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(Hypertension. 2007;49:1415.)
© 2007 American Heart Association, Inc.
Original Articles |
From the National Public Health Institute (J.G.E., T.J.F., E.K.), Department of Health Promotion and Chronic Disease Prevention, Diabetes Unit, Helsinki, Finland; the Department of Public Health (J.G.E.), University of Helsinki, Helsinki, Finland; MRC Epidemiology Resource Centre (C.O.), University of Southampton, Southampton General Hospital, Southampton, United Kingdom; and the Heart Research Center (D.J.P.B.), Oregon Health and Sciences University, Portland, Ore.
Correspondence to David J.P. Barker, Developmental Origins of Health and Disease (MP 887), University of Southampton, Princess Anne Hospital, Southampton SO16 5YA, United Kingdom. E-mail djpb{at}mrc.soton.ac.uk
| Abstract |
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Key Words: hypertension kidney fetal programming early growth renin angiotensin system
| Introduction |
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We hypothesized that hypertension is associated with 2 different paths of childhood growth. In one small size up to the age of 2 years is followed by rapid growth; in the other there is persisting small size through childhood. We ascertained hypertension by examining a random sample of 2003 subjects at the age of 62 years. We linked size at birth, infant growth, and child growth to the later occurrence of hypertension, both previously diagnosed and newly diagnosed.
| Methods |
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At the clinic they were asked about their medical history and medication. A total of 644 of them had been diagnosed previously as having hypertension; 333 of these were on the national register of people receiving reimbursement from the state for the costs of their medication.7 Compared with the 311 not receiving reimbursement, they had higher mean blood pressures, weights, waist circumferences, and body mass indices. Adjusting for age and sex, their mean systolic pressure was 5 mm Hg higher (SE: 1.5), and their mean waist circumference was 3.7 cm greater (SE: 1.0). A 75-g standard oral glucose tolerance test was performed. Plasma glucose concentrations were measured using the hexokinase method, whereas plasma insulin and proinsulin concentrations were determined by a 2-site immunometric assay.8,9 We used World Health Organization 1999 criteria for the diagnosis of type 2 diabetes (fasting plasma glucose
7.0 mmol/L or 2-hour glucose
11.1 mmol/L after a standard 75-g oral glucose challenge). Serum total cholesterol, high-density lipoprotein cholesterol, apolipoprotein B, and triglyceride concentrations were measured using standard enzymatic methods.10,11 Height was measured with a Kawi stadiometer. Weight was measured on a Seca alpha 770 scale. Waist circumference was measured using a soft tape at a point midway between the lowest rib and the iliac crest. Blood pressure was measured from the right arm while the subject was in the sitting position and was recorded as the mean of 2 successive readings from a standard sphygmomanometer. We defined hypertension as a systolic blood pressure of
140 mm Hg or a diastolic blood pressure of
90 mm Hg.12 Using this definition, we identified 802 subjects with previously undiagnosed hypertension. Written informed consent was obtained from each subject before any procedures were carried out. The ethics committee at the National Public Health Institute approved the study.
Statistical Analysis
We calculated z scores for height, weight, and body mass index (the weight in kilograms divided by the square of the height in meters) for each child at birth and at each birthday until 11 years of age. A z score represents the difference from the mean value for the whole cohort and is expressed in SDs. We used multiple logistic regression analysis, adjusting for age and sex, to examine the effect of measurements of body size on either diagnosed or undiagnosed hypertension, using normotensive subjects as controls. We used multiple linear regression analysis, again adjusting for age and sex, to compare biochemical variables in the 2 hypertensive groups with normotensive subjects. In the analysis, we define infancy as the period between birth and 2 years of age, because we have shown previously that low weight gain during this period, with consequent thinness at 2 years of age, predicts coronary heart disease5 and stroke.6
| Results |
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Current Body Size
Table 1 also shows current body size. Both groups of hypertensive people were shorter in stature than the normotensive subjects, but they had higher weights, body mass indices, and waist circumferences. These measures were higher in the previously diagnosed than in the newly diagnosed hypertensive subjects, and more of the previously diagnosed hypertensive subjects were obese, defined by a body mass index >30 kg/m2.
Biochemical Profiles
Table 2 shows the biochemical characteristics of the normotensive and hypertensive subjects. Glucose, insulin, and lipid concentrations rose with increasing body mass index and, more strongly, with increasing waist circumference. We, therefore, adjusted the P values for waist circumference. Twenty-nine percent of the diagnosed hypertensive subjects were taking lipid-lowering medications compared with 13% in each of the other 2 groups. All 361 people on these medications were excluded from the lipid analyses. When compared with the normotensive subjects, the diagnosed hypertensive subjects had marked elevations of serum triglyceride and plasma proinsulin concentrations and of plasma glucose and insulin concentrations, both fasting and 2 hours after a standard glucose challenge. Twenty-eight percent of them had type 2 diabetes. The undiagnosed hypertensive subjects had raised serum total, high-density lipoprotein, and non-high density lipoprotein cholesterol concentrations and raised apolipoprotein B concentrations.
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Body Size at Birth
The mean birth weight of the study sample was 3410 g (SD: 486 g); the mean length at birth was 50.3 cm (SD: 2.0 cm); the mean body mass index was 13.4 kg/m2 (SD: 1.2 kg/m2); and the mean length of gestation was 280 days (SD: 11 days). In comparison with the normotensive subjects, the subjects with diagnosed hypertension had low birth weight, short length, and low body mass index at birth. After adjustment for length of gestation, the odds ratio for previously diagnosed hypertension associated with a 1-kg increase in birth weight was 0.53 (95% CI: 0.40 to 0.70). The corresponding values for length and body mass index were 0.86 (95% CI: 0.80 to 0.92) for a 1-cm increase in length and 0.83 (95% CI: 0.75 to 0.92) for a 1-kg/m2 increase in body mass index. In contrast, the subjects with newly diagnosed hypertension were short at birth in comparison with the normotensive subjects, but there was no statistically significant difference in their birth weights and body mass indices. After adjustment for gestation, the odds ratio for newly diagnosed hypertension associated with a 1-cm increase in length at birth was 0.93 (95% CI: 0.87 to 0.99).
Infant and Childhood Growth
The Figure shows the mean z scores for weight, height, and body mass index between birth and age 11 years in the 3 groups of subjects. The mean values for all of the subjects are set at 0, and on such a chart children tend to follow horizontal paths of growth, retaining their position as large or small in relation to other children. Subjects with previously diagnosed hypertension had below average body size at birth and remained small for the first 2 years, after which they caught up to the average in height, weight, and body mass index. Weight gain between birth and 2 years reduced the risk of diagnosed hypertension. After allowing for birth weight, the odds ratio associated with 1-kg higher weight at 2 years was 0.87 (95% CI: 0.77 to 0.97). In contrast, weight gain after the age of 2 years increased the risk of previously diagnosed hypertension so that the odds ratio associated with a unit increase in z score for weight between 2 and 11 years was 1.30 (95% CI: 1.14 to 1.48). The corresponding figures for height and body mass index were 1.22 (95% CI: 1.06 to 1.40) and 1.14 (95% CI: 1.02 to 1.27). In contrast to this association with increase in height and body mass index, the average z scores for height and body mass index at ages 2 and 11 years were not associated with previously diagnosed hypertension (odds ratio: 0.91, 95% CI: 0.79 to 1.03; odds ratio: 0.91, 95% CI: 0.80 to 1.05, respectively). We compared the effects of increase in height and body mass index from 2 to 7 years and 7 to 11 years. The odds ratios for increase between 2 and 7 years were 1.15 (95% CI: 0.97 to 1.35) for height and 1.15 (95% CI: 1.01 to 1.31) for body mass index compared with 1.26 (95% CI: 0.95 to 1.66) and 1.07 (95% CI: 0.91 to 1.28) for increases between 7 and 11 years.
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Among the subjects with newly diagnosed hypertension, the z scores for height, weight and body mass index fell after birth and remained below the average until age 11 years. After allowing for birth weight, the odds ratio associated with a 1-kg higher weight at 2 years was 0.85 (95% CI: 0.76 to 0.94). We again calculated the combined mean z-scores for body size at 2 and 11 years of age. The odds ratios were 0.82 (95% CI: 0.72 to 0.93) for height, 0.82 (95% CI: 0.71 to 0.93) for weight, and 0.89 (95% CI: 0.78 to 1.02) for body mass index.
Table 3 summarizes the different paths of growth of children who later developed hypertension, showing odds ratios according to a 1-kg increase in body weight at different ages. When compared with normotensive people, those with previously diagnosed hypertension had low weight at birth and at age 2 years but not at age 7 or 11 years. In contrast, newly diagnosed hypertension was unrelated to birth weight but was related to low weight at ages 2, 7, and 11 years.
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Table 4 shows the simultaneous effects of birth weight and current weight on the percentage prevalence of previously diagnosed hypertension within the study cohort. Current weight is divided into fifths using different cutoff points for men and women. The prevalence fell with increasing birth weight and rose with increasing current weight. It was 4% among people with birth weights >4 kg but current weights in the lowest fifth but rose to 63% among people with birth weights <3 kg but current weight in the highest fifth. In a simultaneous regression, the odds ratios were 0.42 (95% CI: 0.32 to 0.56; P<0.0001) for a 1-kg increase in birth weight and 1.85 (95% CI: 1.66 to 2.05; P<0.0001) for a 10-kg increase in current weight.
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Table 5 shows the simultaneous effects of weight at 2 years and current weight on the prevalence of newly diagnosed hypertension, after exclusion of people with previously diagnosed hypertension. The prevalence fell with increasing weight at 2 years and rose with increasing current weight. It was 38% among people whose weight at age 2 years was >14 kg but whose current weight was in the lowest fifth. It rose to 94% among people whose weight at age 2 years was <11 kg but whose current weight was in the highest fifth. In a simultaneous regression, the odds ratios were 0.75 (95% CI: 0.68 to 0.84; P<0.0001) for a 1-kg increase in weight at 2 years and 1.42 (95% CI: 1.28 to 1.57; P<0.0001) for a 10-kg increase in current weight.
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| Discussion |
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All of the residents in Finland have access to publicly funded primary health care. Our findings show that people already diagnosed as having hypertension tend to be obese. Special state reimbursement for the costs of medication is subject to the approval of a physician and is intended for people with persisting, severe hypertension or for those with complications of the disease or with other disorders, such as type 2 diabetes. These people tend to be obese. The prevalence of diagnosed hypertension in our study was similar to national figure for the same age group in Finland.13 The prevalences of previously diagnosed and newly diagnosed hypertension were similar to those among men and women in the same age group in the United Kingdom.14
Childhood Growth
Compared with people with normal blood pressure, those with previously diagnosed hypertension were small, short, and thin at birth and had low weight gain during infancy. After 2 years of age they grew rapidly. The risk of later hypertension depended on the rate of growth rather than the body size attained at any particular age. These findings are consistent with those from an older cohort in Helsinki7 in which children who later developed both hypertension and type 2 diabetes grew rapidly during their school years. An association with rapid growth in height has also been shown in a study of Swedish men, among whom the highest blood pressures occurred in those who had had low birth weight but were currently tall.15 Compared with people with normal blood pressure, those with newly diagnosed hypertension had slow linear growth, which began before birth. Their z scores for height and body mass index fell after birth and remained below the average until 11 years of age. This path of growth has not previously been linked with hypertension.
A feature shared by both groups of people with hypertension is that, in comparison with people with normal blood pressure, their weight gain between birth and 2 years was less than that predicted by their birth weights. This is consistent with findings in a national cohort of British children among whom slow growth in height between birth and 4 years predicted raised systolic blood pressure in middle age.4 It is also consistent with other observations in this cohort showing that low weight gain in infancy and thinness at 2 years of age are associated with increased risk of coronary heart disease and stroke, for both of which hypertension is a risk factor.5,6 Among the people already diagnosed as having hypertension, rapid growth after the age of 2 years may have been a response to their shortness and thinness in infancy. Among animals, a period of undernutrition, leading to stunting and thinness, may be followed by a period of rapid compensatory growth when normal levels of nutrition are restored.16
Limitations of the Study
We have previously discussed possible limitations of our data.5 Our study was restricted to people who had attended child welfare clinics. Although the majority of children attended these clinics, which were free, attendance was voluntary. At birth the distribution of social class, as indicated by fathers occupations, was similar to that in the city as a whole, where at the time
60% of the men were employed as laborers.
Biological Mechanisms
It has been postulated that hypertension is initiated in response to the reduced number of nephrons in the kidneys of people who had low birth weight.17,18 Restriction of fetal growth is known to be associated with altered renal shape, reduced renal volume, and fewer nephrons.1924 In animals, fetal growth restraint reduces the number of nephrons and elevates blood pressure.2527 A reduced number of nephrons leads to glomerular hyperfiltration and an increase in glomerular pressure. Over time this may result in glomerular hypertension and sclerosis and premature nephron death.17,18 This establishes a self-perpetuating cycle of rising blood pressure and further nephron loss. Rapid increase in body size after birth may exacerbate glomerular injury, because greater body size leads to increased excretory load. Indirect evidence supporting a link between fewer nephrons and hypertension in humans has come from a study of the kidneys of people killed in road accidents.28 Those being treated for hypertension had 50% fewer glomeruli than normotensive control subjects.
The effects of reduced nephron number at birth, in association with low birth weight, followed by an increased excretory load, in association with rapid growth after birth, offer a mechanistic explanation for the path of growth that we found to precede previously diagnosed hypertension. In the Helsinki birth cohort, we have shown that this same path of growth leads to coronary heart disease5 and insulin resistance.5,29 Consistent with this, we found that people with diagnosed hypertension had markers of insulin resistance, with raised plasma insulin and glucose concentrations and raised plasma triglycerides. Both hypertension and insulin resistance are known biological risk factors for coronary heart disease.
The processes that link slow growth before and after birth with newly diagnosed hypertension are not known. In a previous analysis of the cohort we have shown that a similar path of growth leads to stroke.6 We speculated that slow growth was associated with impaired development of the cerebral vasculature. In addition, we suggested that the association between slow linear growth after birth and thrombotic stroke was mediated through resetting of blood coagulation and lipid metabolism as a consequence of altered liver development. The livers development continues after birth, and its function may be permanently changed by influences that affect its growth at this time.3032 Consistent with this hypothesis, we found that people with newly diagnosed hypertension had atherogenic lipid profiles, with raised serum nonhigh-density lipoprotein cholesterol and apolipoprotein B concentrations.
We suggest that the 2 groups of hypertensive patients have raised blood pressure through different biological processes and may respond differently to medication. There is preliminary evidence supporting this. Among white hypertensive patients in the United States, those who had low birth weight were more likely to be receiving second line treatment with angiotensin-converting enzyme inhibitors.33 There was a similar finding in an elderly cohort in Helsinki.34 A possible explanation is that low birth weight is associated with insulin resistance, which alters regulatory responses of the reninangiotensin system that are already perturbed by the reduced number of nephrons. Insulin enhances signaling by angiotensin II, a potent vasoconstrictor, and in this setting angiotensin-converting enzyme inhibitors may be effective.
Perspectives
In a clinical study of 2003 people randomly selected from the Helsinki birth cohort, we found that 2 different paths of fetal, infant, and childhood growth preceded the development of hypertension in adult life. In one that was associated with more severe hypertension in people who tended to be obese, small body size at birth and during infancy were followed by rapid growth: at age 11 years, the childrens body size was around the average. In the other, which was associated with less severe hypertension, slow linear growth in utero and during infancy were followed by persisting small body size: at age 11 years, the children were short and thin. In previous analyses of this birth cohort we have shown that the first path of growth led to coronary heart disease,5 whereas the second led to stroke.6 The 2 paths are also associated with different biochemical profiles in adult life. The first is associated with insulin resistance, whereas the second is associated with alteration of liver function. We suggest that they lead to hypertension through different biological mechanisms and may respond differently to medication.
| Acknowledgments |
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This study was supported by the British Heart Foundation, the Academy of Finland, the Paivikki and Sakari Sohlberg Foundation, the Finnish Diabetes Research Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Medical Society Duodecim, Yrjo Jasson Foundation, and Finska Lakaresällskapet.
Disclosures
None.
Received December 6, 2006; first decision January 10, 2007; accepted March 25, 2007.
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