Long-term Mortality Effects of In-Utero Exposure - The 1918/19 Pandemic as a Natural Experiment with Relevance for the Future?

Infectious diseases and especially pandemics can have long-term health effects in addition to the immediate ones. This also applies to the intra-uterine environment, as the so-called Barker hypothesis states. Prospectively, one can only speculate whether the COVID-19 pandemic will have an impact on the current birth cohorts in the coming decades. A look back into the past could serve as a warning as it has been shown that the birth cohort of 1918/19 (in utero during the 'Spanish flu' and during the end of World War 1) had a reduced life expectancy from the age of 50 than the birth cohorts before and after. However, what has not yet been investigated are the specific causes of death leading to a higher mortality risk of the 1918/19 birth cohort later in life. So far, it is not known what the exact reasons for the increased mortality risk are and what causes of death lead to it, and if the causes of death depend on trimester in which the in-utero exposure took place. Furthermore, it is not known yet, if the causes of death depend on birth place, which can be attributed to the severity of the "Spanish flu" in the respective place. The latter is particularly important for Switzerland, a multilingual country with cultural diversity, which also has regional differences in pandemic policy and mortality.Therefore, the first objective of this study is to identify the main causes of death for the 1918/19 birth cohort in Switzerland and to compare the risk of dying from these causes with that of the surrounding birth cohort. The annual changes of the main causes of death are shown visually via a Lexis surface plot and modelled with an adapted hierarchical age-period-cohort model. The second object is to investigate whether the causes of death depend on the trimester in which the in-utero exposure took place, which is analysed with Fine and Gray competing risk regression models estimating hazard ratios of the cause-specific mortality. Third, the study identifies the spatial pattern of cause-specific mortality in later life of the birth place for those born in 1918/19 and relates it to the spatial pattern of the severity of "Spanish flu" (estimated by excess mortality, influenza morbidity or mortality) in each district using Bayesian diseased mapping models and spatial fusion models.Studying this is important to better understand how much exposure to an infectious disease during pregnancy affects life expectancy and how the risk of certain causes of death is affected by the severity of exposure. Since Switzerland was affected differently by the "Spanish flu" (due to geographical, demographic and cultural differences), spatial data help to analyse differences in cause-specific mortality due to different levels of exposure across the districts and due to exposure in different trimesters. In order to determine the main causes of death in those born in 1918/19, individual anonymised death data from 1969 - 2021 for cause-specific deaths are made available by legal agreements with the Swiss Federal Statistical Office. The weekly number of "Spanish flu" morbidity and mortality of each district will be transcribed and digitized to a database from the "Bulletin of the Swiss Health Office" for the years 1918/19.This study will result in a deeper understanding on long-term effects of an in-utero exposure to an infectious disease and assist in deriving appropriate interventions. Post-pandemic surveillance of a pandemic on neonatal health should be an important component of public health policy, in the post-COVID-19 era and also in future pandemics. Effects of in-utero exposure to COVID-19 of the current birth cohorts later in adulthood cannot yet be studied. However, the impact of past pandemics on in-utero exposed birth cohorts can be studied to raise awareness among today's health policies.