Department of Social Medicine, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark
Correspondence: Merete Osler, Department of Social Medicine, Institute of Public Health, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: m.osler{at}pubhealth.ku.dk
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Abstract |
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Methods In all 10 753 male singletons born in the metropolitan area of Copenhagen, Denmark in 1953 whose birth certificates had been traced manually in 1965 were followed from 1968 to 2002 for information on parents' and own vital status by linkage with the Civil Registration System. Causes of death for the cohort members were identified by record linkage with the Cause-of-Death Registry. Hazard ratios and 95% CI were calculated using Cox regression models.
Results Low birthweight and especially short birth length were strongly associated with adult mortality risk, but no relationship between low ponderal index at birth and mortality was found. The relationship between birth size and early adult mortality was only slightly attenuated after adjustment for early-life social position and/or maternal and paternal lifespan. The associations between birthweight/birth length and mortality were stronger for the age group 3549 years compared with the age group 1534 years. Cause-specific mortality was inversely related to small birth dimensions for all causes of death, but strongest and graded for death from liver cirrhosis. Offspring birth dimensions showed an inverse association with parental mortality, which was most pronounced for maternal mortality.
Conclusions The strong inverse association between birth dimensions and adult mortality, but lack of association between ponderal index and mortality, indicates that more complicated mechanisms than a general long-term detrimental effect of intrauterine growth retardation explain the association between birth size and adult mortality. The heterogeneous associations between birth dimensions and mortality in young and later adulthood, the minor differences in relative risk of cause-specific mortality, and the heterogeneity in the association between birth dimensions and maternal and paternal mortality, respectively, indicate that several mechanisms (factors related to social position, common genetic factors, and specific organ programming) may account for the relation between birth measures and later mortality.
Accepted 3 April 2003
A number of studies have shown an inverse association between birth dimensions and mortality from particularly cardiovascular diseases (CVD) later in life, an association that most often persists after adjustment for socioeconomic circumstances.13 These observations have lent support to the fetal programming hypothesis, suggesting that intrauterine growth has an important impact on health in adult life. However, one of the preferred criticisms of this hypothesis is that the association between size at birth and adult health is spuriously created by confounding factors, of which social position of the parents has been the one preferred.4 Others have suggested that common background factors, such as specific genotypes determining low birthweight and disease risk in the offspring should account for the association.57 This latter explanation has been supported by a number of studies from Finland, Norway, Sweden, and the UK showing that offspring birthweight is associated with long-term parental mortality from all causes and CVD.813
A few studies have failed to show an association between birthweight and CVD mortality,14 and an analysis using Danish twin data has questioned the very existence of an association between birthweight and adult mortality.15
In the present study, we have analysed the relation between size at birth and mortality in a cohort of Danish men born in 1953. The data allowed us to look at different measures of size at birth and later all-cause and cause-specific mortality, taking information on parental social position and lifespan into account. To further address the question of common genetic background factors we have analysed maternal and paternal mortality in relation to offspring birthweight.
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Methods |
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The Danish Civil Registration System (CPR-Registry) was established in 1968. The registry allocated a unique personal identification number (CPR-number) to everyone living in Denmark by 1 April 1968 and to all liveborn or those taking up residence in Denmark from that date. The 10-digit number indicates the day, month, and year of birth, and a unique four-digit identifier. The CPR-Registry keeps information on vital status of each individual, links to parents and children of the individual, and registers residency and date of changes in these data.
From the original Project Metropolit a total of 11 532 people were registered in the CPR-Registry, i.e. alive and resident in Denmark on 1 April 1968. Of these, 156 subjects were excluded from the cohort, since they had requested the CPR-Registry not to pass on any information for research purposes. The remaining 11 376 people constitute the Metropolit2000 Cohort and are the study population of the present study.
Data sources and variables
Data from birth certificates, including information on date and place of birth, birthweight and birth length, singleton or multiple birth, mother's age and marital status, and father's occupational status at time of delivery were manually collected for all members of the original study population in 1965. A total of 230 boys born as twins and triplets and 393 boys with missing birth data were excluded, leaving 10 753 cohort members for the present analyses.
In January 2002, the Metropolit2000 Cohort was followed up with regard to vital status by record linkage with the CPR-Registry. If a person had died or emigrated we received information on date of death or date of emigration/disappearance. Furthermore, registered information on personal identification number and vital status of parents was obtained.
We identified causes of death in the Metropolit2000 Cohort, covering the period from 1 April 1968 to 31 December 1998, by record linkage with the Cause-of-Death Registry at the Danish National Institute of Public Health.
Birthweight was recorded in 100-g groups and analysed as a continuous variable in five categories: <2500, 25002999, 30003499, 35003900, and 4000+ g. The initial data analyses showed equal estimates in the two categories from 2500 g to 3499 g and in the two categories from 3500 g to 4000+ g, respectively, and consequently these categories were pooled. Birth length was recorded in centimetres and categorized into the groups appearing in Table 1. Ponderal index was calculated as birthweight (kg)/birth length (m) raised to the third power and entered into the models in quintiles.
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Fathers' and mothers' lifespan was calculated based on information from the CPR-Registry regarding date of birth of the parents and date of change in vital status. When the variable was entered into the analyses it was categorized as follows: −49 years, 5064 years, 65+ years, and unknown. This categorization was done because all parents, irrespective of age at reproduction, would have reached 65 years of age in 2002 or had died before that age.
Cause-of-death data were based on official death certificates, coded according to the 7th Revision of the International Classification of Diseases (ICD-7) for 19681969, ICD-8 for 19701993, and ICD-10 from 1994. Causes of death were categorized into death from CVD (ICD-7 codes: 330468; ICD-8 codes: 390458; ICD-10 codes: I00I52, I60I99), death from cirrhosis (ICD-7 code 581; ICD-8 code 571; ICD-10 code K70), accidents and suicide (ICD-7and ICD-8 codes: 800999; ICD-10 codes: V01-Y99), and other causes (all other codes).
Statistical methods
Associations between birthweight, other covariates and mortality were analysed using Cox's proportional hazards regression models with age as the underlying time scale. Entry time was age on 1 April 1968 and follow-up ended at the age of death, emigration, or on 22 January 2002, whichever came first. The Cause-of-Death Registry was updated until 31 December, which is also the latest follow-up date in the analyses of cause-specific mortality. The proportional hazards assumption was evaluated for all variables by comparing estimated -ln(-ln) survivor curves over the different categories of the variables being investigated versus ln(analysis time), and by tests based on the generalization as described by Grambsch and Therneau.17 We used STATA version 7 for statistical analyses.
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Results |
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The distribution of size at birth, socioeconomic indicators at birth, and parental lifespan for the cohort is shown in Table 1 together with the unadjusted relative death intensity ratios according to these characteristics. We found a strong and graded inverse association between birthweight and risk of death from age 15 to 49 years and the same was found for birth length. In contrast to these findings, we found no association between ponderal index at birth and mortality.
In addition, indicators of low parental social position at birth (father's occupation and mother's marital status) and a short parental lifespan were associated with increased mortality. We succeeded in tracing the identity and lifespan of 7197 mothers and 6547 fathers in the CPR-Registry. The fact that the CPR-Registry removed links between parents and their children when they left home or had offspring themselves during 19681978 accounted for the high proportion of missing information. However, the participants with missing information on parents' lifespan had a mean birthweight and a mortality risk that were comparable to those with information on one or both parents (Table 1).
Entering social indicators and parents' lifespan into the model separately attenuated the birthweight/length association with mortality marginally. However, entering all four parameters into the model decreased the risk estimates between low birthweight and adult mortality to 1.37 (95% CI: 1.01, 1.85). Still, the mortality risk was higher among those born with a short stature, while no clear association could be demonstrated between ponderal index and later mortality (Table 2). The analyses were repeated in the sub-cohort restricted to those with information on parental lifespan. This did not significantly change the reported associations.
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Discussion |
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The association between birthweight and mortality in later life has been shown in a variety of data during the past 10 years. It has, however, been suggested that selection bias in the data in which the association has been shown could account for the findings.18 The present data consist of all singletons born in a well-defined area (covering one-third of the Danish population) who survived to the age of 15 years. By using population-based registers we managed to get complete follow-up information, and consequently the present results are based on birth and mortality data on more than 95% of this non-selected population. Hence, we do not believe that selection bias could account for the associations found.
Birthweight has, in this area of research, been understood as a proxy measure of fetal growth. Birthweight is, however, a combined measure ofat leastthe two components: fetal growth rate and gestational age at birth.19 Lacking data on gestational age at birth we considered birth length, due to the suggestion that fetal body length shows an almost linear increase during the last months of pregnancy, whereas the body weight of the fetus increases exponentially. Our idea was that a larger proportion of the short babies would represent babies born preterm than the proportion of babies born preterm with a birthweight below 2500 g. The finding of a strong and graded inverse relation between birth length and mortality may suggest that factors related to preterm birth partly account for the association between birthweight and later adult mortality.
The ponderal index is a measure of fetal growth, which in theory should discriminate between intrauterine well-fed and disproportionately growth-restricted newborns. We did not find any indication of an association between quintiles of ponderal index and adult mortality. This result contrasts what was reported from a Finnish cohort study of 4630 men, where the hazard ratios for CVD increased with decreasing ponderal index at birth20,21 and the finding challenges the idea of a general effect of intrauterine growth.22
We find, however, some support for the idea of specific long-term detrimental effects of factors in fetal life causing low birth dimensions. Mortality between ages 15 and 34 years did not show any particular association with birth dimensions, in contrast to the findings in the older age group, where death from chronic diseases dominates the causes of death. As expected, CVD mortality was inversely related to birth dimensions, but so were accidents and suicides, although to a smaller extent. The latter finding speaks in favour of confounding of the association by factors related to social position. An alternative explanation has been put forward by authors who reported inverse associations between infant weight gain and suicide,23 and between birthweight and depression later in life for men.24 They suggested that altered programming of hormone release might induce depression, which in turn leads to increased risk of suicide. A recent study on a cohort born in 1946 in the UK demonstrated that mortality between ages 26 and 54 years was strongly influenced by socioeconomic conditions in childhood as well as early adulthood.25 We have no reason to believe that this finding should not apply to the Danish cohort, which in many aspects is comparable with the UK cohort.
It has been stressed that the findings of an association between birthweight and adult health may be confounded by factors related to socioeconomic status.26 Use of several indicators describing different aspects of wealth and indicators of social position over the life course is recommended.27 Paternal occupation at time of birth is an accepted indicator of social position in early life and maternal marital status was a sensitive social indicator in 1953. However, the few measures on social position used in this study may not sufficiently adjust for confounding by socioeconomic factors and the possibility of residual confounding by social factors may partly account for the reported associations.
The finding of the association between birth dimensions and death from cirrhosis of the liver was not expected, but we think that the strong and graded association speaks in favour of a realif not causalassociation. We are not aware of any studies that have reported this before, but some studies have indicated that liver function in adult life might be influenced by intrauterine experiences.28 Death from liver cirrhosis among men in this age group is clearly related to alcohol consumption, but unfortunately we did not have information on alcohol consumption in the cohort. So, whether the mechanism behind this finding is an increased susceptibility to alcohol among those born small (organ programming) or confounding by alcohol consumption (which probably is a marker of social circumstances and may well be related to birth size) is not clear. Adjustment for parental social position did not, however, change the estimates substantially.
Parental lifespan may reflect genetic factors for early mortality but might also be considered as a rough proxy measure of a number of different parental characteristics (including social factors) which may influence the health of their children. The fact that the inclusion of parental lifespan in the model reduced the offspring mortality hazard ratios indicates a potential confounding effect and could be consistent with common genetic determinants of both small birth dimensions and later mortality. Genetic factors have been suggested to play a role for intrauterine growth retardation by authors who found that mothers born small-for-gestational-age (SGA) had a double risk of giving birth to an SGA infant,29 and by authors who found an independent contribution of paternal birthweight to offspring birthweight.30 Our finding of an inverse association between parental mortality and offspring birth dimensions, which has also been shown in previous studies,911 adds support to the theory of common intergenerational influence on birthweight and disease developmentso do reports of associations between offspring birthweight and paternal diabetes and maternal insulin resistance.31,32 Similar to the findings in the Renfrew and Paisley study,8 the association between size at birth and maternal mortality was stronger than the corresponding relationship to paternal mortality. Davey Smith has put forward the argument that maternal and paternal mortality should be equally associated with offspring birth dimensions if common genetic factors were the explanation behind the associations found between birth dimensions and disease later in life.33 Consequently, our findings of a strong association with maternal mortality and the fact that associations between low birthweight/short birth length and mortality were weaker for the individual himself than for the mother suggest that maternal health characteristics (e.g. hypertension) and/or behaviour (e.g. smoking, poor nutrition, alcohol drinking) influencing both the size of the offspring and the maternal mortality may play a role for the associations found. Such behavioural factors tend to cluster in families, primarily for social reasons, and this might to some extent explain the association between birth size and paternal mortality. To address this latter explanation, we replicated the analysis of offspring birth measures and parental mortality on the subset of families for which data on lifespan were available for both parents and adjusted mutually for the other parent's lifespan. The fact that the estimates were unaffected by this procedure speaks against a strong confounding of the association by socioeconomic or behavioural characteristics shared by the parents. Unfortunately, we had no direct information on parents' health behaviour such as smoking, which was rather prevalent among Danish men and women in 1953,34 and the number of cancer events was too small to study mortality of clearly known smoking-related cancers, such as lung cancer. However, the Renfrew and Paisley study showed little effect of adjusting for smoking on the association between birthweight and parental mortality.
The findings presented here provide, however, clear support for the existence of a relation between size at birth and adult mortality in men, which cannot be fully explained by confounding by parental lifespan or socioeconomic factors.
In conclusion, the association between birth dimensions and adult mortality seems to reflect more complicated mechanisms than a long-term detrimental effect of intrauterine growth retardation in general, since no association between ponderal index at birth and mortality was found. The finding of a strong inverse relationship between birth length and mortality suggests that gestational age at birth may play an independent role, which calls for further investigation.
The inverse association found between birth dimensions and mortality from various causes of death indicates that the association between birth dimensions and later mortality may partly reflect confounding, for which socioeconomic factors are likely candidates. However, the differences between risk estimates for cause-specific mortality could indicate an organ-specific susceptibility established in fetal life. The heterogeneity in risk of very early adult death and later adult death points in the same direction. The finding of a strong inverse relationship between offspring birth measures and maternal mortality suggests that maternal health characteristics (e.g. blood pressure or health behaviour), which influence both size of the offspring and maternal mortality, may account for some of the associations found. The much weaker association with paternal mortality indicates that common genetic factors predisposing to both low birthweight and early mortality seem to play a less influential role.
We find that this study supports the contention that several mechanisms (confounding by factors related to social position, common genetic factors, and specific organ programming) account for the relation between birth measures and later mortality.
KEY MESSAGES
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Acknowledgments |
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References |
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