Infant mortality at time of birth and cause-specific adult mortality among residents of the region of Madrid born elsewhere in Spain

Enrique Regidora, Juan L Gutiérrez-Fisacb, M Elisa Callea, Pedro Navarroa and Vicente Domíngueza

a Department of Preventive Medicine and Public Health, Faculty of Medicine, Universidad Complutense de Madrid, Spain.
b Department of Preventive Medicine and Public Health, Faculty of Medicine, Universidad Autónoma de Madrid, Spain.

Enrique Regidor, Department of Preventive Medicine and Public Health, Faculty of Medicine, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain. E-mail: enriqueregidor{at}hotmail.com

Abstract

Background To investigate the association between infant mortality at time of birth and mortality from various causes of death in adulthood in men and women.

Methods Linked mortality study based on mortality records for 1996 and 1997 and on 1996 population census data of the Region of Madrid (Spain). Deaths from five cancer sites and from five chronic diseases were estimated for 1 224 894 people aged 35–74 years residing in the Region of Madrid who were born elsewhere in Spain.

Results A gradient in mortality by infant mortality quartile was seen for mortality from stomach cancer, colon cancer, diabetes mellitus and chronic liver disease in men, and for stomach cancer, ischaemic heart disease and chronic liver disease in women. The association was positive for stomach cancer and negative for all other causes. The relative mortality rates adjusted for age and adult socioeconomic factors for men belonging to infant mortality quartiles 3 and 4 (highest) versus those belonging to quartiles 1 and 2 as baseline were 1.06 (95% CI : 0.75–1.56) for stomach cancer, 0.67 (95% CI : 0.47–0.95) for colon cancer, 0.59 (95% CI : 0.35– 1.00) for diabetes mellitus, and 0.70 (95% CI : 0.49–0.99) for chronic heart disease. The relative mortality rates for women were 2.06 (95% CI : 1.09–3.88) for stomach cancer, 0.58 (95% CI : 0.41–0.80) for ischaemic heart disease, and 0.44 (95% CI : 0.27–0.70) for chronic liver disease.

Conclusion Higher infant mortality at time of birth is associated with adult mortality from diabetes mellitus and colon cancer in men, from ischaemic heart disease in women, and from stomach cancer and chronic liver disease in both sexes. These results most likely reflect adverse living conditions and/or nutritional deprivation in childhood.

Keywords Infant mortality, deprivation in childhood, living conditions, mortality, cancer, chronic diseases

Accepted 15 November 2001

Ecological studies carried out since the late 1970s have shown a strong geographical correlation between mortality from various causes of death in adulthood and infant mortality around the time of birth in those whose risk of mortality was studied.1–5 Infant mortality was taken to be an index of deprivation in childhood that reflected nutritional deprivation and/or living conditions in early life. In general, these studies have shown that mortality from stomach cancer, stroke and chronic obstructive pulmonary disease is predicted more strongly by infant mortality or by the distribution of poverty in the early 20th century than by current socioeconomic conditions.

Individual-level studies that have been carried out to test this hypothesis have focused mainly on two diseases: ischaemic heart disease and stroke. Most such studies have shown that the risk of ischaemic heart disease is associated with adverse living conditions in early life, although the magnitude of the association decreases when adult socioeconomic conditions are taken into account.6–9 In the case of stroke, some studies have observed this relation,9,10 whereas others have not.7,8

Except for one study in women,7 most of these investigations at the individual level have been carried out in men. Furthermore, only one study has analysed the influence of adverse socioeconomic conditions in early life on other chronic diseases.9 To assess the importance of deprivation in early life on a large variety of diseases in men and women, we investigated the association between infant mortality in the place of birth at the time of birth and mortality from the five cancer sites and the five chronic diseases that cause the largest number of deaths in Spain. The study subjects were Spanish migrants residing in the Region of Madrid.

Methods

This study is based on information from the 1996 population census and from the 1996 and 1997 mortality registries for the Region of Madrid. Both sources of data contain information about the population residing in the region. The 1996 population census includes all those who resided in the Region of Madrid on 1 May 1996, therefore deaths occurring between 1 January and 30 April 1996 were excluded from the present study. The two data sets were linked using personal characteristics, and linkage was achieved for 70% of all the deceased. No significant variations in this percentage were found by sex or age group. Place of birth, area of residence and socio-demographic characteristics were taken from the population census, while cause of death was taken from the mortality registry.

The analysis was restricted to men and women aged 35–74 years who were born in Spain, but in a place other than the Region of Madrid. The childhood deprivation index, the main study variable, was obtained as follows: in each of the eight 5-year periods between 1922 and 1961 the 50 provinces of Spain (49 provinces plus the Region of Madrid) were ordered by infant mortality rate from lowest to highest. For each period we estimated the quartiles for the distribution of infant mortality; that is, the first quartile included the provinces with the lowest infant mortality rates in each 5-year period, while the fourth quartile included those with the highest. Each individual was then assigned to one of the four quartiles of infant mortality depending on the province and year of birth. People born in Madrid were excluded from the analysis because they do not share a common characteristic with the rest of the population: migration. Furthermore, because they are so large in number compared with the migrant population, the magnitude of the mortality in the quartile where they were included would have to be mainly attributed to their presence.

The confounding variables included in the present study were age, educational level (elementary or less, lower secondary, upper secondary, and tertiary), employment status (employed or not in the labour force) and deprivation category based on area of residence. Deprivation category varied from 1 (least deprived) to 4 (most deprived) and was estimated from the mean household income in 200 areas of residence. Most of these areas had a population of fewer than 20 000, although 10% of them were districts of the city of Madrid with a mean population of 140 000.

Men and women were analysed separately. Mortality was analysed for the cancer sites and the chronic diseases that produce the largest number of deaths in Spain, and whose association with living conditions—stomach and lung cancers, ischaemic heart disease, stroke, and chronic obstructive pulmonary disease—and/or with nutritional deprivation—colon, prostate and breast cancers, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and diabetes mellitus—in early life had been studied in previous investigations. In addition, we included another important chronic disease that has not been examined in such studies: chronic liver disease and cirrhosis. The statistical analyses were based on the Poisson regression model with cause-specific mortality as the dependent variable. The parameters of the Poisson models are presented as relative mortality rates according to infant mortality quartiles, adjusted first for age and second for both age and adult socioeconomic variables. Test for trends of relative mortality rates were obtained by Poisson regression with the infant mortality quartile coded as a continuous variable, and with the rest of the variables included in the model.

Results

The data on individual socioeconomic characteristics by infant mortality quartile at time of birth are shown in Table 1Go. People belonging to quartiles 1 and 2 were more likely to have tertiary education and less likely to live in the most deprived area of the Region of Madrid.


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Table 1 Population characteristics by infant mortality quartile in place of birth at time of birth
 
Table 2Go shows the relative mortality rates for men adjusted for age and adjusted for both age and adult socioeconomic factors, for each cause of death analysed. After adjustment for all variables, men born in provinces with the highest infant mortality had a greater risk of mortality from stomach cancer and a lower risk of mortality from colon cancer, diabetes mellitus and chronic liver disease than men born in provinces with the lowest infant mortality, with a significant test for trend across the infant mortality quartiles. Men belonging to infant mortality quartiles 3 and 4 had a relative mortality rate in comparison to those belonging to quartiles 1 and 2 from stomach cancer, colon cancer, diabetes mellitus and chronic liver disease of 1.09 (95% CI : 0.75– 1.56), 0.67 (95% CI : 0.47–0.95), 0.59 (95% CI : 0.35–1.00) and 0.70 (95% CI : 0.49–0.99), respectively.


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Table 2 Relative mortality rates (95% CI) for men adjusted for age and for adult socioeconomic factors, with number of deaths
 
Table 3Go shows the relative mortality rates for women adjusted for age as well as for both age and adult socioeconomic factors. After adjustment for all factors, women from provinces with the highest infant mortality had a greater risk of mortality from stomach cancer, with a significant test for trend across the infant mortality quartiles. On the other hand, women born in provinces belonging to quartiles 3 and 4 of infant mortality had a lower risk of mortality from ischaemic heart disease and chronic liver disease than those belonging to quartiles 1 and 2. Women belonging to infant mortality quartiles 3 and 4 had a relative mortality rate in comparison to those belonging to quartiles 1 and 2 from stomach cancer, ischaemic disease and chronic liver disease of 2.06 (95% CI : 1.09–1.52), 0.58 (95% CI : 0.41–0.80) and 0.44 (95% CI : 0.27–0.70), respectively.


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Table 3 Relative mortality rates (95% CI) for women adjusted for age and for adult socioeconomic factors, with number of deaths
 
Discussion

This is the first study at the individual level that analyses the effect of a proxy for deprivation in early life on a large variety of causes of death in men and women, after adjusting for socioeconomic conditions in adulthood. For this purpose, we studied cause-specific mortality in residents of the Region of Madrid who were born in other provinces of Spain.

Stomach cancer
Previous studies have shown correlations between infant mortality at the time of birth or socioeconomic conditions in childhood and adult mortality from stomach cancer.4,5,9 In the present study the confidence intervals of the relative risks in men include the value of the null hypothesis; however, when we estimated a global measure of the effect by means of the trend, the association between infant mortality at time of birth and stomach cancer was significant. Over the last decade increasing evidence has pointed to the key role of Helicobacter pylori infection in the aetiology of stomach cancer.9,11 This infection is thought to be acquired in childhood in conditions of poor hygiene and inadequate housing standards. Thus, the results of this study probably reflect a larger burden of early H. pylori infection in people born in places with high infant mortality. The association was found to be stronger in women than in men, similar to a study that analysed the relation between the prevalence of H. pylori in adulthood and mortality from gastric cancer in people under 70.12 Emerging evidence suggests that factors that influence the ecology of the gastric niche or the immune response may also influence persistence,13 thus it could be hypothesized that H. pylori infection in early life requires other co-factors to produce its effects. These unknown co-factors may also explain why the influence of conditions in childhood on risk of mortality from stomach cancer are different in each sex.

Colon, breast and prostate cancer
In addition to poor sanitary conditions, the higher infant mortality rate in the first half of the 20th century probably reflects a lower energy intake in early life. Animal studies have shown that lifelong restriction of total energy intake or reduced food consumption in early postnatal life inhibits tumourigenesis.14 Likewise, epidemiological studies in humans have observed that early excess energy intake relative to requirements, manifested as increased height or leg length, has negative consequences with regard to several major cancers.15,16 Some of the mechanisms postulated include greater exposure to mitogenic factors, and there is empirical evidence of the relation between insulin-like growth factor-I and the development of colon cancer, premenopausal breast cancer, and prostate cancer.17

No significant association with mortality from prostate cancer and breast cancer was observed in this study. Nevertheless, in the case of breast cancer the relative mortality risk in women belonging to quartiles 3 and 4 compared with those in quartiles 1 and 2 was 0.80 (95% CI : 0.70–0.86) in women aged 35–54 years, but 1.00 (95% CI : 0.52–1.24) in women aged 55–74 years (data not shown).

The results obtained in colon cancer in men are also compatible with this theory: those born in places with higher infant mortality had a lower risk of mortality from this cause. A study that evaluated the relation between height and leg length and mortality from cancer unrelated to smoking found that the magnitude of the association was greater in men than in women;18 likewise, another study found that the relation between height and mortality from colon cancer was statistically significant in men but not in women.19 In a similar way obesity, another indicator of positive energy balance, is also associated with colon cancer in men but not in women.20

Diabetes mellitus and ischaemic heart disease
Men born in places with higher infant mortality also had a lower risk of mortality from diabetes mellitus. Different observational epidemiological studies have found that non-insulin dependent diabetes and colon cancer share a constellation of risk factors associated with insulin resistance and hyperinsulinaemia.20,21 It is likely that excessive energy intake in early life leads to a greater risk of hyperglycaemia due to greater body mass resulting from excessive growth, and that the increased secretion of growth hormone during puberty may also counteract insulin in the peripheral tissues.

In experimental animals it has been observed that growth retardation resulting from dietary restriction is greater in males than in females.22 One author has noted that men also experience more growth retardation than women as a result of adverse environments.23 This may be the reason why some effects of nutritional insults are manifested more in men than in women.

Several studies have shown an association between low birthweight and risk of type 2 diabetes mellitus during adulthood.24 It could be hypothesized that the proportion of people with low birthweight was higher among those who were born in areas with higher infant mortality, and thus the risk of mortality from diabetes mellitus should have been higher. This most likely did not occur because the variation in birthweight in the people included in this study is probably quite small. It has been observed that the mean birthweight of migrants is higher that than of non-migrants,25,26 however, in an already selected population of migrants there are unlikely to be large variations in birthweight.

Ischaemic heart disease is also associated with low birthweight, and the relation between reduced fetal growth and the risk of ischaemic heart disease is increased by ‘catch up’ growth in the early years of life.27,28 In women this increased risk is associated with an above average height in childhood, whereas in men it is associated with an above average body mass index in childhood. It is likely that the results found depend exclusively on growth in childhood due to the small variation in the prevalence of low birthweight as a consequence of selective migration. Thus, the greater dietary restriction to which people born in places with higher infant mortality were presumably exposed, resulting in less growth in height, probably explains the results observed in women for this cause of death.

Chronic liver disease and remaining causes of death
The findings with respect to chronic liver disease may be related to the occurrence of hepatitis B infection in early life, when the probability of developing chronic liver disease is higher.29 Although this form of transmission is now infrequent in the more developed countries, it may have been a frequent mechanism in the first part of the 20th century. In fact, the decline in mortality from this disease may be a result of the reduced prevalence of hepatitis B infection due to improved socioeconomic conditions. The risk of chronic infection is greater the earlier the infection is acquired, and in this respect it has been observed that children with older siblings are exposed much earlier.30 This could explain the results found in this study, since the longer survival of children in places with lower infant mortality could result in a greater prevalence of infection than in places where infant mortality is higher.

No relation was found between infant mortality at time of birth and mortality from stroke, lung cancer and chronic obstructive pulmonary diseases. Most studies have found a relation between socioeconomic conditions in early life and mortality from chronic obstructive pulmonary disease. The absence of a relation in this study may be due to the lack of variation in birthweight mentioned, since it has been observed that birthweight is associated with reduced adult lung function and with adult mortality from chronic obstructive airways disease.31

Limitations of the study
Some limitations should be taken into account when interpreting these results. In the first place, it was not possible to control fully for adult socioeconomic status due to the fact that important variables such as income or asset wealth were not available. In addition, although information on the duration of residence is very important in studies of migrant populations, this variable was not available. Nevertheless, differences in the mean duration of residence in each infant mortality quartile are unlikely, since the mean age of the people studied was similar. One must also consider the possibility of a bias if the percentage of individuals for whom mortality register data could be linked with the population census was different depending on the infant mortality rate in the place of birth. However, this percentage was similar in the different categories of the variable of exposure.

It has been noted that the migrant population is healthier than the non-migrant population as the result of a selection bias. Thus it has been assumed that, within an already selected population, there are unlikely to be variations in the characteristics that give rise to migration in each of the infant mortality quartiles. However, if the characteristics that predict migration to Madrid vary by the level of exposure, the possible existence of a selection bias cannot be ruled out. Migration to Madrid from well-off areas—those with low infant mortality—may have been a fairly random event, whereas among people born in disadvantaged areas, it may be that only those with characteristics predictive of better survival were able to migrate to Madrid. After adjusting for age, sex and the remaining variables included in the study, mortality among residents who were born elsewhere compared to that of residents who were born in Madrid was 0.91 for people from areas 1 and 2, and 0.80 for those from areas 3 and 4. These estimates suggest that migration from wealthier areas was probably not a random event, but rather occurred among healthier people, and that this selection bias was likely to have been much greater in migration from poorer areas. This would produce a systematic underestimate of the mortality of migrants from high infant mortality areas compared to migrants from low infant mortality areas. However, if this selection bias is assumed to exist, one would also have to assume that this bias was differential depending on the cause of death, since otherwise the underestimate would have to be very large to neutralize the strong relation observed in some causes of death studied.

In summary, the results obtained are compatible with studies that have suggested an effect of living conditions and nutritional status in early life on mortality from various causes of death.


KEY MESSAGES

  • Infant mortality at time of birth was used as an indicator of living conditions and/or nutritional status in early life in residents of the Region of Madrid who were born elsewhere.
  • Infant mortality at time of birth is positively associated with adult mortality from stomach cancer, especially in women.
  • Infant mortality at time of birth is negatively associated with adult mortality from diabetes mellitus and colon cancer in men, from ischaemic heart disease in women, and from chronic liver disease in both sexes.
  • The possibility of a selection bias cannot be ruled out in interpreting these results. However, this bias would have to be differential with respect to the causes of death, since the association found with some causes of death was quite strong.

 

Acknowledgments

This study was supported by a grant from the Consejería de Educación de la Comunidad de Madrid (no. 06/0092/1999) and by a grant from the Fondo de Investigaciones Sanitarias (no. 00/0514/ 1999). We would like to express our thanks to Salvador de Mateo for their comments about statistical analysis.

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