndrome, with or without hypertension, independent of contemporaneous BMI and independent of the age at which hypertension was first diagnosed. The effects of recurrent EBP in childhood on hypertension and the metabolic syndrome, with or without hypertension, in adulthood were also examined independent of contemporaneous BMI values and the age at which hypertension was first diagnosed. Analyses were performed with SAS software (version 9.0.1; SAS Institute, Cary, NC).
| RESULTS |
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Birth weight did not exert a significant effect on childhood systolic or diastolic blood pressure in boys or girls. Among children of the same ages, advanced bone age was associated with significantly higher systolic blood pressures of 1.9 mm Hg per year of advancement for boys and 1.5 mm Hg per year of advancement for girls (P < .05). Advanced bone age was also associated with a significantly higher diastolic blood pressure of 1.3 mm Hg per year of advancement for girls (P < .05) and with a nonsignificantly higher diastolic blood pressure of 0.4 mm Hg per year of advancement for boys.
Part 2
Adult Hypertension
The sample characteristics for the 89 men and 80 women who met the NCEP ATP III criteria for the metabolic syndrome and for the 151 men and 173 women in the Fels Longitudinal Study sample who did not meet the ATP III criteria are presented in Table 3. Table 4 presents the results of a logistic model used to predict hypertension in adulthood. The accuracy of the prediction was evaluated by using a receiver operating characteristic (ROC) curve (Fig 3). A ROC curve is a plot of the true-positive rate (sensitivity) versus the false-positive rate (1 specificity). The closer the curve is to the top-left border of the ROC space, the more accurate the logistic model is. The closer the curve is to the 45° diagonal of the ROC space, the less accurate the model is. The area under the curve is denoted as the c statistic and is a measure of predictive accuracy. The c statistics were 0.86 for male subjects and 0.91 to 0.93 for female subjects, which indicates excellent predictive accuracy for both genders. The high c statistics demonstrate the ability of the criterion values for childhood blood pressure established in part 1 to predict correctly the children who will become hypertensive as adults and those who will not.
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30 years of age for 5- to 18-year-old girls and 5- to 12-year-old boys with mean systolic blood pressure at any examination within an age interval that exceeded age- and gender-specific criterion values were 3 to 4 times greater than those for girls and boys in the same age intervals whose blood pressure measurements never exceeded these criterion values (Table 5).
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| DISCUSSION |
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The age- and gender-specific criterion values we established in part 1 predicted hypertension and the metabolic syndrome, with or without hypertension, later in life. The relative risk of adult hypertension for children with repeated measurements of systolic blood pressure exceeding criterion values was greater for 5- to 7-year-old children than for older children and adolescents. This observation suggests that prevention of adult hypertension should begin as early as 5 years of age and that prevention and intervention programs may be more effective for 5- to 7-year-old children than for older children.
Although blood pressure has been found to be elevated in association with increased BMI in childhood,19 in this study we found that childhood BMI values did not contribute significantly to adult hypertension or the metabolic syndrome independent of childhood blood pressure. In the present study sample, the age-specific correlations between BMI and systolic blood pressure ranged from 0.26 to 0.48 for boys and from 0.20 to 0.56 for girls, and increases in childhood BMI of 1 kg/m2 resulted in average increases in systolic blood pressure of 1.0 ± 0.2 mm Hg for boys and 0.8 ± 0.2 mm Hg for girls. Therefore, the effects of childhood BMI on adulthood hypertension and the metabolic syndrome seem to be mediated by childhood blood pressure.
Birth weight and relative bone age were included in the longitudinal models as covariates. Birth weight has been reported to affect adulthood blood pressure,20 and advanced maturation, assessed as relative bone age, is associated with EBPs in childhood.19,21 In this study, we found no effect of birth weight on blood pressure in adulthood, but we did observe that advanced maturation, assessed as relative bone age, was associated with EBPs in childhood. This association may reflect the influence of obesity on early maturation.22
The age- and gender-specific values for systolic blood pressure among children in the Fels Longitudinal Study who subsequently developed hypertension and the metabolic syndrome are similar to the mean values generated with the cross-sectional data for white children in the Bogalusa Heart Study23 and are lower than the corresponding mean values for children in the NHANES in 1999 to 2000.24 Age- and gender-specific values for systolic blood pressure in childhood among adults with hypertension and the metabolic syndrome were slightly below the 50th percentile for systolic blood pressure of children of median height whose data were included in the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents.25 The discrepancy between our data and the NHANES 1999/2000 data may be explained by our adjustment for relative bone age and by the habituation associated with the collection of serial measurements in the Fels Longitudinal Study.19 Our data indicate that, to remain free of hypertension or the metabolic syndrome, with or without hypertension, childhood blood pressures should remain below the 50th percentile for age and gender, as indicated in the Fourth Report.25 If mean systolic blood pressure readings exceed age- and gender-specific criterion values (presented graphically in Fig 2) at any examination from 5 years to 18 years of age for boys or from 8 years to 18 years of age for girls, then the child or adolescent has an increased risk of developing the metabolic syndrome, with or without hypertension, as an adult.
Ideally, for validation of the predictive accuracy of the criterion values established in part 1, another independent sample would have been studied. However, such a sample would require access to serial data collected from childhood into adulthood for the same individuals and is not available. Therefore, data from the 205 subjects analyzed in part 1 were included in the final validation sample of 493 subjects. This approach avoids the need to split the data set arbitrarily into a model-fitting discovery sample and a validation sample.
There was a significant increase in the prevalence of childhood obesity in the US population from 1963 to 1991.26 A secular trend toward higher blood pressure in children has also been reported.24 The Fels Longitudinal Study participants in this study were born between 1930 and 1983. Among the annual cohorts in the Fels Longitudinal Study, we have observed increased BMI values over the past 20 years (S.S.S., unpublished data, 2006). However, a significant secular trend toward higher blood pressure has not been observed for the Fels Longitudinal Study subjects. The Fels Longitudinal Study population was drawn from southwestern Ohio, and participants in the Fels Longitudinal Study are nearly all non-Hispanic white. Therefore, our findings may not be applicable to other races and ethnicities.
The ability to predict adult hypertension and the metabolic syndrome by measuring levels of blood pressure in childhood as early as 5 years of age is of clinical and public health importance. Such prediction might signal the need for corrective interventions that could be made during childhood. This approach is preferable to waiting until adulthood, when the deleterious clustering of risk factors has been established and when lifestyle changes are difficult to implement.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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Address correspondence to Shumei S. Sun, PhD, Department of Community Health, Wright State University Boonshoft School of Medicine, 3171 Research Blvd, Dayton, OH 45420. E-mail: shumei.sun{at}wright.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| REFERENCES |
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