The Dutch famine birth cohort study
The Dutch famine study provided the first direct evidence in humans that undernutrition during gestation increases the risk of many diseases that plague our society, such as heart disease, diabetes, airways disease, obesity, renal disease and cancer. The effect size is striking: compared to controls, men and women conceived during the Dutch famine have twice as much cardiovascular disease, and women exposed to famine during gestation even had a 5-fold increase in breast-cancer risk.
The effects of famine appeared to depend on its timing during gestation, and the organs and tissues undergoing critical periods of development at that time. Early gestation appeared to be the most vulnerable period. People who were conceived during the famine – and who had been exposed to famine in early gestation – had a more atherogenic plasma lipid profile (14), altered blood coagulation (15), unhealthy lifestyle choices (16), were more responsive to stress (17) and had an doubled risk of coronary heart disease (18,19). Women in this group also tended to have the highest body mass index (20), and had an increased risk of breast cancer (21). It is of interest to note that people exposed to famine in early gestation were not small at birth, but did have the most health problems in later life. Although many of these diseases (such as coronary heart disease) were linked to small size at birth, the effects of famine were independent of this. Based on the size of these babies at birth one would not have predicted these health effects. The transition from poor nutrition in early gestation to better nutrition later on may have lasting consequences for health in later life.
We found that undernutrition during any period of gestation was associated with reduced glucose tolerance and raised insulin concentrations at age 50 and 58. Importantly, this effect was larger than could be explained by the lower birth weights of babies born during the famine and by the low weight gain of their mothers. (22,23). Also, exposure to famine in mid gestation was linked to a 3.2 fold increase in occurrence of microalbuminurea in adulthood and a 10% increase in creatinine clearance, neither of which can be explained by cardiovascular confounders (24). We propose that mid gestational exposure to famine – the period of rapid increase in nephron number- may prevent formation of sufficient glomeruli and thus increase the risk for microalbuminurea and possibly affect renal function in adulthood. This supports the concept that intrauterine conditions during distinct, organ-specific periods of sensitivity may permanently determine health outcome in later life. Another finding in our study also supports this concept: we found that people who had been exposed to famine in mid gestation had an increased prevalence of obstructive airways disease (25). These observations were not paralleled by reduced lung function or increased serum concentrations of IgE. This suggests that the increased prevalence of symptoms and disease may be attributable to increased bronchial reactivity rather than to irreversible airflow obstruction or atopic disease. Because the bronchial tree grows most rapidly in mid gestation, our findings support the hypothesis that fetal undernutrition permanently affects the structure and physiology of the airways during ‘critical periods’ of development that coincide with periods of rapid growth.
Women – but not men – who were exposed to the Dutch famine of 1944-45 in utero were more reproductively successful than women who were not exposed to famine during their fetal development; they had more offspring, more twins, were less likely to remain childless and started reproducing at a younger age (26). The increased reproductive success of these women is unlikely to be explained by genes which favor fertility and are passed from mothers to their daughters. In utero exposure to famine did not affect the reproductive success of males. These findings suggest that poor nutrition during fetal development, followed by improved nutrition after birth can give rise to a female phenotype characterized by greater reproductive success.
The constellation of reproductive and metabolic adaptations during fetal development in response to undernutrition in utero may be part of a thrifty phenotype which is associated with enhanced reproduction. Post-war Holland provided a postnatal environment of food abundance, which was unlike the conditions anticipated by the environment in utero. This disadaptation of a thrifty phenotype may be important in the later occurrence of chronic disease. We have shown that people exposed to famine during gestation have increased risk of cardiovascular disease, metabolic disease, breast cancer and obesity rates. In conclusion, our findings are consistent with the theory of life history regulation, which proposes that the two traits fertility and body maintenance are mutually balanced, investments in one, are traded off by reduction in investment in the other (27). Our findings show that the balance in phenotypic traits underpinning life history regulation may be set by the environmental conditions during fetal development.
We found preliminary evidence that grand-maternal exposure to famine for a brief period during gestation is associated with increased neonatal adiposity and poorer health in the grand-offspring (28). These findings constitute the first direct evidence in humans that the detrimental effects of poor maternal nutrition during gestation on health in later life pass down to subsequent generations. This may imply that improved maternal nutrition during gestation may benefit the health of many generations to come. Also, these findings indicate that the transgenerational effects of famine exposure in utero on health in later life differ depending on the exposed parent’s sex. Increased neonatal adiposity was only found among the children of prenatally exposed women, whereas poor health was reported among the offspring of both men and women who had been conceived in famine. Importantly, this indicates that effects on health in later life also pass down transgenerationally through the male line. Transgenerational effects of a poor intrauterine environment may thus affect the entire generation parented by exposed individuals.
The findings of the Dutch famine birth cohort study broadly support the fetal origins hypothesis. Chronic diseases originate in the womb through adaptations made by the fetus in response to undernutrition. The effects of undernutrition, however, depend upon its timing during gestation and the organs and systems developing during that critical time window. Furthermore, our findings suggest that maternal malnutrition during gestation may permanently affect adult health without affecting the size of the baby at birth. This gives the fetal origins hypothesis a new dimension. This may imply that adaptations that enable the fetus to continue to grow may nevertheless have adverse consequences for health in later life. Coronary heart disease may be viewed as the price paid for adaptations made to an adverse intra-uterine environment. It also implies that the long-term consequences of improved nutrition of pregnant women will be underestimated if these are solely based on the size of the baby at birth.
The Dutch famine study has established the importance of maternal nutrition during early pregnancy for the offspring’s cardiovascular risk. The nutritional experience of babies who were exposed to famine in early gestation may resemble that of babies in developing countries whose mothers are undernourished in early pregnancy and receive supplementation later on, but also of babies in developed countries whose mothers suffer from severe morning sickness. Morning sickness is common in the first trimester, and severe morning sickness is associated with metabolic changes in the mother which are similar to those seen during starvation. Since the results of our study consistently show that the effects of undernutrition are independent of size at birth, the assumption that the long-term consequences of hyperemesis gravidarum will be limited because of the normal size of the babies at birth no longer holds. The consequences of hyperemesis gravidarum for the health of the offspring need to be investigated. We also need to study the consequences of dieting before pregnancy, or unbalanced diets as well as fasting during pregnancy. Although the Dutch famine was an exceptional situation, the nutritional experience of these babies may resemble that of babies developing today. We need to use this information to optimize maternal nutrition before and during pregnancy in order to prevent chronic degenerative diseases in generations to come.