Prenatal and early-life exposure to the Great Chinese Famine increased the risk of tuberculosis in adulthood across two generations

Abstract

Global food security is a major driver of population health, and food system collapse may have complex and long-lasting effects on health outcomes. We examined the effect of prenatal exposure to the Great Chinese Famine (1958-1962)-the largest famine in human history-on pulmonary tuberculosis (PTB) across consecutive generations in a major center of ongoing transmission in China. We analyzed >1 million PTB cases diagnosed between 2005 and 2018 in Sichuan Province using age-period-cohort analysis and mixed-effects metaregression to estimate the effect of the famine on PTB risk in the directly affected birth cohort (F1) and their likely offspring (F2). The analysis was repeated on certain sexually transmitted and blood-borne infections (STBBI) to explore potential mechanisms of the intergenerational effects. A substantial burden of active PTB in the exposed F1 cohort and their offspring was attributable to the Great Chinese Famine, with more than 12,000 famine-attributable active PTB cases (>1.23% of all cases reported between 2005 and 2018). An interquartile range increase in famine intensity resulted in a 6.53% (95% confidence interval [CI]: 1.19-12.14%) increase in the ratio of observed to expected incidence rate (incidence rate ratio, IRR) in the absence of famine in F1, and an 8.32% (95% CI: 0.59-16.6%) increase in F2 IRR. Increased risk of STBBI was also observed in F2. Prenatal and early-life exposure to malnutrition may increase the risk of active PTB in the exposed generation and their offspring, with the intergenerational effect potentially due to both within-household transmission and increases in host susceptibility.

Keywords: Great Chinese Famine; food systems; infectious disease; nutrition; tuberculosis.

Fig. 1.

Spatial variation in (A) CSSI, an indicator of famine intensity based on shrinkage in average birth cohort size over the famine period; and (B) annual mean active PTB incidence rate 2005–2018.

Fig. 2.

Active PTB incidence rate by year of diagnosis and age group at diagnosis among (A) men and (B) women. Colors represent the incidence rate, with red representing higher incidence rates and blue representing lower (note the differing scales in A and B). Each row represents the incidence rate across calendar years for that age group; each column represents the incidence rate across age groups for that year; and each diagonal line represents the change in incidence rate for that birth cohort as they age. The boxes outline the famine birth cohort (F1) and their likely offspring (F2). See definitions of F1 and F2 in Materials and Methods.

Fig. 3.

Marginal IRRs for active PTB in each (A) age group, (B) period, and (C) cohort group in relation to the overall geometric mean incidence rate of all groupings given by the intrinsic estimator per model [1]. Estimation was conducted separately for men (blue) and women (red). Colored solid lines and the surrounding shaded areas represent estimated effects and 95% CIs, while dashed lines in C represent counterfactual cohort effects in the absence of famine predicted by smoothing splines. In C, the black vertical lines indicate the midpoint of the F1 and F2 cohorts.

Fig. 4.

Impact of the Great Chinese Famine on active PTB risk in directly affected birth cohort (F1). (A) Province-level IRR by sex. (B) Spatial heterogeneity in prefecture-level IRR. Prefectures are colored according to their IRRs, with darker colors representing higher IRRs. (C) Scatterplot of CSSI and IRR of F1 across prefectures (dots). The size of the dot is proportional to the inverse variance of the estimated IRR of that prefecture. The line represents the metaregression fit, and the shaded area represents the 95% CI.