Medical Research Council National Survey of Health and Development, Department of Epidemiology and Public Health, Royal Free and University College Medical School, London, UK
Correspondence: Rebecca Hardy, Medical Research Council National Survey of Health and Development, Department of Epidemiology and Public Health, Royal Free and University College Medical School, 119 Torrington Place, London WC1E 6BT, UK. E-mail: rebecca.hardy{at}ucl.ac.uk
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Abstract |
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Methods A total of 3157 men and women from a British birth cohort study where the survey members have been followed up regularly since their birth in 1946 were included in analyses. The associations between birthweight, childhood growth and blood pressure at 43 years of age were assessed using multiple regression models.
Results Systolic blood pressure (SBP) decreased by 2.3 mmHg (95% CI: 0.8, 3.5) for men and 1.8 mmHg (95% CI: 0.1, 3.5) for women per 1-kg increase in birthweight. The effect was stronger in first born or those born to younger mothers. There was no confounding with any maternal, socioeconomic, or childhood growth variable. SBP increased by 1.45 mmHg (95% CI: 0.11, 2.78) in women and 0.46 mmHg (95% CI: −0.70, 1.62) in men per standard deviation of body mass index (BMI) change between ages 7 and 15 years. Among women this effect was not completely accounted for by adult size and was independent of birthweight.
Conclusions The determinants of birthweight, possibly related to maternal health during pregnancy, may impact on the relationship with SBP in middle life. The importance of tackling the increasing levels of childhood obesity seen in later cohorts is highlighted by the detrimental impact on SBP of large increases in BMI during adolescence.
Accepted 2 September 2003
The fetal programming hypothesis1 states that undernutrition during fetal life programmes the development of risk factors, such as high blood pressure, for cardiovascular disease in adult life. Many studies have considered the association between birthweight and systolic blood pressure (SBP), and systematic reviews of such studies suggest a reasonably consistent negative relationship in both children and adults,24 although a recent review questions the validity of this conclusion.5 The contribution of maternal and pregnancy related factors to the birthweightblood pressure association remains unclear,58 and there is continuing concern that the association may be confounded with lifetime socioeconomic circumstances,5 although two studies found little evidence of this.9,10 The birthweight effect may reflect postnatal rather than fetal growth if the negative association emerges only after adjustment for current body size.11 Alternatively, there may be influences of postnatal growth on blood pressure in addition to fetal growth. Fetal and postnatal childhood growth have been investigated in relation to childhood blood pressure,1215 early adult blood pressure,1619 or treatment received for hypertension in adulthood.20 Few studies have been able to consider both prenatal and childhood growth in relation to midlife and later life blood pressure.21,22
We use the Medical Research Council (MRC) National Survey of Health and Development (NSHD) to extend previous research by assessing whether the association between birthweight and blood pressure is confounded with or modified by maternal or socioeconomic factors or childhood body size. We then ask whether childhood growth up to the age of 15 years has an additional effect on adult blood pressure.
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Methods |
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Blood pressure at 43 years was measured for 3157 (3148 with a birthweight recorded) cohort members by a team of trained nurses at interviews and examinations in the study member's home. Two measurements of blood pressure were taken using a Hawksley random zero sphygmomanometer with regular (12 x 23 cm) upper arm cuff. A correction was made for arm circumference.26 The second measurement was used in analyses. Study members were asked whether they had taken any prescribed medicines or tablets for high blood pressure in the year preceding the interview.
Birthweight of cohort members, to the nearest quarter of a pound, was extracted from medical records within a few weeks of delivery and converted into kilograms. Heights and weights measured at 2, 4, 7, and 15 years, and at 43 years were used in analyses. Body mass index (BMI), defined as weight/height2, was calculated at each age.
The following maternal and pregnancy related factors, which may influence the birthweight of the offspring, were considered: mother's age at birth of the cohort member (in years), mother's height (measured when the cohort member was 4 years old), birth order of the cohort member (categorized as 1, 2, 3+), and mother's education (categorized into primary school only or more than primary). Socioeconomic position was measured by social class (categorized into non-manual and manual) in childhood, based on father's occupation when the cohort member was aged 4 years, and adulthood, based on cohort member's own occupation at age 43 years.
Statistical analysis
All analyses were carried out for both systolic (SBP) and diastolic blood pressure (DBP) at 43 years using regression models with blood pressure as a continuous outcome measure. Initially, the four models proposed by Lucas et al.11 for investigating the fetal programming hypothesis were fitted. These are the unadjusted associations between birthweight and adult BMI and blood pressure, the model including birthweight and BMI, and a model additionally including the interaction between birthweight and BMI, as some studies show the strongest birthweight effect in those who are later overweight.27
All further analyses were carried out using standardized (sex-specific) birthweight and body size measures (z-scores), to allow easier comparison of the size of the effects at different ages. Since each of the potential confounding variables had missing data for a different subset of the sample, the association between birthweight and blood pressure was adjusted for each confounding variable one at a time. Tests for interaction between each confounding variable and birthweight were performed.
Regression models were then fitted including both BMI and height at each age (2, 4, 7, 15, and 43 years) separately. Birthweight was added to each model to test whether the effect of birthweight on blood pressure was mediated through childhood growth. To assess whether early childhood growth influenced blood pressure independently of birthweight, differences between the z-scores in birthweight and both z-scores in BMI and height at age 2 years were calculated, and a model including birthweight and these two growth variables was fitted. Growth between birth and each of the ages 4, 7, and 15 years was similarly assessed. Later childhood growth was investigated in equivalent models by considering the difference in z-scores for BMI and height between each pair of ages between 2 and 15 years (i.e. 24, 7, 15; 47, 15; 715), leading to estimates of the effect of change in height and BMI for a given initial body size. Social class in childhood and adulthood were added to each model as potential confounding variables. Tests for interaction between birthweight and each growth variable and social class and each growth variable were performed.
Analyses were carried out separately for men and women, but tests of interaction by sex were performed to make formal comparisons. Associations with all anthropometric variables were modelled as linear after tests for deviation from the linear trend had been carried out. Finally, the independence of any of the body size variables observed to be important was assessed.
Since some cohort members (n = 107) were on medication for high blood pressure at the time of examination, all analyses were repeated excluding those on treatment. In addition, all analyses were repeated using multiple imputation methods28,29 to deal with missing explanatory variables, based on the sample with complete 43-year information (1582 men and 1566 women).
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Results |
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There was a weak negative association between birthweight and DBP for men (−0.5 mmHg per kg of birthweight, 95% CI: −1.7, 0.6) and women (−0.4 mmHg, 95% CI: −1.7, 0.8). Adult BMI was strongly and positively related to DBP, and no interaction was found between birthweight and adult BMI. Given the lack of association with birthweight, we will not report on DBP further in this paper.
Birthweight, maternal, and socioeconomic factors and adult SBP
The unadjusted association between birthweight, now considered as a z-score, and SBP is presented in Table 2 for men and women separately. None of the potential confounding variables had a substantial effect on the size of the estimated effect (Table 2). The negative effect of birthweight was stronger in first born than later born children (P-value for interaction = 0.02). This is illustrated in Figure 1 by splitting birthweight into three categories using cut points ±1 standard deviation from the mean. The association among third or later born children appeared to be U-shaped. Among women, the negative effect was only seen in those born to younger mothers (P-value for interaction = 0.04) as illustrated in Figure 2 with young mothers defined as being under 30 years. The effect was also stronger in women from a non-manual compared with a manual social class in childhood (−2.45 mmHg per standard deviation increase in birthweight for non manual and −0.31 mmHg for manual: P-value for interaction = 0.02).
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Missing data and sensitivity analyses
Men and women who reported taking medication for high blood pressure had considerably higher SBP than those who did not (mean SBP 135 mmHg versus 125 mmHg for men, 136 mmHg versus 121 mmHg for women). In the untreated subsample, the conclusions to be drawn from the analysis remained the same. Regression coefficients, after multiple imputation had been implemented, were slightly different to those obtained in the main analyses, but again there were no differences in the conclusions that would be drawn.
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Discussion |
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Since the effects of birthweight on SBP are stronger in women born to younger mothers and men of earlier birth order, the same underlying mechanism may be involved. The interaction with birth order in men had previously been observed with SBP at 36 years as the outcome.30 The determinants of birthweight may be different in later compared with earlier births or older compared with younger mothers. Maternal health during pregnancy may determine both the birthweight and the future risk of hypertension of the offspring. Pre-eclampsia and high blood pressure, contributors to intrauterine growth retardation,3134 are more common in first pregnancies.31,35,36 Offspring from pregnancies with both these complications may be susceptible to hypertension in adult life. They have been found to have, respectively, higher blood pressure32,37 and a greater risk of impaired glucose tolerance and obesity3840 in childhood than offspring from normal pregnancies. This might contribute to the higher blood pressure in offspring of low birthweight from first compared with later pregnancies. Older mothers are more likely to develop gestational diabetes41 and gestational diabetes and increased glucose intolerance are associated with delivery of higher birthweight babies42 and an increased incidence of macrosomia.43 This could explain the higher blood pressure in offspring of high birthweight born to older compared with younger mothers. Information on these maternal health characteristics during pregnancy was not collected in the NSHD, and neither was information on other determinants of birthweight such as smoking.
In our study, the effect of birthweight was greater in women who experienced better socioeconomic conditions during childhood. The mechanism behind such an effect remains unclear and replication of this analysis is required in other studies as it may be a chance finding. A Finnish cohort study considering hypertension defined by prescription of medication as the outcome found an interaction between father's social class and birthweight,44 but in the opposite direction to that observed in our study. The effect of birthweight on hypertension was greater in labourers' children than in middle class children leading to the suggestion that poor living conditions in childhood may alter the hypothalamic-pituitary-adrenal axis, resulting in high blood pressure.44 Individuals who were small babies are also known to have altered stress responses and raised serum cortisol concentrations in adult life.45
Childhood growth and adult blood pressure
Shorter height was associated with higher adult SBP in this study. Poor height growth up to 4 years relative to birthweight showed an effect over and above that of birthweight which was confounded with social class in childhood. Thus poor childhood growth may provide a partial explanation for the social class gradient in blood pressure.46 Socially distributed factors such as childhood diet, illness, and psychosocial deprivation4749 may, through endocrine control, simultaneously influence growth of the arteries50 and of the bones at specific hormonally controlled phases of development, leading to both short height and high blood pressure in adult life. Alternatively, children exposed to the environmental factors that retard growth may be more likely to also be exposed to adult factors which raise blood pressure.
Previous studies have observed that high weight gain during childhood or adolescence is related to higher blood pressure in early adulthood.19,51,52 Part of the association between large increases in BMI during childhood and high SBP probably reflects the beginning of the upward trend in BMI which sets the trajectory to overweight in adult life. Health behaviours such as poor diet and lack of physical activity, established during childhood, continuing across the life course and leading to adult overweight are likely to be at least part of the pathway. A British study of a cohort born between 1975 and 197719 found that weight increase in early childhood (between 1 and 5 years), rather than during adolescence as in our study, was associated with increased SBP in early adulthood and this was largely accounted for by adult BMI. This effect of growth at an earlier stage of development may reflect the initiation of the trajectory towards high BMI in adulthood possibly starting at a younger age in later cohorts. In agreement with our findings, a Finnish study20 found that children who had become fatter between 7 and 15 years were more likely to be treated for hypertension in later adult life. The Finnish study was not able to account for current body size, but we show that among women current BMI did not entirely explain the childhood growth effect.
Our findings therefore support the possibility that childhood growth has an independent influence on adult blood pressure. During childhood, adiposity is associated with higher blood pressure,53,54 and with adverse levels of other components of the metabolic syndrome.5557 These characteristics cluster in childhood and track into adult life5860 suggesting that the metabolic syndrome may partly originate in childhood.61 Insulin resistance and adiposity in childhood may precede the development of hypertension.62
The social class difference in the effect of BMI change during earlier childhood on SBP among women indicates that the detrimental impact of fast childhood weight gain can be offset by, for example, participation in physical activity throughout the life course, which was greater in those of higher socioeconomic status.23,63 In the NSHD those from a manual social class in childhood have previously been shown to have higher mean BMI at 20 years and faster subsequent increase than those from a non manual class.64
Study limitations
Although the NSHD is unique in having data on birthweight, childhood and adult heights and weights and adult blood pressure in middle life, it lacks gestational age, birth length, and anthropometric measurements between birth and 2 years of age. Thus linear growth from birth cannot be distinguished from change in adiposity and very early catch-up growth cannot be investigated. Since boys and girls mature at different rates and within sexes there is wide variability in growth rates, the specific parameter of growth which is important in determining later blood pressure may not be available (for example, maximum growth velocity). Missing data are unavoidable in long-running birth cohort studies such as the NSHD, but our findings are very similar to those observed when using multiple imputation techniques to account for missing covariate information. Certain assumptions are required for such methods to be valid28,29 and we did not impute missing outcome data. There is no reason to suspect, however, that the differences in the characteristics of those with missing outcome data compared with the rest should have an impact on our findings.
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Conclusions |
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KEY MESSAGES
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Acknowledgments |
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References |
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