IJE Advance Access originally published online on March 11, 2005
International Journal of Epidemiology 2005 34(3):655-663; doi:10.1093/ije/dyi048
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Article |
Size at birth as a predictor of mortality in adulthood: a follow-up of 350 000 person-years
1 National Public Health Institute, Helsinki, Finland
2 MRC Epidemiology Resource Centre, University of Southampton, Southampton SO16 6YD, UK
3 Developmental Origins of Adult Health and Disease Centre, University of Southampton, Southampton SO16 6YD, UK
4 Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland
* Corresponding author. National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland. E-mail: eero.kajantie{at}helsinki.fi
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Abstract |
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Background Small body size at birth, as a marker of an adverse intrauterine environment, has recently emerged as an important risk factor for death from cardiovascular disease. Our aim was to study the relationship between small size at birth and all-cause and non-cardiovascular mortality, which has been poorly documented.
Methods We studied 13 830 individuals born between 1924 and 1944 in Helsinki, Finland, at term as singletons. Dates and primary causes of death between 1971 and 1998 were obtained from the Finnish National Death Register.
Results 1668 men and 671 women died during the follow-up at the mean age of 56.0 (range 26.7–74.9) years. Lower birthweight was associated with increased all-cause mortality in females (Odds ratio (OR) for 1 kg decrease in birthweight 1.25, 95% CI 1.05–1.49; P = 0.01) but not in males (OR 1.08; 0.96–1.19; P = 0.2; P for sex–birthweight interaction = 0.09). Similarly, short length at birth was a predictor of all-cause mortality in females (OR for 1 cm decrease 1.10; 1.05–1.15; P < 0.0001) but not in males (OR 1.01; 0.98–1.02; P = 0.4; P for sex–length at birth interaction = 0.002). Low birthweight and short length at birth predicted premature death in adulthood (<55 years) in both sexes. In males, death from cardiovascular disease (n = 654) was associated with lower birthweight (OR for 1 kg decrease 1.33; 1.12–1.59; P = 0.001), and length (OR 1.05; 1.00–1.10; P = 0.03), and in females death from cardiovascular disease (n = 179) was associated with short length at birth (OR 1.11; 1.02–1.20; P = 0.02). In females death from non-cardiovascular diseases was predicted by low birthweight (OR 1.25; 1.01–1.54; P = 0.04) and short length at birth (OR 1.09; 1.03–1.15; P = 0.003) (n = 475), but not in males (n = 975; P for interaction = 0.02 and 0.004, respectively). Cancer-related death was associated with higher birthweight (OR for 1 kg decrease 0.76; 0.61–0.95; P = 0.02) and ponderal index (OR for 1 kg/m3 increase 0.95; 0.91–0.99; P = 0.01) in males (n = 361) but not in females (n = 269).
Conclusions Small size at birth is associated with increased all-cause mortality at all ages among adult women but only with premature death in adult men. Among women death from both cardiovascular and non-cardiovascular causes is associated with small body size at birth. Among men an association between small birthsize and later cardiovascular disease is counterbalanced by an association between large body size at birth and later cancer.
Keywords Birthweight, developmental plasticity, fetal origins, programming, death
Accepted 31 January 2005
Small size at birth or in infancy is associated with increased mortality from cardiovascular disease in adulthood.1–12 Together with experimental work, these observations have introduced the concept that adult disease is initiated by adverse environmental conditions at critical periods of development, in particular during fetal life.13 However, apart from cardiovascular disease little is known about how fetal growth is associated with all-cause mortality in later life. Therefore, we have examined how size at birth, a marker of intrauterine environment, is related to all-cause and non-cardiovascular mortality.
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Subjects and methods |
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The study cohort comprises 13 830 men and women who were born at term (
37 weeks of gestation) in the Helsinki University Central Hospital during 1924–44, who went to school in the City of Helsinki, and who were resident in Finland in 1971.6,10,11 These subjects had detailed birth records which included the newborn's weight and length at birth as well as the date of the mother's last menstrual period. The newborn's ponderal index was calculated as weight/length3 (kg/m3) and gestational age as the time between the last menstrual period and birth. A unique personal identification number was assigned to every resident of Finland in 1971. Using this number, we followed up the subjects from January 1, 1971 to December 31, 1998 by linking their birth data to the Finnish National Death Register. This register includes the date and cause of death, coded according to International Classification of diseases 8 (ICD-8) until the end of 1986, thereafter ICD-9 until the end of 1996, and ICD-10 from 1997 onwards. The deaths were classified into disease categories based on the ICD code of the primary cause of death as shown in Table 1.
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We examined trends in hazard ratios with birth characteristics using Cox proportional hazards model, stratified into four classes according to the year of birth: ‘1’ for 1924–28; ‘2’ for 1929–33; ‘3’ for 1934–38 and ‘4’ for 1939–44. The proportionality assumption of the Cox model was assessed by using a time-varying indicator variable, determining whether the hazard ratio for each birth measurement was the same at ages below and above 55 years. For all causes, the P-value of the difference between hazard rates in the two age groups was 0.03 for birthweight and 0.03 for length at birth in males, and 0.2 for birthweight and 0.08 for length at birth in females. This finding is further discussed in the Results section. For specific groupings (cardiovascular, non-cardiovascular, and cancer) the time-varying indicator variables all had P-values of >0.05. In addition to linear trends, we assessed the presence of quadratic trends, which are reported whenever statistically significant (P <0.05). All regression equations were adjusted for gestational age at birth.
The study protocol was approved by the Ethics Committee of the National Public Health Institute, Helsinki, Finland.
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Results |
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Among the 13 830 subjects (7203 men and 6627 women), there were 2339 deaths (1668 men and 671 women). Mean age at death was 55.3 years in men and 57.6 years in women (range 26.7–74.9 years). The leading causes of death were cardiovascular disease (39% of all deaths in men and 27% in women), cancer (22% in men and 40% in women), and non-natural death (12% in men and 5% in women) (Table 1). The measurements at birth of the cohort are shown in Table 2.
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Table 3 shows hazard ratios for all-cause mortality according to size at birth. Low birthweight was associated with increased mortality in women but not in men: women weighing <2500 g at birth had 2-fold higher mortality than those with birthweight >4000 g (P = 0.01) (P for sex–birthweight interaction = 0.09). Short length at birth was similarly associated with increased mortality in women (P < 0.0001) but not in men (P = 0.4) (P for birth length–sex interaction = 0.002). By contrast, low ponderal index, a measure of thinness at birth, was not related to all-cause mortality in either sex.
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We examined whether the predictors of premature adulthood mortality, before 55 years of age which is approximately the median age at death in this cohort, differed from those of late mortality. Table 4 shows that in particular mortality before age 55 was predicted by low birthweight and short length at birth in both sexes. Mortality after that age was predicted only by short birth length in women. The time-dependent covariate interaction term P-value for birthweight–death before 55 years interaction was 0.03 in males and 0.2 in females, and for length at birth–death before 55 years interaction it was 0.03 in males and 0.08 in females.
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We examined the effects of body size at birth on deaths from different causes. Table 5 shows that death from cardiovascular disease was more common in men (n = 654) than in women (n = 179), and consequently a trend with a comparable effect size—2-fold risk of dying between birthweight groups <2500 g and >4000 g—reached statistical significance only in males (P = 0.001 in males and P = 0.3 in females; P for birthweight–sex interaction = 0.7). However, short length at birth predicted death from cardiovascular disease in both sexes. Low ponderal index at birth predicted cardiovascular mortality in men but there was no linear relationship in women (P for ponderal index at birth–sex interaction = 0.01). In women, cardiovascular mortality was higher both at the high and low ends of the ponderal index spectrum (P for quadratic trend = 0.04).
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Non-cardiovascular mortality was unrelated to body size at birth in men. By contrast, in women it was predicted by low birthweight (P = 0.04) and short length at birth (P = 0.003) (P for birthweight–sex interaction = 0.02; length–sex interaction = 0.004) (Table 6). Of all deaths from non-cardiovascular causes, there were sufficient from cancer to allow separate examination. Death from cancer appeared to be associated with higher birthweight (P = 0.02) and ponderal index (P = 0.01) in males, while no relationship with birth measurements was seen in females (Table 7). We further assessed whether size at birth was related to any specific cancer listed in Table 1. There were associations between death rates from prostate cancer (n = 22) and high birthweight (hazard ratio for 1 kg decrease in birthweight 0.42; 95% CI 0.17–1.01; P = 0.05) and between lung cancer in males (n = 103) and high birthweight (for 1 kg decrease 0.70; 95% CI 0.46–1.06; P = 0.09) and ponderal index (for 1 kg/m3 decrease 0.89; 95% CI 0.83–0.96; P = 0.002). Death from breast cancer (n = 70 females) was not associated with size at birth (hazard ratio for one kg decrease in birthweight 0.93; 95% CI 0.54–1.59; P = 0.8) Death from all other causes than cardiovascular disease or cancer was unrelated to size at birth in males but in females it was associated with low birthweight (for 1 kg decrease 1.49; 95% CI 1.08–2.06; P = 0.01; P for sex–birthweight interaction = 0.03) and short length at birth (for 1 cm decrease 1.12; 95% CI 1.03–1.21; P = 0.008; P for sex–length at birth interaction = 0.01). Moreover, non-natural death was not associated with size at birth in either sex (all P
0.3).
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Discussion |
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The fetal origins hypothesis proposes that adverse conditions, such as undernutrition, during critical developmental periods cause life-long alterations in body composition, organ structure and function that increase the risk of common adult disorders. Although there is a considerable amount of epidemiological observations about cardiovascular disease1–12 supporting this hypothesis, the present study is among the first to show that at least in females small size at birth is related to all-cause mortality and specifically to non-cardiovascular mortality in adulthood. Elucidating the determinants of this association has a considerable potential public health significance as non-cardiovascular causes account for the majority of all deaths. The importance of small size at birth is further emphasized by our finding of its particularly strong association, at least in males, with premature mortality during adulthood before the age of 55 years. This finding is consistent with a recent observation from a Danish cohort of men, followed-up from 15 to 49 years, showing an association between all-cause mortality and low weight or short length at birth.14
While measurements of body size at birth are the best available markers of fetal growth, they remain only rough indicators of the hormonal and nutritional environment in utero. Our findings of robust relationships between them and all-cause premature mortality in adulthood implies a major impact of intrauterine conditions on health during later life. As the study population consisted of term-born individuals and the analysis was adjusted for gestational age, small size at birth can be considered an indicator of slow growth in utero, not premature birth.
How might the memory of intrauterine conditions be stored and later expressed? Studies have suggested several mechanisms. Organs whose growth is restricted in utero may retain a reduced functional capacity throughout the life course. For example, reduced number of nephrons, lesser elastin in blood vessel walls, or reduced muscle mass may contribute to the development of hypertension and impaired glucose tolerance.13,15 Intrauterine conditions may cause life-long alterations of key hormonal axes such as the hypothalamic–pituitary–adrenal axis, predisposing to elevated blood pressure and impaired glucose tolerance.16,17 In many cases, these same changes that increase cardiovascular risk may also increase risk of dying from other disorders. For example, long-term follow-up studies have shown increased non-cardiovascular mortality in subjects with diabetes.18 Recent animal studies suggest that intrauterine conditions may have a profound impact on adult behavioural characteristics such as stress responses17,19 and level of physical activity20 that are likely to affect mortality. A study within the Helsinki cohort showed that men who were small at birth were more vulnerable to the increased risk of coronary heart disease that is associated with low income: this association may be mediated through psycho-social stress.12
Epidemiological studies on fetal origins of cardiovascular disease have frequently raised questions about the extent and nature of possible sex differences. For example, previous studies in the Helsinki birth cohort have shown that while small size at birth predicts cardiovascular disease in both sexes, the determining measurement is thinness in males9,11 but shortness in females.10 Our findings in the present study suggest an extension of these sex differences to death from non-cardiovascular causes, which were strongly related to small size and shortness at birth in women but unrelated to body size at birth in men. However, it should be noted that sex differences, like all subgroup analyses, should be interpreted with caution. A recent meta-analysis of studies on the relationship between birthweight and systolic blood pressure in later life showed that sex-specific analyses are more likely to have been conducted in studies with weaker overall effects, suggesting publication bias.21 Nevertheless, there are several putative biological mechanisms that could account for this dissimilarity between sexes. Frequencies of different causes of death obviously differ greatly between sexes. Moreover, female fetuses grow more slowly. Because different parts of the body grow at different phases of gestation, sex differences in growth rates could lead to differences in body proportions at birth. In animals the rate of intrauterine growth is known to modify the effects of a brief period of maternal undernutrition on the offspring's body composition at birth.22 Experimental studies in rodents show that many sex characteristics are a result of programming by sex steroids during intrauterine and post-natal life and may be completely changed by manipulating this exposure.19,23 Minor variations in sex hormone concentrations during the fetal period may thus be a direct cause of changes that affect the risk of different common adult-onset disorders. Therefore, we believe that the sex difference we found in the relationship between size at birth and non-cardiovascular mortality represents a real biological phenomenon, but to confirm this requires replication in other studies and a more detailed understanding of the underlying mechanisms.
Since the major predictor of female all-cause mortality in this population, short length at birth, is also a strong predictor of morbidity from coronary heart disease,10 one might speculate whether this similarity could be due to actual cardiovascular deaths being coded as non-cardiovascular deaths. However, detailed validation studies have confirmed a high accuracy of the Finnish National Death Register in distinguishing between cardiovascular and non-cardiovascular deaths.24
In contrast to their increased all-cause and cardiovascular mortality,9,11 males who were born light or thin were less likely to die from cancer. This finding is consistent with several population-based and case–cohort studies showing a similar relationship concerning the incidence of individual cancers in both sexes. In particular breast,25,26 prostate,27 and renal28 cancers have been associated with high birthweight, while the risk for testicular cancer is increased at both ends of the birthweight spectrum.29 Differences in sex steroid exposure during intrauterine growth have been suggested to play a role in these associations.26,27 Moreover, a number of endocrine and paracrine growth factors that regulate somatic growth, such as the insulin-like growth factor system, in addition stimulate cancer cell proliferation, migration, and adhesion.30 However, different types of cancer may have different prenatal risk factors. To elucidate early-life determinants of specific types of cancer is not possible with the sample size of the present study. For example, our finding of a weak association between high birthweight and mortality from lung cancer was not observed in another study with approximately equal number of deaths in males but no data on length at birth available1 and remains to be confirmed. Moreover, it is important to note that the outcome in the present study was mortality from cancer. As most other studies have assessed the incidence of cancers with a relatively favourable prognosis, our findings may reflect, in part, types of cancer with a poorer prognosis.
Small size at birth is related to increased all-cause mortality at all ages among women but not in men. Among women, small size at birth predicts increased mortality from both cardiovascular and non-cardiovascular causes. Among men the well-known association between small birthsize and later cardiovascular disease is counterbalanced by an association between large body size at birth and later cancer. The significance of small size at birth on adult health is further highlighted by its particularly strong association with premature adulthood death.
KEY MESSAGES
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Acknowledgments |
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We thank Terttu Nopanen, Tiina Saarinen, Hillevi Öfverström-Anttila, Arja Purtonen, Tiina Valle, Hanna Pehkonen, and Ulla Tarvainen for abstracting the data from the records. Sigrid Rosten was responsible for data management. Liisa Toivanen coordinated data abstraction. The study was supported by grant from the Academy of Finland, British Heart Foundation, Finnish Diabetes Foundation, Finnish Heart Foundation, Finnish Medical Society Duodecim, Finska Läkaresällskapet, Foundation for Pediatric Research, Jalmari and Rauha Ahokas Foundation, Päivikki and Sakari Sohlberg Foundation, Signe and Ane Gyllenberg Foundation, The Royal Society, and Yrjö Jahnsson Foundation. No funding organization took any part in the design and conduct of the study; collection, management, analysis, or interpretation of data; or approval of the manuscript.
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