Early-life exposure to the Chinese famine of 1959-61 and type 2 diabetes in adulthood: a systematic review and meta-analysis

Background The Chinese famine of 1959-61 has been widely interpreted as an important driver of current and future type 2 diabetes (T2D) epidemics. We conducted a systematic review and meta-analysis of prenatal famine exposure and type 2 diabetes (T2D) in China to summarize study characteristics, examine impacts of control selections and other selected characteristics on study results, identify other characteristics influencing results, and formulate recommendations for future studies. Methods We searched English and Chinese databases for studies that examined the relationship between T2D and prenatal exposure to the Chinese famine up to February 8th, 2022. From included studies, we extracted information on the number of T2D cases and populations at risk among individuals born during the famine (famine births), before the famine (pre-famine births), and after the famine (post-famine births). We compared the risk of T2D in famine births to different controls: post-famine births, pre- and post-famine births combined, and pre-famine births. Heterogeneity across studies was assessed, and random-effects models were used to calculate summary estimates. Meta-regressions were used to examine the relationship between effect estimates and age differences. Subgroup analyses were performed based on selected characteristics, including participants' sex, age, T2D measurement, famine intensity, residence, and publication language. Findings In total, 23 studies met our inclusion criteria. Sample sizes ranged from below 300 to over 350,000. All studies defined famine exposure based on participants' date of birth, and 18 studies compared famine births to controls of post-famine births to estimate famine effects on T2D. Famine and post-famine births had an age difference of three years and over in each study. Using post-famine births as controls, a random-effects model shows an increased risk of T2D (OR 1.50, 95% CI 1.34-1.68) among famine births. In contrast, a marginally increased risk of T2D (OR 1.12, 95% CI 1.02-1.24) can be observed using pre- and post-famine births combined as controls, and a decreased risk (OR 0.89, 95% CI 0.79-1.00) using pre-famine births as controls. Studies with larger age differences between comparison groups had larger famine effects. Effect estimates comparing famine births to pre- and post-famine births combined depend on none of above selected characteristics. Studies showed a large variation in sampling sources, famine intensity assessment, and confounding adjustment. Interpretation Current estimates of a positive relation between prenatal exposure to the Chinese famine and adult T2D are mainly driven by uncontrolled age differences between famine births and post-famine controls. Marginal or no effects remain after controlling for the differences in most Chinese famine studies. It remains an open question to what extent the famine is related to current T2D patterns in China. Studies with more rigorous methods including age-balanced controls and robust famine intensity measures will be needed to quantify this relationship. Funding None.