S. R. de Rooij

Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine

We previously showed that maternal under‐nutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. Also, we found increased neonatal adiposity among the grandchildren of women who had been undernourished during pregnancy. In the present study we investigated whether these transgenerational effects have led to altered body composition and poorer health in adulthood in the grandchildren.

The sex-specific effects of famine on the association between placental size and later hypertension.

BACKGROUND People who had low birth weight are at increased risk of hypertension. This may reflect fetal programming by undernutrition. Placental size is also associated with hypertension. Maternal undernutrition during the Dutch famine reduced placental surface area. We examined whether maternal undernutrition altered the relationship between placental size and later hypertension. METHODS Retrospective cohort study among 860 subjects born in Amsterdam during 1943-47. 216 subjects were taking anti-hypertensive medication. Birth records included placental length and breadth from which we calculated its area. RESULTS Among men who were not in utero during the famine hypertension was associated with a small placental surface area due to a small placental breadth, and with an oval-shaped surface. The OR for hypertension was 0.83 (95% CI 0.70 to 1.00) for a 40 cm(2) increase in surface area. Among men who were in utero during the famine hypertension was associated with a large placental surface area due to a large placental breadth, and with a round-shaped surface. The OR for hypertension was 1.34 (95% CI 0.99 to 1.80) for a 40 cm(2) increase in surface area. The associations between placental size and hypertension in men who were and were not in utero during the famine were significantly different (p values for interaction = 0.008 for placental surface area, 0.001 for the breadth and 0.01 for the difference in the two diameters). Among women hypertension was not associated with placental size. CONCLUSIONS Our study provides the first direct evidence that changes in maternal diet during pregnancy alter the relationship between placental size and later hypertension among men but not women. We suggest that among men who were not in utero during the famine, hypertension was related to impaired implantation, whereas among men who were in utero during the famine it was related to compensatory expansion of the placental surface.

Depression and anxiety are associated with a diagnosis of hypertension 5 years later in a cohort of late middle-aged men and women.

The aim of this study is to examine the association between symptoms of depression and anxiety and hypertension status. Participants (n=455, 238 women) were drawn from the Dutch Famine Birth Cohort Study. In 2002–2004, they attended a clinic assessment during which socio-demographics, anthropometrics, resting systolic blood pressure (SBP) and health behaviours were measured. Symptoms of depression and anxiety were measured using the Hospital Anxiety and Depression Scale. In 2008–2009, participants completed a questionnaire, which asked whether they ever had a physician diagnosing them as suffering from hypertension. In separate regression models that initially adjusted for age and then additionally for sex, socio-economic status, smoking, sports participation, alcohol consumption, resting SBP, antidepressive and anxiolytic medication, whether or not participants were exposed to the Dutch famine in utero, BMI and waist:hip ratio, both depression and anxiety were positively associated with hypertension status. Those who met the criterion for possible clinical depression and anxiety were also more likely to be hypertensive, and these associations remained statistically significant in the fully adjusted regression model. In conclusion, symptoms of depression and anxiety were associated with a diagnosis of hypertension assessed 5 years later, although the mechanisms underlying these associations remain to be determined.

Prenatal famine exposure, health in later life and promoter methylation of four candidate genes

Poor nutrition during fetal development can permanently alter growth, cardiovascular physiology and metabolic function. Animal studies have shown that prenatal undernutrition followed by balanced postnatal nutrition alters deoxyribonucleic acid (DNA) methylation of gene promoter regions of candidate metabolic control genes in the liver. The aim of this study was to investigate whether methylation status of the proximal promoter regions of four candidate genes differed between individuals exposed to the Dutch famine in utero. In addition, we determined whether methylation status of these genes was associated with markers of metabolic and cardiovascular disease and adult lifestyle. Methylation status of the GR1-C (glucocorticoid receptor), PPARγ (peroxisome proliferator-activated receptor gamma), lipoprotein lipase and phosphatidylinositol 3 kinase p85 proximal promoters was investigated in DNA isolated from peripheral blood samples of 759 58-year-old subjects born around the time of the 1944-45 Dutch famine. We observed no differences in methylation levels of the promoters between exposed and unexposed men and women. Methylation status of PPARγ was associated with levels of high-density lipoprotein cholesterol and triglycerides as well as with exercise and smoking. Hypomethylation of the GR promoter was associated with adverse adult lifestyle factors, including higher body mass index, less exercise and more smoking. The previously reported increased risk of cardiovascular and metabolic disease after prenatal famine exposure was not associated with differences in methylation status across the promoter regions of these candidate genes measured in peripheral blood. The adult environment seems to affect GR and PPARγ promoter methylation.

Prenatal stress and epigenetics

In utero exposure to environmental stress in both animals and humans could result in long-term epigenome alterations which further lead to consequences for adaptation and development in the offspring. Epigenetics, especially DNA methylation, is considered one of the most widely studied and well-characterized mechanisms involved in the long-lasting effects of in utero stress exposure. In this review, we outlined evidence from animal and human prenatal research supporting the view that prenatal stress could lead to lasting, broad and functionally organized signatures in DNA methylation which, in turn, could mediate exposure-phenotype associations. We also emphasized the advantage of using stressor from quasi-randomly assigned experiments. Furthermore, we discuss challenges that still need to be addressed in this field in the future.

Self-reported depression and anxiety after prenatal famine exposure: mediation by cardio-metabolic pathology?

Evidence from previous studies suggests an association between prenatal exposure to famine and increased risk for depression. The aim of this study was to investigate whether prenatal exposure to the Dutch famine is associated with self-reported depression/anxiety and whether a potential association is mediated by the presence of cardio-metabolic disease. A total of 819 persons, born as term singletons around the 1944-1945 Dutch famine, filled out the Hospital Anxiety and Depression Scale (HADS) and were asked about their medical history. As indicators of cardio-metabolic disease we included type 2 diabetes (T2D), hypertension and coronary heart disease (CHD). In the total study population, exposure to famine during early gestation was associated with the presence of self-reported mild-to-severe anxiety. Evidence was found for several interactions between exposure in early gestation and sex. Subsequent analyses according to sex showed that men exposed to famine during early gestation scored higher on the HADS depression scale. Self-reported mild-to-severe anxiety symptoms were more prevalent among early exposed men. No such differences were found in women. T2D and hypertension were not correlated with any of the depression and anxiety measures. Adjusting for the presence of CHD did minimally attenuate the size of the reported associations. In conclusion, the present results do not match those previously reported in prenatally famine-exposed individuals. We found only weak evidence for an association between prenatal famine exposure and symptoms of depression and anxiety, which was shown exclusively in men exposed during early gestation.

Transgenerational effects of prenatal exposure to the Dutch famine

Sir, We note with interest the recent report in this journal by Painter et al. on the follow up of men and women born in the former Wilhelmina Gasthuis Hospital, Amsterdam, between November 1943 and February 1947. The authors claim that their 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’. We were particularly interested in this claim as we have already published on the same topic. In our earlier work, we interviewed many of women studied by Painter et al. when they were on average 43 years. In a series of publications, we reported that women with prenatal famine exposure early in pregnancy showed a parity-specific effect on their offsprings’ birthweights, which could not be explained by differences in the women’s age at delivery, number of deliveries, or interpregnancy interval. At the time, we concluded that ‘there may be long-term biological effects, even into the next generation, of maternal intrauterine nutrition, which do not correspond to the effects on the mothers’ own birthweights’. Separately, we showed that the famine affected offspring birthweights through an effect of prenatal famine exposure on their mothers’ birthweights. It is puzzling that our previous studies and conclusions in the same study population were not discussed by Painter et al. We fail to see how the omission of this relevant work could be helpful to the reader. j

Polymorphisms in the Melatonin Receptor 1B Gene and the Risk of Delirium

Background/Aims: A disturbed sleep-wake rhythm cycle can be seen in delirium and as melatonin regulates this cycle via melatonin receptors, genetic variations in these receptors may contribute to susceptibility to delirium. The purpose of this study was to investigate whether genetic variants in the melatonin receptor 1B (MTNR1B) gene are associated with delirium. Methods: Elderly medical and hip surgery patients were included in the study. Five single-nucleotide polymorphisms (SNPs) were determined in the MTNR1B gene, i.e. rs18030962, rs3781638, rs10830963, rs156244 and rs4753426. Results: In total, 53% of 171 hip fracture patients and 33% of 699 medical patients were diagnosed with delirium. None of the polymorphisms were found to be associated with the occurrence of delirium. Conclusion: Future research could focus on sequencing this gene to look for other functional SNPs in relation to delirium.

A systematic review and meta-analysis of lifestyle interventions in women of reproductive age with overweight or obesity: the effects on symptoms of depression and anxiety: Lifestyle interventions and symptoms of depression and anxiety

Obesity is a rising problem, especially among women of reproductive age. Overweight and obesity reduce both physical and mental health. Lifestyle interventions could have beneficial effects on both, but an overview of the effects on mental health, especially in women of reproductive age, is currently lacking. Therefore, the aim of this review was to assess the effect of lifestyle interventions on symptoms of depression and anxiety in women of reproductive age with overweight or obesity. The databases MEDLINE, EMBASE and PsycINFO were searched from inception to June 2018 for published randomized controlled trials (RCTs). We included lifestyle intervention RCTs in women of reproductive age with overweight or obesity that assessed effects on symptoms of depression and/or anxiety. The difference between baseline and post‐intervention scores on symptoms of depression and anxiety for the intervention and control group was analysed. Meta‐analysis was performed with a random effects model. The search resulted in 5,316 citations, and after screening five RCTs were included, in which 571 women were randomized. The effect of lifestyle interventions on depression scores was investigated among 224 women from five RCTs. The pooled estimate for the mean difference was −1.35 (95% CI, −2.36 to −0.35, p = 0.008). The effect of lifestyle interventions on anxiety levels was studied among 148 women from four RCTs, resulting in a pooled estimate of −1.74 (−2.62 to −0.87, p < 0.001). Based on five RCTs, meta‐analyses showed that lifestyle interventions in women of reproductive age with overweight or obesity consistently reduce symptoms of depression and anxiety.

The risk of stroke after prenatal exposure to famine

Prenatal exposure to famine is associated with an increased risk of metabolic and cardiovascular diseases in the offspring at adult age. The aim of this study was to assess whether prenatal exposure to undernutrition increases the risk of stroke. This study was performed in the Dutch famine birth cohort, which consist of 2414 members who were born between 1943 and 1947 in the Netherlands. In a subsample of 1177 individuals, interviews were conducted using standardized questionnaires to obtain information about medical history (which included specific questions regarding stroke) and lifestyle. Information on stroke-related mortality was collected by linking the cohort with Statistics Netherlands. A Coxs proportional hazard analysis was performed to calculate hazard ratios (HRs) comparing the incidence of non-fatal stroke between participants who were exposed, subdivided into early, mid and late gestation, and unexposed to famine prenatally. Three cohort members died of stroke. Of the 1177 subjects who responded to the questionnaires 49 (4.2%) survived a stroke. Unadjusted and adjusted HRs for the risk of non-fatal stroke did not show a significant difference between the unexposed and exposed subjects: HR 1.23 (95% CI 0.53-2.83), HR 1.23 (95% CI 0.53-2.82), HR 1.12 (95% CI 0.46-2.71) for those exposed in late, mid and early gestation, respectively. We were unable to find evidence for a major effect of prenatal exposure to famine on the risk of stroke in later life, although one should be aware that this study was underpowered and the study population too selected and young to identify smaller risks.