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Objective: Numerous experiments in animals have been performed to investigate the effect of prenatal undernutrition on the development of hypertension in later life, with inconclusive results. We systematically reviewed animal studies examining the effects of maternal undernutrition on SBP, DBP, and mean arterial blood pressure (BP) in offspring., Methods: A search was performed in Medline and Embase to identify articles that reported on maternal undernutrition and hypertension in experimental animal studies. Summary estimates of the effect of undernutrition on SBP, DBP, and mean arterial BP were obtained through meta-analysis., Results: Of the 6151 articles identified, 194 were considered eligible after screening titles and abstracts. After detailed evaluation, 101 met the inclusion criteria and were included in the review. Both maternal general and protein undernutrition increased SBP [general undernutrition: 14.5 mmHg, 95% confidence interval (CI) 10.8-18.3; protein undernutrition: 18.9 mmHg, 95% CI 16.1-21.8] and mean arterial BP (general undernutrition: 5.0 mmHg, 95% CI 1.4-8.6; protein undernutrition: 10.5 mmHg, 95% CI 6.7-14.2). There was substantial heterogeneity in the results. DBP was increased by protein undernutrition (9.5 mmHg, 95% CI 2.6-16.3), whereas general undernutrition had no significant effect., Conclusion: The results of this meta-analysis generally support the view that in animals, maternal undernutrition--both general and protein--results in increased SBP and mean arterial BP. DBP was only increased after protein undernutrition. The results depended strongly on the applied measurement technique and animal model.

Environmental adversities in pre- and early postnatal life may have life-long consequences. Based upon a series of epidemiological and clinical studies and natural experiments, this review describes how the early life environment may affect psychological functions and mental disorders later in life. We focus on studies that have examined the associations of small body size at birth and prematurity as proxies of prenatal environmental adversity. We also review literature on materno-fetal malnutrition, maternal prenatal glycyrrhizin in licorice consumption and hypertension-spectrum pregnancy disorders as factors that may compromise the fetal developmental milieu and hence provide insight into some of the mechanisms that may underlie prenatal programming. While effects of programming mostly take place during the first 1000 days after conception, we finally present evidence from prospective studies suggesting that programming can occur also during later critical periods of development or 'windows of plasticity'. The studies may bear relevance for future prevention and intervention programs targeting the potentially modifiable environmental factors that will aid at promoting mental well-being and health of an individual., (Copyright © 2012. Published by Elsevier Ltd.)

The developmental origins hypothesis proposes that undernutrition during early development is associated with an increased type 2 diabetes risk in adulthood. We investigated the association between undernutrition during childhood and young adulthood and type 2 diabetes in adulthood. We studied 7,837 women from Prospect-EPIC (European Prospective Investigation Into Cancer and Nutrition) who were exposed to the 1944-1945 Dutch famine when they were between age 0 and 21 years. We used Cox proportional hazards regression models to explore the effect of famine on the risk of subsequent type 2 diabetes in adulthood. We adjusted for potential confounders, including age at famine exposure, smoking, and level of education. Self-reported famine exposure during childhood and young adulthood was associated with an increased type 2 diabetes risk in a dose-dependent manner. In those who reported moderate famine exposure, the age-adjusted type 2 diabetes hazard ratio (HR) was 1.36 (95% CI [1.09-1.70]); in those who reported severe famine exposure, the age-adjusted HR was 1.64 (1.26-2.14) relative to unexposed women. These effects did not change after adjustment for confounders. This study provides the first direct evidence, using individual famine exposure data, that a short period of moderate or severe undernutrition during postnatal development increases type 2 diabetes risk in adulthood.

Objective: In recent analyses of data from a large community sample, negative cross-sectional and prospective associations between cardiac stress reactivity and obesity were observed. The present study reexamined the association between cardiovascular reactivity and adiposity in the Dutch Famine Birth Cohort, with the additional aim of examining the association between cortisol reactivity and adiposity., Methods: Blood pressure, heart rate, and salivary cortisol were measured at rest and in response to standard laboratory stress tasks in 725 adults. Height, weight, waist-and-hip circumference, and skinfold thickness were measured. Between 4 to 7 years later, 460 participants reported current height and weight. Obesity was defined as a body mass index of 30 kg/m(2) or higher., Results: Those with a greater body mass index (β = -0.39 beats per minute (bpm)), waist-to-hip ratio (β = -0.15 bpm), and triceps and subscapular skinfold thicknesses (β = -1.0 and -1.8 bpm) or who were categorized as obese (-3.9 bpm) displayed smaller cardiac reactions to acute stress (all p < .001). With the exception of waist-to-hip ratio, the same negative associations emerged for cortisol reactivity (all p ≤ .01). In prospective analyses, low cardiac reactivity was associated with an increased likelihood of becoming or remaining obese in the subsequent 4 to 7 years (odds ratio = 1.03, p = .01). All associations withstood adjustment for a range of possible confounders., Conclusions: The present analyses provide additional support for the hypothesis that it is low not high cardiac and cortisol stress reactivity that is related to adiposity.

These analyses examined the association between blood pressure reactions to acute psychological stress and subsequent hypertension status in a substantial Dutch cohort. Blood pressure was recorded during a resting baseline and during three acute stress tasks, Stroop colour word, mirror tracing and speech. Five years later, diagnosed hypertension status was determined by questionnaire. Participants were 453 (237 women) members of the Dutch Famine Birth Cohort. In analysis adjusting for a number of potential confounders, systolic blood pressure reactivity was positively related to future hypertension. This was the case irrespective of whether reactivity was calculated as the peak or the average response to the stress tasks. The association was strongest for reactions to the speech and Stroop tasks. Diastolic blood pressure reactivity was not significantly associated with hypertension. The results provide support for the reactivity hypothesis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Glucocorticoids are the key regulators of the biological stress response and act by binding to glucocorticoid receptors (GR). Expression of GR is altered by DNA methylation. Methylation patterns in GR promoters have been shown to be highly variable between individuals, but little is known about the functional consequences of this variation for the acute stress response. The present study investigated associations between methylation status of the GR 1-C promoter and cortisol, cardiovascular and perceived stress responses to a psychosocial stress protocol in a large healthy adult population., Methods: A total of 725 overall healthy men and women, aged 55-60 years, participated in a standardized psychosocial stress protocol consisting of three different stressors. At different stages during the stress protocol, salivary cortisol levels, continuous blood pressure and heart rate (HR) levels as well as perceived stress were measured. Stress reactivity was calculated as the increase between basal and peak measurements. Methylation status of the GR 1-C promoter was assessed in DNA isolated from peripheral blood samples using a methylation sensitive PCR assay for 675 of the 725 participants., Results: A decrease in methylation of the GR 1-C promoter was associated with a decrease in stress reactivity as indicated by lower cortisol and lower HR reactivity. A 1% decrease in GR 1-C methylation corresponded with a cortisol decrease by 0.14% (95% CI: 0.03-0.25, p=0.02) and an HR decrease by 0.10 bpm (0.03-0.16, p=0.003). Adjusting for sex, lifestyle and education largely abolished these associations. A decrease in methylation of the GR 1-C promoter was also associated with an increase in stress perception as indicated by higher perceived stress (0.03 points [0.00-0.06, p=0.05]), lower perceived performance (-0.03 points [-0.05 to -0.01], p=0.02), and lower perceived control (-0.03 points [-0.05 to 0.00], p=0.04). After adjusting for sex and educational level the associations were no longer statistically significant. GR 1-C methylation status was not associated with blood pressure responses to the stress protocol., Discussion: Although effects were small, variation in methylation status in the GR 1-C promoter was associated with physical and perceived acute stress responses. Interestingly, these associations could largely be explained by differences in lifestyle and education., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

It has been argued that blunted cardiovascular and cortisol reactions to acute psychological stress reflect a dysregulation of the neural system that supports motivation. We examined the association between forced expiratory volume in 1 s, an effort (hence motivation) dependent measure of lung function measured by spirometry, and cardiovascular and cortisol reactions to a battery of standard psychological stress tasks, assessed 7 years later. Irrespective of how it was expressed, low forced expiratory volume was associated with blunted heart rate and cortisol stress reactivity. The association survived adjustment for smoking, a range of anthropometric and sociodemographic covariates, and commitment to the stress tasks, as well as cognitive ability., (Copyright © 2012 Society for Psychophysiological Research.)

Background: Previous studies have shown that prenatal exposure to the Dutch famine is associated with an increased risk for several psychiatric disorders. Variation in personality characteristics and in stress appraisal may underlie mental disorders., Aims: To investigate whether prenatal famine exposure is associated with personality characteristics and stress appraisal., Study Design: Cohort study., Subjects: Participants included a total of 572 men and women, born as term singletons in a local hospital in Amsterdam around the time of the 1944-1945 Dutch famine., Outcome Measures: Scores on the Big Five Inventory and the Perceived Stress Scale (PSS)., Results: There were no statistically significant differences in the personality traits openness, conscientiousness, extraversion, agreeableness and neuroticism or in PSS scores between those unexposed and those exposed to famine during early, mid or late gestation. However, there were statistically significant (P=0.01) and borderline significant interactions (P=0.07) respectively between exposure to famine during early gestation and sex on conscientiousness and agreeableness. Subsequent analyses showed that men exposed to famine during early gestation had lower conscientiousness scores and women exposed during early gestation had higher agreeableness scores., Conclusions: We conclude that conscientiousness and agreeableness may differ between men and women unexposed and exposed to famine during early gestation. As evidence was not very robust, future research should confirm the present findings., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Given evidence linking blunted cardiovascular and cortisol reactions to acute stress and a range of adverse behavioral outcomes, the present study examined the associations between cardiovascular and cortisol reactivity and cognitive ability measured independently of the stress task exposure. Cognitive ability was assessed using the Alice Heim-4 test of general intelligence and two memory tasks in 724 men and women who were part of the Dutch Famine Birth Cohort Study. Blood pressure and heart rate, as well as cortisol reactivity, were measured to a battery of three standard acute stress tasks. Poorer cognitive ability was associated with lower cardiovascular reactions to stress and lower cortisol area under the curve. Our results are consistent with recent findings implicating low physiological stress reactivity in a range of adverse behavioral and health outcomes., (Copyright © 2011 Society for Psychophysiological Research.)

Aims The developmental origins hypothesis proposes that undernutrition during foetal life, infancy, or childhood is associated with an increased risk of cardiovascular disease in adulthood. As data on postnatal developmental programming are scarce, we investigated whether exposure to undernutrition during childhood, adolescence, or young adulthood is related to coronary heart disease (CHD) and stroke in adult life. Methods and results We studied 7845 women from the Prospect-EPIC cohort who had been exposed at various degrees to the 1944-45 Dutch famine when they were aged between 0 and 21 years. We used Cox proportional hazard regression models to explore the effect of famine on the risk of CHD and stroke, overall and within exposure age categories (0-9, 10-17, ≥18 years). We adjusted for potential confounders, including age at famine exposure, smoking, and level of education as a proxy for socio-economic status. Overall, stronger famine exposure was associated with higher CHD risk. Among those who experienced the famine between ages 10 and 17 years, CHD risk was significantly higher among severely exposed women compared with unexposed women (HR 1.38; 95% CI 1.03-1.84), which only slightly attenuated after adjustment for confounding (HR 1.27; 95% CI 0.94-1.71). We observed a lower stroke risk among famine exposed women (HR 0.79; 95% CI 0.61-1.02). Adjustment for potential confounders produced similar results (HR 0.77; 95% CI 0.59-0.99). Conclusion Exposure to undernutrition during postnatal periods of development, including adolescence, may affect cardiovascular health in adult life.

Objective: To investigate whether SIRT1, a nutrient-sensing histone deacetylase, influences fetal programming during malnutrition., Research Design and Methods: In 793 individuals of the Dutch Famine Birth Cohort, we analyzed the interaction between three SIRT1 single nucleotide polymorphisms (SNPs) and prenatal exposure to famine on type 2 diabetes risk., Results: In the total population (exposed and unexposed), SIRT1 variants were not associated with type 2 diabetes. A significant interaction was found between two SIRT1 SNPs and exposure to famine in utero on type 2 diabetes risk (P = 0.03 for rs7895833; P = 0.01 for rs1467568). Minor alleles of these SNPs were associated with a lower prevalence of type 2 diabetes only in individuals who had been exposed to famine prenatally (odds ratio for rs7895833 0.50 [95% CI 0.24-1.03], P = 0.06; for rs1467568 0.48 [0.25-0.91], P = 0.02)., Conclusions: SIRT1 may be an important genetic factor involved in fetal programming during malnutrition, influencing type 2 diabetes risk later in life.

Background: Adverse intrauterine conditions are known to be associated with an increased risk of chronic diseases in adult life. Previously, we showed that prenatal famine exposure increased the incidence of cardiovascular and metabolic disease in adulthood., Objective: We examined the association between prenatal famine exposure and adult mortality., Design: We studied adult mortality among 1991 term singletons from the Dutch Famine Birth Cohort. We compared overall and cause-specific adult mortality among people exposed to famine in late, mid, and early gestation with those unexposed to famine in utero by using Cox proportional hazard models., Results: A total of 206 persons (10%) had died by the end of follow-up. Compared with unexposed women, women exposed to famine in early gestation had a significantly higher risk of overall adult mortality (HR: 1.9; 95% CI: 1.1, 3.4), cardiovascular mortality (HR: 4.6; 95% CI: 1.2, 17.7), cancer mortality (HR: 2.3; 95% CI: 1.1, 4.7), and breast cancer mortality (HR: 8.3; 95% CI: 1.1, 63.0). In men exposed to famine in early gestation, these associations were as follows compared with unexposed men: overall adult mortality (HR: 0.4; 95% CI: 0.2, 1.1), cardiovascular mortality (HR: 0.9; 95% CI: 0.3, 3.1), and cancer mortality (HR: 0.3; 95% CI: 0.0, 1.9)., Conclusions: Women exposed to famine in early gestation had a higher overall adult, cardiovascular, cancer, and breast cancer mortality risk than did women not exposed to famine. No such effects were observed in men exposed to famine in early gestation.

Objective. To examine the association between undernutrition during postnatal periods of development and the risk of overweight in adulthood. Methods. We studied 8,091 women from Prospect-EPIC, exposed to the Dutch famine at ages between 0 and 21 years, recruited at ages between 49 and 70 years. We used linear and logistic regression models to explore the effect of famine on BMI, waist circumference, and the risk of overweight. Results. Overall, postnatal famine exposure was associated with increased BMI and waist circumference in a dose-dependent manner (P  for trend < 0.01). Furthermore, risk of overweight was increased following famine exposure (P  for trend = 0.01), with those severely exposed at ages 0-9 years having 25% (95% CI 1.05 to 1.50) higher risk compared to unexposed women. Conclusions. This study is the first to directly show a positive association between short and transient undernutrition during postnatal development and BMI, waist circumference, and overweight in adulthood.

An increasing body of evidence suggests that poor nutrition at the very beginning of life - even before birth - leads to large and long term negative consequences for both mental and physical health. This paper reviews the evidence from studies on the Dutch famine, which investigated the effects of prenatal undernutrition on later health. 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 were at increased risk of schizophrenia and depression, they had a more atherogenic plasma lipid profile, were more responsive to stress and had a doubled rate of coronary heart disease. Also, they performed worse on cognitive tasks which may be a sign of accelerated ageing. People exposed during any period of gestation had more type 2 diabetes. Future investigation will expand on the finding that the effects of prenatal famine exposure may reach down across generations, possibly through epigenetic mechanisms. Recent evidence suggests that similar effects of prenatal undernutrition are found in Africa, where many are undernourished. Hunger is a major problem worldwide with one in seven inhabitants of this planet suffering from lack of food. Adequately feeding women before and during pregnancy may be a promising strategy in preventing chronic diseases worldwide., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: To describe the characteristics of women who suffer from hyperemesis gravidarum, and explore the independent effect of hyperemesis gravidarum on pregnancy outcome., Study Design: In The Netherlands Perinatal Registry, we used all data on singleton pregnancies of at least 24 weeks and 500 g without congenital anomalies in the years 2000-2006. We examined the characteristics of women who suffered from hyperemesis gravidarum and their children., Results: Women who suffered from hyperemesis gravidarum were slightly younger; more often primiparous, of lower socio-economic status, of non-Western descent and substance abusers; had more often conceived through assisted reproduction techniques and more often had pre-existing hypertension, diabetes mellitus and psychiatric diseases than women who did not suffer from hyperemesis gravidarum. Also, their pregnancies were more often complicated by hypertension and diabetes and they more often carried a female fetus. Pregnancies complicated by hyperemesis gravidarum significantly more often had an adverse outcome (prematurity or birth weight below the 10th percentile). The increased risk of adverse pregnancy outcomes after hyperemesis gravidarum was largely explained by the differences in maternal characteristics (crude OR 1.22 (95% CI 1.10-1.36), adjusted OR was 1.07 (95% CI 0.95-1.19))., Conclusion: Hyperemesis gravidarum is associated with adverse pregnancy outcomes. This is largely explained by differences in maternal characteristics. Given the impact of the early environment on later health (which is independent of size at birth), studies that aim to assess the long-term consequences of hyperemesis gravidarum need to be given high priority., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: It is unknown whether elevated maternal low-density lipoprotein cholesterol (LDL-C) levels lead to dyslipidemia in the offspring. Because this could have important consequences for cardiovascular prevention in mother and child, we explored the relationship between maternal familial hypercholesterolemia (FH) and lipids in adult offspring., Methods and Results: In a large cohort of both Dutch and Canadian origin, we compared lipid profiles between patients, aged 18 to 85 years, who inherited FH maternally (n=1069) and those who inherited FH paternally (n=1270). This relationship was evaluated using multivariate regression analyses. Levels of total cholesterol (TC), LDL-C, and apolipoprotein B 100 (ApoB100) were significantly elevated in patients who inherited FH maternally compared with patients who inherited FH paternally (adjusted differences in TC: 0.156 mmol/L, P=0.037; LDL-C: 0.187 mmol/L, P=0.012; ApoB: 0.064 g/L, P=0.022)., Conclusions: Our data show that maternal hereditary hypercholesterolemia slightly increases TC, LDL-C, and ApoB levels in their offspring later in life. Although the molecular mechanisms underlying these observations still require elucidation, our data suggest that maternal hypercholesterolemia during pregnancy may program lipid metabolism to a certain extent in the fetus.

In a recent study, the association between cardiovascular reactions to acute psychological stress and self-reported health was examined. Participants with excellent or good self-reported health exhibited higher cardiovascular reactivity than those who reported fair or poor health. We investigated this association in a population-based cohort of whom 725 men and women, aged 55-60 years, participated in a standardized psychological stress test. We measured continuous blood pressure and heart rate as well as cortisol reactivity. Good subjective health was associated with higher cardiovascular and cortisol reactions to psychological stress. Results of the present study confirm those of the previously reported study showing that greater cardiovascular reactivity may not always be associated with negative health outcomes. In addition, the same holds for cortisol reactivity., (Copyright © 2010 Society for Psychophysiological Research.)

At the end of World War II, a severe 5-mo famine struck the cities in the western part of The Netherlands. At its peak, the rations dropped to as low as 400 calories per day. In 1972, cognitive performance in 19-y-old male conscripts was reported not to have been affected by exposure to the famine before birth. In the present study, we show that cognitive function in later life does seem affected by prenatal undernutrition. We found that at age 56 to 59, men and women exposed to famine during the early stage of gestation performed worse on a selective attention task, a cognitive ability that usually declines with increasing age. We hypothesize that this decline may be an early manifestation of an accelerated cognitive aging process.

Background: Depression and anxiety have been linked to higher as well as lower reactivity to stressful circumstances. Large, population-based studies investigating the association between depression and anxiety, perceived and physiological stress responses are lacking., Methods: We studied 725 men and women, aged 55-60 years, from a population-based cohort, who filled out the Hospital Anxiety and Depression Scale (HADS). We performed a standardized interview on medical history and lifestyle. We measured continuous blood pressure (BP) and heart rate (HR) reactivity, saliva cortisol reactivity and perceived stress during a psychological stress protocol., Results: Albeit not statistically significant in all groups, systolic BP (SBP), diastolic BP (DBP), HR and cortisol reactivity to the psychological stress protocol were lower in those with mild-to-severe depression or anxiety symptoms and those ever clinically diagnosed with depression or anxiety, while perceived levels of stress were higher compared to those without depression or anxiety symptomatology. Maximum SBP, HR and cortisol stress responses significantly decreased and perceived stress scores significantly increased with increasing scores on the HADS depression subscale (HADS-D) and HADS anxiety subscale (HADS-A) (all P<0.05). The same held for stress responses in relation to the total HADS score (all P<0.05) and, in this case, the maximum DBP stress response was also significantly lower with an increasing HADS score (P=0.05). In addition, the maximum DBP stress response was significantly lower for those ever clinically diagnosed with depression (P=0.04). Adjusting for sex, use of anti-hypertensive medication, anti-depressant and anxiolytic medication, smoking, alcohol consumption, socio-economic status (SES) and body mass index (BMI) did not attenuate the results., Conclusion: The present study results suggest that the biological stress response of middle-aged men and women who experienced depressed and anxious feelings does not completely correspond with how stressed they feel at that moment. Although differences were not substantial in all cases, response to a psychological stress protocol seemed to be decreased in the groups with experience of depressed and anxious feelings, while the perception of stress seemed to be increased., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Maternal psychosocial problems may affect fetal growth through maternal cortisol. This large prospective cohort study examined among 2810 women (1) the association of maternal cortisol levels with offspring birthweight and small for gestational age (SGA) risk and (2) the mediating role of maternal cortisol on the relation between maternal psychosocial problems and fetal growth. Pregnant women in Amsterdam were approached during their first prepartum visit (+/-13 weeks gestation). Total maternal cortisol level was determined in serum and maternal psychosocial indicators were collected through a questionnaire. Maternal cortisol levels were negatively related to offspring birthweight (B=-0.35; p<.001) and positively to SGA (OR=1.00; p=.027); after adjustment (for gestational age at birth, infant gender, ethnicity, maternal age, parity, BMI, and smoking), these effects were statistically insignificant. Post hoc analysis revealed a moderation effect by time of day: only in those women who provided a blood sample < or =09:00h (n=94), higher maternal cortisol levels were independently related to lower birthweights (B=-0.94; p=.025) and a higher SGA risk (OR=1.01; p=.032). Maternal psychosocial problems were not associated with cortisol levels. In conclusion, although an independent association between maternal cortisol levels in early pregnancy and offspring birthweight and SGA risk was not observed, exploratory post hoc analysis suggested that the association was moderated by time of day, such that the association was only present in the early morning. The hypothesis that maternal psychosocial problems affect fetal growth through elevated maternal cortisol levels could not be supported., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Objectives: Stressful events during early life have been suggested to play an important role in the development of the irritable bowel syndrome (IBS). In this study, we evaluate whether an exposure to severe wartime conditions during gestation and in early life are associated with an increased prevalence of IBS., Methods: We assessed the prevalence of IBS using the Rome II questionnaire among 816 men and women (aged 58+/-1 years) who were born as term singletons in Wilhelmina Gasthuis, Amsterdam, The Netherlands around the time of World War II., Results: Of a total of 816 participants, 9.6% (n=78, 52F) met the criteria for IBS. Exposure to severe wartime conditions in utero was not associated with the prevalence of IBS in adulthood (8.3%). Early-life exposure to severe wartime conditions was associated with an increased prevalence of IBS. The prevalence of IBS among individuals exposed up to 0.5 years of age, 1 year of age, and 1.5 years of age was 8.1%, 12.5%, and 15.3%, respectively. The increased IBS prevalence was not associated with an increased stress response., Conclusions: Our data indicate that exposure to severe wartime conditions in early life is associated with an increased risk of developing IBS. To what extent this is attributable to the stressful environment of war, to severe undernutrition, or to the increased prevalence of infectious diseases is, however, unclear.

Objective: Fetal malnutrition may predispose to type 2 diabetes through gene programming and developmental changes. Previous studies showed that these effects may be modulated by genetic variation. Genome-wide association studies discovered and replicated a number of type 2 diabetes-associated genes. We investigated the effects of such well-studied polymorphisms and their interactions with fetal malnutrition on type 2 diabetes risk and related phenotypes in the Dutch Famine Birth Cohort., Research Design and Methods: The rs7754840 (CDKAL1), rs10811661 (CDKN2AB), rs1111875 (HHEX), rs4402960 (IGF2BP2), rs5219 (KCNJ11), rs13266634 (SLC30A8), and rs7903146 (TCF7L2) polymorphisms were genotyped in 772 participants of the Dutch Famine Birth Cohort Study (n = 328 exposed, n = 444 unexposed). Logistic and linear regression models served to analyze their interactions with prenatal exposure to famine on type 2 diabetes, impaired glucose tolerance (IGT), and area under the curves (AUCs) for glucose and insulin during oral glucose tolerance testing (OGTT)., Results: In the total population, the TCF7L2 and IGF2BP2 variants most strongly associated with increased risk for type 2 diabetes/IGT and increased AUC for glucose, while the CDKAL1 polymorphism associated with decreased AUC for insulin. The IGF2BP2 polymorphism showed an interaction with prenatal exposure to famine on AUC for glucose (beta = -9.2 [95% CI -16.2 to -2.1], P = 0.009)., Conclusions: The IGF2BP2 variant showed a nominal interaction with exposure to famine in utero, decreasing OGTT AUCs for glucose. This may provide a clue that modulation of the consequences of fetal environment depends on an individual's genetic background.

Sexual differentiation of the human brain has been suggested to take place through exposure to sex steroids during intrauterine development. Animal experiments have shown that interference in this process by underfeeding of the mother can result in feminization of the male offspring. We explored the possible effects of prenatal exposure to famine on sexual orientation and gender identity in humans. We used the Klein Sexual Orientation Grid to assess sexual orientation and also assessed gender identity in a group of 380 men and 472 women who were born as term singletons around the time of the 1944-1945 Dutch famine. Prenatal exposure to famine did not affect sexual orientation in men or in women. Three people indicated having some gender identity problems: one woman born before the famine and one man and woman exposed to famine in late gestation. In men, a later birth order was associated with a non-exclusively heterosexual identification. In conclusion, we found no evidence for a significant association between exposure to famine in utero and altered sexual orientation and gender identity. The small sample size of participants with non-exclusively heterosexual identification (possibly due to underreporting of homosexuality) may have reduced our power to detect any differences.

Context: Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined., Objective: To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults., Data Sources and Study Selection: Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included., Data Extraction: Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations., Data Synthesis: Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight-type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I(2) = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias., Conclusion: In most populations studied, birth weight was inversely related to type 2 diabetes risk.

Background: Evidence from animal models suggests that fetal undernutrition can predispose to hypercholesterolemia and metabolic disorders directly by programming cholesterol metabolism and may indirectly influence lifestyle choices. We have shown that persons who were exposed to the Dutch famine in early gestation have a more atherogenic lipid profile., Objective: We now investigate whether the excess in hypercholesterolemia may be a result of a more atherogenic diet or a reduction in physical activity., Design: We measured lipid profiles, dietary intake, and physical activity in 730 men and women (aged 58 y) born in the Wilhelmina Gasthuis in Amsterdam, Netherlands, around the time of the Dutch famine, whose birth records have been kept., Results: No differences were observed in mean intake of total energy or percentage of protein, carbohydrate, and fat in the diet between the different exposure groups. However, persons exposed to famine in early gestation were twice as likely (odds ratio: 2.1; 95% CI: 1.2, 3.9) to consume a high-fat diet (defined as the highest quartile of percentage of fat in the diet: >39% of energy from fat). They also tended to be less physically active (45% did sports compared with 52% in the unexposed group), although this did not reach statistical significance., Conclusions: This is the first direct evidence in humans that prenatal nutrition may affect dietary preferences and may contribute to more atherogenic lipid profiles in later life.

Background: Prenatal exposure to the Dutch famine is associated with an increased risk of chronic degenerative disease. We now investigate whether prenatal famine exposure affected reproductive success., Methods: We assessed reproductive success (number of children, number of twins, age at delivery, childlessness) of men and women born around the time of the Dutch famine of 1944-1945 in the Wilhelmina Gasthuis, Amsterdam, whose birth records have been kept., Results: Women who were exposed to the Dutch famine of 1944-1945 in utero are more reproductively successful than women who were not exposed to famine during their fetal development; they have more offspring, have more twins, are less likely to remain childless and start reproducing at a younger age. 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., Conclusions: 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.

Background: Epidemiologic studies have shown that the metabolic syndrome may originate in utero., Objective: We aimed to determine whether exposure to prenatal famine is associated with a greater prevalence of the metabolic syndrome., Design: We assessed the prevalence of the metabolic syndrome according to the National Cholesterol Education Program definition in 783 members of the Dutch Famine Birth Cohort. Participants were born as term singletons around the time of the 1944-1945 Dutch famine., Results: Exposure to famine during gestation was not significantly associated with the metabolic syndrome (odds ratio: 1.2; 95% CI: 0.9, 1.7). Birth weight also was not significantly associated with the metabolic syndrome (odds ratio: 1.3/1-kg decrease in birth weight; 95% CI: 0.9, 1.8/1-kg decrease in birth weight). Exposure to famine during gestation was associated with significantly higher triacylglycerol concentrations (0.1 g/L; 0.0, 0.2 g/L). Men exposed to famine in early gestation had significantly lower HDL-cholesterol concentrations (-0.08 mmol/L; -0.14, 0.00 mmol/L) than did unexposed men., Conclusions: Prenatal exposure to famine or reduced birth weight is not associated with a significantly greater prevalence of the metabolic syndrome. Our findings suggest that, although elements of the metabolic syndrome may be programmed by fetal undernutrition, the origin of the syndrome as a whole is not likely to be found in poor nutrition during gestation.

Objective: Experimental evidence indicates that maternal undernutrition during gestation may program hypertension in the offspring. We investigated whether maternal undernutrition leads to increased arterial stiffness., Methods: We measured carotid artery lumen diameter (LD), distensibility (DC), stiffness (beta), and compliance (CC) by M-mode ultrasound in 673 individuals, aged 56-61 years, who had been born as term singletons around the time of the 1944-45 Dutch famine., Results: Maternal famine exposure had no effect on any of the measures of carotid size or stiffness in the offspring. Low maternal weight at the end of pregnancy and low birth weight were associated with decreased LD (0.01 mm/kg maternal weight, sex-adjusted P < 0.001; 0.1 mm/kg birth weight, sex-adjusted P = 0.08) and CC (0.002 mm2/kPa per kg maternal weight, sex-adjusted P = 0.001; 0.03 mm2/kPa per kg birth weight, sex-adjusted P = 0.03), but neither was associated with increased beta, or decreased DC. These effects were not attenuated by adjusting for maternal protein/carbohydrate ratio in the third trimester. The association of low birth weight with increased CC diminished after adjusting for maternal weight. The association of maternal weight with CC was smaller when adjusted for LD., Conclusion: Our findings suggest that small maternal size, not poor maternal diet, in late gestation programs decreased arterial compliance in the adult offspring by affecting vessel size rather than vessel wall stiffness.

Experimental studies in animals show that prenatal undernutrition leads to lifelong alterations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Some studies have shown associations between low birth weight and an increased HPA response to psychological stress. We tested the hypothesis that prenatal exposure to the Dutch 1944-1945 famine leads to an elevated HPA response to psychological stress in adult life. We measured salivary cortisol responses to a psychological stress protocol among 694 adults who were born as term singletons in Amsterdam, the Netherlands, around the time of the 1944-1945 Dutch famine. We compared cortisol profiles of participants exposed to famine during late (n=120), mid (n=100), or early gestation (n=62) to profiles of participants unexposed to famine during gestation (n=412). The mean increase in cortisol concentrations from baseline was 30% (95% CI 23-37). There were no statistically significant differences in the mean profile of cortisol response to the psychological stress protocol between participants exposed and unexposed to famine in utero. The mean sex and BMI adjusted difference in cortisol response for those exposed compared to those unexposed was -6% (95% CI: -15 to 2). The cortisol profiles of those exposed in late (-4% [95% CI: -16 to 7]), mid (-9% [95% CI: -22 to 3]) or early gestation (-4% [95% CI: -20 to 10]) did not differ from the profile of those unexposed to famine. We conclude that prenatal exposure to famine does not seem to be associated with the response of the HPA axis to psychological stress. However, the stress protocol we have used may have been unsuccessful in inducing a strong enough HPA axis activation to be able to detect famine related differences.

Objective: There is increasing evidence that restricted prenatal growth is associated with exaggerated blood pressure responses to stress. We investigated the effect of maternal undernutrition on the adult offspring's stress response., Design: A historical cohort study., Methods: We performed continuous blood pressure and heart rate measurements during a battery of three 5-min physiological stress tests (Stroop test, mirror-drawing test and a public speech task) in 721 men and women, aged 58 years, born as term singletons in Amsterdam at about the time of the Dutch 1944-1945 famine., Results: During the stress tests, the systolic blood pressure (SBP) rose from baseline by 20 mmHg during the Stroop test, by 30 mmHg during the mirror-drawing test and by 47 mmHg during the public speech task. The SBP and diastolic blood pressure increase during stress was highest among individuals exposed to famine in early gestation compared with unexposed subjects (4 mmHg extra systolic increase, P = 0.04; 1 mmHg diastolic increase, P = 0.1, both adjusted for sex). Exposure during mid and late gestation was not associated with a stress-related increment of blood pressure (P adjusted for sex > 0.6). Correcting for confounders in a multivariable model did not attenuate the association between famine exposure in early gestation and the SBP increment. The heart rate increment was not related to famine exposure during any part of gestation., Conclusion: We found a greater blood pressure increase during stress among individuals exposed to famine in early gestation. Increased stress responsiveness may underlie the known association between coronary heart disease and exposure to famine in early gestation.

Objective: We previously reported that people prenatally exposed to famine during the Dutch Hunger Winter of 1944-1945 have higher 2-h glucose concentrations after an oral glucose tolerance test in later life. We aimed to determine whether this association is mediated through alterations in insulin secretion, insulin sensitivity, or a combination of both., Research Design and Methods: We performed a 15-sample intravenous glucose tolerance test in a subsample of 94 normoglycemic men and women from the Dutch Famine Birth Cohort. We used the disposition index, derived as the product of insulin sensitivity and the first-phase insulin response to glucose as a measure of the activity of the beta-cells adjusted for insulin resistance. In all analyses, we adjusted for sex and BMI., Results: Glucose tolerance was impaired in people who had been prenatally exposed to famine compared with people unexposed to famine (difference in intravenous glucose tolerance test K(g) value -21% [95% CI -41 to -4]). People exposed to famine during midgestation had a significantly lower disposition index (-53% [-126 to -3]) compared with people unexposed to famine. Prenatal exposure to famine during early gestation was also associated with a lower disposition index, but this difference did not reach statistical significance., Conclusions: Impaired glucose tolerance after exposure to famine during mid-gestation and early gestation seems to be mediated through an insulin secretion defect.

Background: Limited evidence suggests that maternal undernutrition at the time of conception is associated with increased cardiovascular disease risk in adult offspring., Objective: We investigated whether persons conceived during the Dutch famine of World War II had an early onset of coronary artery disease (CAD)., Design: We compared the age at onset and cumulative incidence of CAD between persons born as term singletons who were exposed to the 1944-1945 Dutch famine during late (n = 160), mid- (n = 138), or early (n = 87) gestation and 590 unexposed subjects at age 50 or 58 y. Age at CAD onset was defined as the age at which angina pectoris was identified (according to the Rose questionnaire), Q waves were observed on an electrocardiogram (Minnesota codes 1-1 or 1-2), or coronary revascularization was performed (by angioplasty or bypass surgery)., Results: Of the 83 CAD cases identified, persons conceived during the famine were 3 y younger than the unexposed persons at the time of CAD diagnosis (47 y compared with 50 y) and had a higher cumulative incidence of CAD [13%; hazard ratio (HR) adjusted for sex: 1.9; 95% CI: 1.0, 3.8] than did the unexposed persons. The HR changed little after adjustment for smoking (HR: 1.8), social class (HR: 2.0), or size at birth (HR: 2.0)., Conclusions: We found an earlier onset of CAD among persons conceived during the famine, which suggests that maternal nutrition in early gestation may play a role in the onset of CAD. This finding agrees with evidence from animal experiments that identify periconceptional maternal diet as important in the offspring's adult health.

Objective: The hypothalamic-pituitary-adrenal (HPA) axis has been proposed to be susceptible to fetal programming, the process by which an adverse fetal environment elicits permanent physiological and metabolic alterations predisposing to disease in later life. It is hypothesized that fetal exposure to poor circumstances alters the set point of the HPA axis, leading to increased HPA axis activity and subsequent increased cortisol concentrations. In this study, we tested the hypothesis that prenatal exposure to famine during different periods of gestation is associated with increased activity of the HPA axis., Design and Methods: We assessed plasma cortisol concentrations after a dexamethasone suppression and an ACTH1-24 -stimulation test in a group of 98 men and women randomly sampled from the Dutch famine birth cohort. Cohort members were born as term singletons around the 1944-1945 Dutch famine., Results: Cortisol profiles after dexamethasone suppression and ACTH1-24 stimulation were similar for participants exposed to famine during late, mid- or early gestation (P = 0.78). Cortisol concentrations after dexamethasone suppression test did not differ between those exposed and those unexposed to famine in utero (mean difference -2% (95% confidence interval (CI) -27 to 23)). Neither peak cortisol concentration (20 nmol/l (95% CI -27 to 66)), cortisol increment (-5 nmol/l (95% CI -56 to 47)) or cortisol area under the curve post-ACTH1-24 injection (4% (95% CI -4 to 12)) differed between exposed and unexposed participants., Conclusions: Prenatal famine exposure does not seem to affect HPA axis activity at adult age, at least not at the adrenal level. This does not exclude altered HPA axis activity at the levels of the hippocampus and hypothalamus.

Objective: An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism., Research Design and Methods: We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-gamma2 genotype among 675 term singletons born around the time of the 1944-1945 Dutch famine., Results: A significant interaction effect between exposure to famine during midgestation and the PPAR-gamma2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-gamma2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation., Conclusions: The effects of the PPAR-gamma2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic beta-cell maldevelopment and carrier type of the Ala allele in the PPAR-gamma2 gene.

Low birth weight is associated with cardiovascular disease in adulthood. Poor maternal nutrition during gestation contributes to low birth weight. In this paper, we review the findings from a cohort of 2414 people, aged 50 years, born as term singletons around the time of the 1944-1945 Dutch famine, of which 912 people participated in an interview and 741 subjects were also available for hospital examination. We found more coronary heart disease, raised lipids, altered clotting and more obesity after exposure to famine in early gestation compared to those not exposed to the famine. Exposure in mid gestation was associated with obstructive airways disease and microalbuminuria. We found decreased glucose tolerance in people exposed to famine in late gestation. These findings show that maternal undernutrition during gestation has important effects on health in later life, but that the timing of the nutritional insult determines which organ system is affected. Future research should shed more light upon the underlying pathophysiology of the far-reaching effects of prenatal exposure to famine.

Prenatal famine exposure has previously been shown to be associated with cardiovascular disease and type II diabetes in adulthood. In the current study, we could not demonstrate an effect of prenatal exposure to famine in 2254 term singletons born during the 1944-1945 Dutch famine on adult mortality up to the age of 57 years. Follow-up of this cohort will resolve whether famine exposure is linked to increased adult mortality.

Maternal undernutrition during gestation is associated with an increase in cardiovascular risk factors in the offspring in adult life. The effect of famine exposure during different stages of gestation on adult microalbuminuria (MA) was studied. MA was measured in 724 people, aged 48 to 53, who were born as term singletons in a university hospital in Amsterdam, the Netherlands, around the time of the Dutch famine 1944 to 1945. Twelve percent of people who were exposed to famine in mid gestation had MA (defined as albumin/creatinine ratio >/=2.5) compared with 7% of those who were not prenatally exposed to famine (odds ratio 2.1; 95% confidence interval 1.0 to 4.3). Correcting for BP, diabetes, and other influences that affect MA did not attenuate this association (adjusted odds ratio 3.2; 95% confidence interval 1.4 to 7.7). The effect of famine was independent of size at birth. Midgestation is a period of rapid increase in nephron number, which is critical in determining nephron endowment at birth. Fetal undernutrition may lead to lower nephron endowment with consequent MA in adult life.

People who were undernourished in early gestation are more obese, have a more atherogenic lipid profile, and altered blood coagulation and seem to have an increased risk of coronary heart disease. We now report on whether they also feel less healthy. We therefore assessed the perceived health of 50-year-old-men and women born alive as singletons around the time of the Dutch famine in the Wilhelmina Gasthuis in Amsterdam. People who had been exposed to famine in early gestation, but not those exposed in mid- or late gestation, more often rated their health as poor (10.3% vs. to 4.9% in the unexposed, odds ratio (OR) 2.2 [1.0, 4.8]). The effect of exposure to famine in early gestation on perceived health could only partly be explained by an increased prevalence of coronary heart disease, respiratory diseases, hypertension, type 2 diabetes, hypercholesterolaemia or cancer (adjusted OR 2.2 [0.9, 5.2]). Adjustment for adult risk factors (BMI, LDL/HDL cholesterol ratio, blood pressure, smoking, lung function) also attenuated the results to some extent (adjusted OR 1.9 [0.6, 5.5]). People who were exposed to famine in early gestation were not only less healthy in terms of objective measures of health but they also felt less healthy. Because poor perceived health is a strong predictor of mortality, we may expect increased mortality in people who were exposed to famine in early gestation in the future.