A Life‐Course Approach to Gestational Exposure to Famine and Risk of Mortality

The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that early-life environmental exposures, particularly during critical periods such as prenatal and early postnatal stages, have lasting impacts on an individual's health trajectory and risk of disease across the life-course [1]. Factors such as maternal nutrition, stress and toxic exposures may influence fetal programming, potentially altering physiological systems and metabolic pathways in ways that predispose individuals to chronic conditions like cardiovascular disease, obesity and diabetes. Understanding the long-term effects of these early-life exposures and the mechanisms underlying them is essential for developing effective prevention strategies that target early-life environments. In this issue of Paediatric and Perinatal Epidemiology, Wiegersma et al. [2] provided further support for the DOHaD hypothesis by examining the long-term effects of exposure to the Dutch famine on mortality risk. The Dutch famine—a 6-month period of severe food shortage in the western Netherlands during the final winter of World War II—offers a unique semi-experimental setting and serves as a counterpart to animal models studying the effects of restricted maternal nutrition during various stages of gestation [3]. This study followed individuals exposed to famine in utero up to age 76 and found that women, but not men, exposed to famine during early gestation had higher risks of overall, cardiovascular and cancer mortality [2]. This finding aligns with the authors' previous follow-up study up to age 64 [4], but contrasts with their earlier study that did not demonstrate an association between prenatal famine exposure and cause-specific mortality from ages 18 to 50, although this earlier study did not analyse associations separately for women and men [5]. The extended follow-up in this latest analysis, as the cohort nears the average life expectancy in the Netherlands, is a major strength. Moreover, the findings of higher mortality associated with famine exposure at older, rather than younger, ages support the authors' hypothesis that prenatal famine exposure may increase cardiovascular risk factors and disease, which are more likely to impact mortality later in life. An interesting element of the findings by Wiegersma et al. [2] is the marked sex differences in the effect of famine exposure on. It may be worthwhile to consider multiple potential explanations for these findings, as the mechanism affects the interpretation of results. First, it is possible that sex differences in adult mortality are explained by survivorship bias. The elevated vulnerability of male fetuses to environmental insults during gestation is well described and consistent across multiple deleterious exposures [6]; consistent with survivorship bias, authors note that male fetuses were less likely than female fetuses to be born alive during the famine. If in utero exposure increased the risk of miscarriage or stillbirth among less healthy male fetuses, the group of famine-exposed males born alive could be disproportionately healthier than their unexposed counterparts, which could have lifelong effects. A second potential explanation could be that the adverse effects of prenatal famine exposure manifest differently among adult men and women. For example, men exposed prenatally to the Dutch famine have been found to have smaller brain sizes, which may be linked to an elevated risk of dementia [7]. At the same time, previous research in this cohort reported that the elevated cancer mortality among women was driven by breast cancer [4]. If famine exposure disproportionately causes dementia in men and breast cancer in women, the mortality rate before age 76 may better capture the effects of prenatal exposure on women than men, though both sexes would be severely affected. Third, the authors mention that mediation by gendered factors, such as poorer cardiovascular healthcare among women, may explain the sex-specific effects of famine on health. Gender may also function in another way in this cohort: fig. 1 in the referenced study shows that all groups of men, regardless of famine exposure, appear to have a higher rate of death than unexposed women. Men's overall higher mortality rate in this cohort is consistent with elevated male mortality patterns noted in many societies; some scholars theorise that elevated male mortality is partially due to masculine gender expression (e.g., dangerous jobs, smoking and alcohol use) [8]. The negligible effects of prenatal exposure to famine among men may be a result of the higher baseline rates of mortality among men in this cohort. Finally, the role of chance should be considered: as the authors note, sex-specific variations in the effects of prenatal famine exposure on death are not consistently seen in other studies. The analysis by Wiegersma and colleagues was not designed to fully explore the mechanisms underlying effect modification by sex, but future research may more fully examine sex and gender as mediators and effect modifiers within the DOHaD framework. While the study by Wiegersma et al. [2] sheds further light on the influence of in utero exposures and long-term mortality, these findings should be interpreted within the context of several important considerations. The study findings may have been impacted by exposure misclassification based on the use of gestational age at birth to define the duration and trimester of exposure and the assumption of homogenous effects of exposure. Given the lack of medical technologies to accurately date pregnancies at the time of the Dutch famine, the classification of exposure may have been impacted by suboptimal estimates of gestational age at delivery. The assumption that famine exposure was similar across geographical locations and throughout the 6-month period may not hold as regional differences in the impact of the famine have been previously reported [9]. An additional consideration is the heterogeneous membership of the control group, specifically due to the inclusion of children born immediately following the famine, and infants exposed less than 13 weeks in utero. While the authors mention that ‘children younger than one year were relatively protected from the famine’, prior studies have shown that infants exposed to famine in the first 2 years of life are at increased risk of chronic conditions and mortality in adulthood [10]. Finally, the higher rates of infant mortality reported among infants exposed to the Dutch famine either in utero or in the first months of life, may have resulted in selection bias such that less susceptible or healthier infants survived to be included in the sample population used for this study. In summary, the study by Wiegersma et al. [2] underscores the long-term effects of in utero famine exposure, particularly during early gestation, on mortality risk and highlights notable sex differences. Future research should expand on these findings by linking early-life exposure data with life-course data, such as follow-up measurements from the Dutch famine birth cohort [3], to examine how exposures at various life stages interact with early adversities. This approach would enable researchers to explore resilience and adaptive capacity over time, offering insights into intervention points to reduce health risks associated with early-life adversities. By assessing cumulative exposures and sex-specific pathways within the DOHaD framework, future studies can better clarify the mechanisms underlying these long-term effects and ultimately inform targeted strategies to break the cycle of adverse health outcomes resulting from early-life exposures. All authors conceived and co-wrote this commentary. The authors declare no conflicts of interest.

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