OBJECTIVE To assess the effect of prenatal exposure to maternal malnutrition on coronary heart disease in people born around the time of the Dutch famine, 1944–45. DESIGN Historical cohort study. SETTING Community study. PATIENTS Singletons born alive between November 1943 and February 1947 for whom detailed birth records were available. DESIGN The prevalence of coronary heart disease was compared between those exposed to famine in late gestation (n = 120), in mid-gestation (n = 108), or in early gestation (n = 68), and those born in the year before the famine or those conceived in the year after the famine (non-exposed subjects, n = 440). MAIN OUTCOME MEASURES Prevalence of coronary heart disease, defined as the presence of angina pectoris according to the Rose questionnaire, Q waves on the ECG, or a history of coronary revascularisation. RESULTS The prevalence of coronary heart disease was higher in those exposed in early gestation than in non-exposed people (8.8% v 3.2%; odds ratio adjusted for sex 3.0, 95% confidence interval (CI) 1.1 to 8.1). The prevalence was not increased in those exposed in mid gestation (0.9%) or late gestation (2.5%). People with coronary heart disease tended to have lower birth weights (3215 g v 3352 g, p = 0.13), and smaller head circumferences at birth (32.2 cmv 32.8 cm, p = 0.05), but the effect of exposure to famine in early gestation was independent of birth weight (adjusted odds ratio 3.2, 95% CI 1.2 to 8.8). CONCLUSIONS Although the numbers are very small, this is the first evidence suggesting that maternal malnutrition during early gestation contributes to the occurrence of coronary heart disease in the offspring.

Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.

Background: Small body size at birth has been reported to be associated with an atherogenic lipid profile in humans, and animal experiments have shown that undernutrition during pregnancy permanently alters cholesterol metabolism in the offspring. There is no direct evidence in humans that maternal malnutrition during pregnancy affects the lipid profiles of the offspring. Objectives: We assessed the effects of maternal malnutrition during specific periods of gestation on plasma lipid profiles in persons aged ≈50 y. Design: This was a follow-up study of men and women born at term as singletons in a university hospital in Amsterdam between 1 November 1943 and 28 February 1947 around the time of a severe famine. Results: Persons exposed to famine in early gestation had a more atherogenic lipid profile than did those who were not exposed to famine in utero. Their LDL-HDL cholesterol ratios were significantly higher (by 13.9%; 95% CI: 2.6–26.4%). Additionally, their plasma HDL-cholesterol and apolipoprotein A concentrations tended to be lower, and their plasma total cholesterol, LDL-cholesterol, and apolipoprotein B concentrations tended to be higher, although these differences were not statistically significant. The effect of famine was independent of size at birth and adult obesity. Conclusions: An atherogenic lipid profile might be linked to a transition from poor maternal nutrition in early gestation to adequate nutrition later on. This suggests that maternal malnutrition during early gestation may program lipid metabolism without affecting size at birth.

Background Although cardiorespiratory fitness (CRF) in childhood and adolescence may be linked to future cardiovascular health, there is currently limited evidence for a longitudinal association. Objectives To provide a systematic review on the prospective association between CRF in childhood and adolescence and cardiovascular disease (CVD) risk factors at least 2 years later. Methods Using a systematic search of Medline, Embase, and SPORTDiscus, relevant articles were identified by the following criteria: generally healthy children and adolescents between 3 and 18 years of age with CRF assessed at baseline, and a follow-up period of ≥ 2 years. The outcome measures were CVD risk factors. We appraised quality of the included articles with STROBE and QUIPS checklists. Results After screening 7524 titles and abstracts, we included 38 articles, assessing 44,169 children and adolescents followed up for a median of 6 years. Eleven articles were of high quality. There was considerable heterogeneity in methodology, measurement of CRF, and outcomes, which hampered meta-analysis. In approximately half of the included articles higher CRF in childhood and adolescence was associated with lower body mass index (BMI), waist circumference, body fatness and lower prevalence of metabolic syndrome in later life. No associations between CRF in childhood and adolescence and future waist-to-hip ratio, blood pressure, lipid profile, and glucose homeostasis were observed. Conclusion Although about half of the included articles reported inverse associations between CRF in childhood and adolescence and future BMI, body fatness, and metabolic syndrome, evidence for other CVD risk factors was unconvincing. Many articles did not account for important confounding factors such as adiposity. Recommendations for future research include standardizing the measurement of CRF, i.e. by reporting VO_2max, using standardized outcome assessments, and performing individual patient data meta-analyses.