摘要：Objectives. We sought to analyze how early exposure to the 1918 influenza pandemic is associated with old-age mortality by cause of death. Methods. We analyzed the National Health Interview Survey (n = 81 571; follow-up 1989–2006; 43 808 deaths) and used year and quarter of birth to assess timing of pandemic exposure. We used Cox proportional and Fine-Gray competing hazard models for all-cause and cause-specific mortality, respectively. Results. Cohorts born during pandemic peaks had excess all-cause mortality attributed to increased noncancer mortality. We found evidence for a trade-off between noncancer and cancer causes: cohorts with high noncancer mortality had low cancer mortality, and vice versa. Conclusions. Early disease exposure increases old-age mortality through noncancer causes, which include respiratory and cardiovascular diseases, and may trigger a trade-off in the risk of cancer and noncancer causes. Potential mechanisms include inflammation or apoptosis. The findings contribute to our understanding of the causes of death behind the early disease exposure–later mortality association. The cancer–noncancer trade-off is potentially important for understanding the mechanisms behind these associations. Adverse early life conditions may have lasting effects on old-age health and mortality. 1–8 Some even consider reductions in early life disease exposure to be a primary driver of historical mortality declines. 9 Although the precise mechanisms linking early disease exposure to poor adult health remain unclear, numerous pathways have been postulated including those relating to fetal undernutrition and dysregulation of immune function. 3,10,11 In animal models, experimental evidence suggests a negative causal effect of early disease exposure on later health. 12–14 For humans, historical epidemics have been used to study the effects of early disease exposure on later health. 1,2,4,15 These studies often find that those born around the time of an epidemic exhibit worse adult health and mortality than do neighboring cohorts. 1,2,4 However, the causes of death contributing to the excess mortality are not known. Moreover, research on early exposure to the deadliest epidemic of the 20th century—the 1918 influenza pandemic—is mixed, showing increased cardiovascular disease prevalence and lower socioeconomic attainment, 1,4 but no long-term mortality effects. 15 We investigated whether US cohorts with early exposure to the 1918 pandemic experience differential mortality at old ages compared with neighboring cohorts. The 1918 pandemic, caused by the influenza A virus (subtype H1N1), arrived in the United States in 3 waves. 16 During the first wave, which began in March 1918 and was completed by July 1918, incidence rates were high, but mortality was only slightly elevated. The second and the deadliest wave began in September 1918 and lasted until the end of the year. The third wave, with a mortality impact between those of the first 2 waves, occurred from January 1919 to March 1919. Approximately 30% of the US population was infected and about 0.5% of the population died because of the pandemic, mostly from pneumonia. 16 Excess mortality had an unusual pattern as those aged 20 to 40 years were affected particularly strongly. 16 The advantages of focusing on the 1918 pandemic are threefold. First, the pandemic arrived unexpectedly and lasted for only a short period, allowing treatment of the pandemic as a “natural experiment” wherein cohorts born months apart experienced different exposures but were otherwise compositionally similar in terms of other childhood characteristics and environmental conditions. Moreover, the exposed and nonexposed cohorts were born in a narrow enough time interval that timing of birth is not systematically linked to subsequent differences in the adult environment. Second, in contrast to older epidemics, existing data permit cause-of-death analyses. Third, although food shortages and disease tended to co-occur in historical populations, the 1918 pandemic allows focusing on disease because there were no generalized food shortages in the United States during the pandemic. Nutritional deprivation caused by disease, however, may function as a mediator. We extended previous research in 3 important dimensions. First, although earlier studies have analyzed the relationship between early disease exposure and later-life mortality, 2,15,17 it is not known what causes of death drive the association. We analyzed mortality by cause, which can enhance our understanding of potential mechanisms. Second, previous research on early disease exposure and later mortality has analyzed annual birth cohorts. 2,5,15 We distinguished cohorts by year and quarter of birth, which provides a far more nuanced analysis of exposure timing. Third, previous work on the long-lasting effects of the pandemic has not accounted for the fact that the pandemic arrived in waves. 1,4,15 Because of variation in the immediate mortality effects of each wave, there may be differences with respect to long-lasting effects. Our analysis accounted for exposure to each wave.
