Studies into severe famine in early life and diabetes in adulthood: the need to control for differences in participant age and location

To the Editor: In their very interesting study of China’s Great Famine of 1959–1962, Wang et al conclude that exposure to famine in the fetal or childhood period may increase diabetes risk in adulthood, and that both the prenatal and postnatal periods may offer critical time windows for the determination of diabetes risk [1]. These conclusions are incomplete and potentially misleading.

Our recent systematic review and meta-analysis of the relationship between prenatal exposure to the Chinese famine and long-term health outcomes shows that uncontrolled age differences between famine-exposed individuals and unexposed control individuals in previous studies could explain most of the effects commonly attributed to the famine [2]. This problem cannot be simply fixed by age-adjustment in regression models because there will generally be no overlap in the birth years of those with and without prenatal famine exposure [2]. Therefore, age adjustments will have no impact on risk estimate calculations.

In an attempt to avoid the age bias, Wang et al compared the odds of diabetes among study participants born in the same period but in different locations (severely vs moderately affected areas of China). This approach assumes that participants from the areas with varying famine severity are comparable in all respects, except for famine severity. The data presented by Wang et al (Table 4 in their article), however, show a diabetes prevalence of 9.8% (96/981) among unexposed participants in the severely affected area and only 5.7% (37/651) in unexposed participants in the moderately affected area. These numbers only provide weak support for valid comparisons between individuals from severely and moderately affected areas.

Table 1 further illustrates how sensitive the study results are to the choice of control groups of different ages. The estimated diabetes ORs ranged from 0.54 to 2.69, with the mean age of control groups ranging from 41 to 72 years across the areas of moderate and severe famine.

We conclude that, based on the data previously presented by Wang et al, the odds for diabetes in adulthood could be increased 1.4-fold after fetal exposure to famine among individuals from the areas affected by severe famine but not moderate famine during China’s Great Famine. These estimates are consistent with our findings from the Dutch famine of 1944–1945 [3] and the Ukraine famine of 1959–1962 [4].

These analyses illustrate, again, how important it is to control for age effects and area effects together in analyses carried out to estimate the association between early-life famine exposure and later life health outcomes.