Severe prenatal shocks and adolescent health: Evidence from the Dutch Hunger Winter.

This paper investigates health impacts at the end of adolescence of prenatal exposure to multiple shocks, by exploiting the unique natural experiment of the Dutch Hunger Winter. At the end of World War II, a famine occurred abruptly in the Western Netherlands (November 1944-May 1945), pushing the previously and subsequently well-nourished Dutch population to the brink of starvation. We link high-quality military recruits data with objective health measurements for the cohorts born in the years surrounding WWII with newly digitised historical records on calories and nutrient composition of the war rations, daily temperature, and warfare deaths. Using difference-in-differences and triple differences research designs, we first show that the cohorts exposed to the Dutch Hunger Winter since early gestation have a higher Body Mass Index and an increased probability of being obese at age 18. We then find that this effect is partly moderated by warfare exposure and a reduction in energy-adjusted protein intake. Lastly, we account for selective mortality using a copula-based approach and newly-digitised data on survival rates, and find evidence of both selection and scarring effects. These results emphasise the complexity of the mechanisms at play in studying the consequences of early conditions.

Dairying, diseases and the evolution of lactase persistence in Europe.

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years1. Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions2,3. Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution.

Perinatal famine is associated with excess risk of proliferative retinopathy in patients with type 2 diabetes.

PURPOSE: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR). METHODS: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945. RESULTS: During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05). CONCLUSION: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications.

Early-Life Exposure to the Chinese Great Famine and Later Cardiovascular Diseases.

Objectives: This study aimed to examine the association between early life famine exposure and adulthood cardiovascular diseases (CVDs) risk. Methods: A total of 5,504 subjects were selected using their birthdate from national baseline data of the China Health and Retirement Longitudinal Survey to analyze the association between famine exposure in early life and CVDs risk in adulthood. CVDs was defined based on the self-reported doctor's diagnosis. Results: The prevalence of CVDs in the unexposed group, fetal-exposed, infant-exposed, and preschool-exposed groups was 15.0%, 18.0%, 21.0%, and 18.3%, respectively. Compared with the unexposed group, fetal-exposed, infant-exposed and preschool-exposed groups had higher CVDs risk in adulthood (p < 0.05). Compared with the age-matched control group, infancy exposed to famine had a significantly higher adulthood CVDs risk (OR = 1.52, 95% CI: 1.15, 2.01; p = 0.006). The association seems to be stronger among population with higher education level (P interaction = 0.043). Sensitivity analysis revealed consistent association between early-life famine exposure and adult CVDs risk. Conclusion: Early life exposed to the China great famine may elevate the risk of CVDs in adulthood.

Overweight and obesity at age 19 after pre-natal famine exposure.

BACKGROUND: Weight for height has been used in the past as an indicator of obesity to report that prenatal exposure to the Dutch famine of 1944-1945 determined subsequent obesity. Further evaluation is needed as unresolved questions remain about the possible impact of social class differences in fertility decline during the famine and because being overweight is now defined by a Body Mass Index (BMI: kg/m2) from 25 to <30 and obesity by a BMI of 30 or more. METHODS: We studied heights and weights of 371,100 men in the Netherlands born between 1943 and 1947 and examined for military service at age 19. This group includes men with and without prenatal exposure to the Dutch famine. RESULTS: There was a 1.3-fold increase in the risk of being overweight or obese in young adults at age 19 after prenatal famine exposure in early gestation. The increase was only seen in sons of manual workers born in the large cities of Western Netherlands and not among those born in smaller cities or rural areas in the West. Social class differentials in fertility decline during the famine did not bias study results. CONCLUSIONS: The long-term adverse impact of prenatal famine on later life type 2 diabetes and mortality through age 63 is already showing at age 19 in this population as a significant increase in overweight risk.

Exposure to the Great Famine in Early Life and the Risk of Obesity in Adulthood: A Report Based on the China Health and Nutrition Survey.

Intrauterine malnutrition has a long-term effect on human health. This study aimed to evaluate the associations between exposure to famine in early life and obesity in adulthood in Chinese adults. A total of 5033 participants (22,132 observations) of the China Health and Nutrition Survey (CHNS) in 1991-2015 were classified into three famine exposure groups according to their birth year: unexposed (1963-1966), fetal-exposed (1959-1962) and childhood-exposed (1955-1958). Compared with the unexposed group, the fetal-exposed group had higher levels of body-mass-index (BMI) and waist-circumference (WC), and higher prevalence of overweight and central obesity, whereas the childhood-exposed group had lower levels of the measurements. However, the positive associations of fetal exposure with BMI, WC and prevalence of overweight and central obesity were attenuated by additionally adjusting for age at survey. Stratified analysis showed that the adverse effect of fetal exposure to famine was only observed in subjects at several specific age-groups, and in men living in rural areas and in women living in more severe famine exposed areas (p for interaction < 0.05). Our results provide evidence for the weak effect of fetal exposure to famine on body measurements in adulthood, and suggest the importance of severity of famine exposure and timing of exposure.

Fleeing mass starvation: what we (do not) know about the famine-migration nexus.

The relationship between famine and migration has not been studied adequately to date. A systematic review of scholarship centred on famine and its demographic, political, and socioeconomic effects demonstrates the paucity of academic attention to the issue. This paper surveys the dominant hypotheses and findings regarding the connection between famine and migration. It delineates key questions that an interdisciplinary and case-based exploration of the subject should address, highlighting gaps in the literature with respect to population-level analyses. Primary observations about the literature reviewed include tenuous generalisations about the linkage between famine and migration and partial examination of the role of politics in enabling or prohibiting mobility during hunger-related crises. In addition, disciplinary silos influence which particular aspects of a famine are scrutinised and which are not appraised. In view of these concerns, international legal and humanitarian norms governing migration also need to pay closer attention to its association with famine.

Effects of prenatal exposure to the 1983-1985 Ethiopian great famine on the metabolic syndrome in adults: a historical cohort study.

The Ethiopian great famine was one of the severe forms of global famines ever documented in Africa as well as in the recent history of the world. Earlier famine studies, as natural experiments, had tested the association between prenatal famine exposure and the metabolic syndrome and reported heterogeneous findings. Hence, this study aimed at evaluating the effects of prenatal exposure to the 1983-1985 Ethiopian great famine on the metabolic syndrome in adults. Self-reported birth date and age of the study subjects were used to classify the status of famine exposure. The International Diabetes Federation criterion was used to assess the metabolic syndrome. Multivariable logistic regression models were fitted to examine relationship between prenatal famine exposure and the metabolic syndrome. The findings showed that, adjusted for covariates, adults who had prenatal exposure to famine were 2·94 times more likely to develop the metabolic syndrome compared with non-exposed groups (adjusted OR (AOR) 2·94, 95 % CI 1·66, 5·27). More specifically, famine exposure during prenatal life was associated with increased waist circumference (AOR 2·27 cm, 95 % CI 0·28, 4·26), diastolic blood pressure (AOR 2·47 mmHg, 95 % CI 0·84, 4·11), TAG (AOR 0·20 mmol/l, 95 % CI 0·10, 0·28) and fasting blood glucose (AOR 0·24 mmol/l, 95 % CI 0·04, 0·43) compared with the control groups. Higher proportion of the metabolic syndrome, risky anthropometric and dyslipidaemic parameters were observed among exposed groups. This finding adds further evidence on fetal origin of adult diseases hypothesis. The finding may imply that one potential means of preventing adulthood metabolic syndrome is to optimise maternal nutrition during pregnancy.

Association between famine exposure in early life with insulin resistance and beta cell dysfunction in adulthood.

OBJECTIVES: Famine exposure in early life was associated with type 2 diabetes, non-alcoholic fatty liver disease and metabolic syndrome, etc. But evidence in early famine exposure and insulin resistance and beta cell dysfunction were limited. We aimed to investigate whether the association existed between famine exposure in early life and beta cell dysfunction and insulin resistance in adulthood. METHODS: In all, 7912 non-diabetic participants were included in this study, based on SPECT-China study. Participants with fetal or childhood famine exposure (birth year 1949-1962) were exposure group. Insulin resistance was estimated by the homeostasis model assessment index of insulin resistance (HOMA-IR). Beta cell function, represented by insulin secretion, was estimated by the disposition index. The associations of famine exposure with HOMA-IR and disposition index were assessed via linear regression. RESULTS: In men, we did not observe a significant association between early life famine exposure and ln(HOMA-IR) in all three models (P > 0.05 for all). However, in women, early life famine exposure were found to have significant association with ln(HOMA-IR) after adjustments for urbanization, severity of famine exposure, current smoker, waist circumference, hypertension, and dyslipidemia (unstandardized coefficients 0.055, 95% confidence interval 0.021, 0.088, P = 0.001). Early life famine exposure was observed to be negatively associated with ln(disposition index) after adjustments for the above potential confounders, both in men (model 3: unstandardized coefficients -0.042, 95% confidence interval -0.072,-0.012, P = 0.006) and women (model 3: unstandardized coefficients -0.033, 95% confidence interval -0.058,-0.009, P = 0.008). CONCLUSIONS: In conclusion, exposure to famine in fetal- and childhood- life period is associated with beta cell dysfunction in males and females without diabetes, but early life famine exposure was only associated with insulin resistance in non-diabetic females. These results indicate that malnutrition in early life period may offer a modifiable factor for type 2 diabetes development.

Early Life Famine Exposure, Ideal Cardiovascular Health Metrics, and Risk of Incident Diabetes: Findings From the 4C Study.

OBJECTIVE: We aim to investigate the impact of ideal cardiovascular health metrics (ICVHMs) on the association between famine exposure and adulthood diabetes risk. RESEARCH DESIGN AND METHODS: This study included 77,925 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study who were born around the time of the Chinese Great Famine and free of diabetes at baseline. They were divided into three famine exposure groups according to the birth year, including nonexposed (1963-1974), fetal exposed (1959-1962), and childhood exposed (1949-1958). Relative risk regression was used to examine the associations between famine exposure and ICVHMs on diabetes. RESULTS: During a mean follow-up of 3.6 years, the cumulative incidence of diabetes was 4.2%, 6.0%, and 7.5% in nonexposed, fetal-exposed, and childhood-exposed participants, respectively. Compared with nonexposed participants, fetal-exposed but not childhood-exposed participants had increased risks of diabetes, with multivariable-adjusted risk ratios (RRs) (95% CIs) of 1.17 (1.05-1.31) and 1.12 (0.96-1.30), respectively. Increased diabetes risks were observed in fetal-exposed individuals with nonideal dietary habits, nonideal physical activity, BMI ≥24.0 kg/m2, or blood pressure ≥120/80 mmHg, whereas significant interaction was detected only in BMI strata (P for interaction = 0.0018). Significant interactions have been detected between number of ICVHMs and famine exposure on the risk of diabetes (P for interaction = 0.0005). The increased risk was observed in fetal-exposed participants with one or fewer ICVHMs (RR 1.59 [95% CI 1.24-2.04]), but not in those with two or more ICVHMs. CONCLUSIONS: The increased risk of diabetes associated with famine exposure appears to be modified by the presence of ICVHMs.

Association of Exposure to Chinese Famine in Early Life with the Risk of Metabolic Syndrome in Adulthood.

OBJECTIVE: To explore the association of famine exposure in early life with the risk of metabolic syndrome (MS) in the -Chinese adults. METHODS: Data were obtained from the wave 2009 of the China Health and Nutrition Survey. MS was identified when 3 or more of the following components happened: (1) waist circumference >90 cm in males or >85 cm in females; (2) fasting glucose ≥6.1 mmol/L; (3) systolic blood pressure ≥130 mm Hg/diabolic blood pressure ≥85 mm Hg; (4) fasting triglyceride ≥1.70 mmol/L; and (5) high-density lipids cholesterol <1.04 mmol/L. All participants were divided into 5 groups: no exposure, born after 1961; fetal life exposure, between 1959 and 1961; early childhood exposure, between 1956 and 1958; mid-childhood exposure, between 1953 and 1955; and late childhood exposure, between 1949 and 1952. A total of 2,080 subjects were included in this study. RESULTS: In rural, famine exposure in fetal life and early childhood was associated with the lower risk of MS (p = 0.0491 and 0.0245; OR 0.583 and 0.703; and OR, 95% CI 0.341-0.998 and 0.517-0.956, respectively). But famine exposure in late childhood was associated with the higher risk of MS (p = 0.0140; OR 3.096; and OR, 95% CI 1.257-7.625). Famine exposure in early childhood was associated with the lower risk of MS (p = 0.0120; OR 0.633; and OR, 95% CI 0.443-0.904) in males. CONCLUSIONS: Famine exposure in mid- and late-childhood was associated with the higher risk of MS, especially in rural, males, and severe famine areas.

In utero exposure to the Great Chinese Famine and risk of intracerebral hemorrhage in midlife.

OBJECTIVE: To investigate whether in utero exposure to the Great Chinese Famine in 1959 to 1961 was associated with risk of intracerebral hemorrhage (ICH) in adulthood. METHODS: In this cohort analysis, we included 97,399 participants of the Kailuan Study who were free of cardiovascular disease and cancer at baseline (2006). Cases of incident ICH were confirmed by medical record review. We used the Cox proportional hazards model to calculate the hazard ratio (HR) and 95% confidence interval (CI) for ICH according to in utero famine exposure status. RESULTS: Among 97,399 participants in the current analyses, 6.3% (n = 6,160) had been prenatally exposed to the Great Chinese Famine. During a median 9.0 years of follow-up (2006-2015), we identified 724 cases of incident ICH. After adjustment for potential confounders, the HR of ICH was 1.99 (95% CI 1.39-2.85) for in utero famine-exposed individuals vs individuals who were not exposed to the famine. When exposure to famine and severity of famine were examined jointly, the adjusted HR was 2.99 (95% CI 1.21-7.39) for in utero exposure to severe famine and 1.94 (95% CI 1.32-2.84) for in utero exposure to less severe famine relative to those without exposure to famine. CONCLUSIONS: Individuals with in utero exposure to famine, especially those exposed to severe famine, were more likely to have ICH in midlife, highlighting the role of nutritional factors in susceptibility to this severe cerebral condition.

Association Between Fetal Exposure to Famine and Anthropometric Measures in Adulthood: A Regression Discontinuity Approach.

OBJECTIVE: The aim of this study was to investigate the differences in six anthropometric measurements of people born during and immediately after the 1959 to 1961 Great Chinese Famine using a regression discontinuity approach. METHODS: Data were drawn from the baseline of the China Kadoorie Biobank study, and a subset of data from 76,912 participants was analyzed. We performed regression discontinuity among participants who were born during the famine (October 1959 to October 1962) and immediately after the famine period (November 1962 to October 1964) by using local linear and parametric regressions. All analyses were conducted by sex and study area. RESULTS: Significantly, there were increases of 0.30 kg/m2 (P = 0.007) in BMI, 0.81 kg (P = 0.028) in weight, 8.57 mm (P = 0.004) in waist circumference, and 5.07 mm (P = 0.004) in hip circumference for rural women who were exposed to famine during their fetal period compared with those who were not exposed to famine in utero. However, such statistically significant increases in anthropometric values were not observed in local linear regression and most parametric models among rural men or in the urban population. CONCLUSIONS: Rural Chinese women who were exposed to famine during the fetal period were observed to have higher levels of BMI, weight, waist circumference, and hip circumference in adulthood.

Foetal and childhood exposure to famine and the risks of cardiometabolic conditions in adulthood: A systematic review and meta-analysis of observational studies.

A systematic review and meta-analysis of observational studies was performed to provide a deeper understanding of the associations between foetal and childhood exposure to famine and the risks of type 2 diabetes mellitus (T2DM), metabolic syndrome, hypertension, hyperglycaemia, dyslipidaemia, obesity, overweight, coronary heart disease, stroke, and nonalcoholic fatty liver disease (NAFLD) in adulthood. Both foetal and childhood exposure to famine were positively associated with the risks of T2DM (foetal exposure: RR 1.37, 95% CI, 1.23-1.52; childhood exposure: RR 1.33, 95% CI, 1.08-1.64), metabolic syndrome (RR 1.26, 95% CI, 1.07-1.50; RR 1.24, 95% CI, 1.13-1.35), hypertension (RR 1.30, 95% CI, 1.07-1.57; RR 1.33, 95% CI, 1.02-1.74), hyperglycaemia (RR 1.27, 95% CI, 1.11-1.45; RR 1.25, 95% CI, 1.10-1.42), dyslipidaemia (RR 1.48, 95% CI, 1.33-1.66; RR 1.27, 95% CI, 1.12-1.45), obesity (RR 1.19, 95% CI, 1.02-1.39; RR 1.13, 95% CI, 1.00-1.28), overweight (RR 1.17, 95% CI, 1.07-1.29; RR 1.07, 95% CI, 1.00-1.14), coronary heart disease (RR 1.22, 95% CI, 1.00-1.51; RR 1.21, 95% CI, 1.09-1.35), and moderate-to-severe NAFLD (RR 1.66, 95% CI, 1.07-2.57; RR 1.68, 95% CI, 1.41-1.99) in adulthood. No association was observed for the risks of stroke or mild NAFLD. Adjustments for age, alcohol, smoking, body mass index, and physical activity nullified some associations. The associations were generally stronger in women than in men. In summary, foetal and childhood exposure to famine may confer greater risks of developing certain cardiometabolic conditions in adulthood, particularly in women. The extent to which risks for cardiometabolic conditions are associated with early-life famine appears to be determined by certain factors in adulthood.