Title: Prenatal famine exposure and later-life risk of type 2 diabetes
Description: Background The Chinese famine of 1959–61 has been widely interpreted as an important driver of current and future epidemics of type 2 diabetes (T2D). 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 on study results, and identify whether study results can be related to any characteristics. Methods We searched PubMed, Embase, Wanfang Data, and CNKI databases for studies that examined the relationship between T2D and prenatal exposure to the Chinese famine up to January, 2021. From included studies, we abstracted information on the number of T2D cases and populations at risk among individuals born during the famine (famine births), born before the famine (pre-famine births), and born after the famine (post-famine births). We examined the quality of studies with the modified Newcastle–Ottawa scale. We compared T2D in famine births to different controls: post-famine births, pre-famine and post-famine births combined (age-balanced), and pre-famine births.

Fixed-effects models and random-effects models were used to calculate summary estimates. Heterogeneity across studies was assessed, and subgroup analyses were performed using sex, age at the survey, T2D measurements, famine intensity, residence, and publication language as possible effect modifiers. Findings Of 5,363 studies identified, 18 studies met our inclusion criteria. All studies defined famine exposure based on participants' years and/or months of births. Sample sizes ranged between around 300 and over 80,000 across studies. When post-famine births were used as controls, we found an increased risk of T2D (OR 1.48, 95% CI 1.30–1.68) among famine births based on the random-effects model. Using age-balanced controls, we did not find any increased risk of T2D (1.09, 95% CI 0.98–1.22). When pre-famine births were used as controls, famine was associated with a reduction in risk (0.85, 95% CI 0.75–0.97). Large variations and inconsistencies were identified in study design, famine intensity assessment, and covariate adjustment across studies.

Conclusion Our analysis shows that it still remains an open question whether the Chinese famine has contributed substantially to the current T2D epidemic in China. Studies with more rigorous methods will need to quantify this relationship. The four-level famine intensity instrument developed in this study is a robust measure to identify a potential dose-response relation between famine exposure and health outcomes. It is likely to improve the reproducibility and generalizability of future studies.