Orwik

Depression and anxiety: Associations with biological and perceived stress reactivity to a psychological stress protocol in a middle-aged population.

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 res... expand abstractponses 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. collapse abstract

Maternal cortisol and offspring birthweight: results from a large prospective cohort study.

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 (... expand abstractSGA) 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. collapse abstract

Exposure to severe wartime conditions in early life is associated with an increased risk of irritable bowel syndrome: a population-based cohort study.

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... expand abstract 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. collapse abstract

Maternal pre-pregnancy body mass index explains infant's weight and BMI at 14 months: results from a multi-ethnic birth cohort study.

OBJECTIVE: To investigate the association between (self-reported) maternal pre-pregnancy body mass index (pBMI), and child's weight, height and BMI at age 14 months. DESIGN: Prospective multi-ethnic community-based cohort study. SETTING: Amsterdam, T... expand abstracthe Netherlands. PARTICIPANTS: 8266 pregnant women from the Amsterdam Born Children and their Development study, filled out a questionnaire covering socio-demographic data, obstetric history, lifestyle, dietary habits and psychosocial factors, 2 weeks after their first antenatal visit. 7730 gave birth to a viable term singleton infant with information on birth weight, gender and pregnancy duration. Growth data were available for 3171 of these children. MAIN OUTCOME MEASURES: Weight (g), height (cm) and BMI (kg/m(2)) of the child at age 14 months. RESULTS: pBMI was linearly associated with weight and BMI of the child at age 14 months. One unit increase in pBMI resulted in an increment of 29 g (95% CI 19 to 39) in weight and 0.041 kg/m(2) (95% CI 0.030 to 0.053) in BMI. The effect size decreased after adjustment for birth weight (weight: beta coefficient 19 g, 95% CI 10 to 28; BMI: beta coefficient 0.034 kg/m(2), 95% CI 0.023 to 0.046) and hardly changed after adjustment for all other variables (weight: beta coefficient 21 g, 95% CI 11 to 30; BMI: beta coefficient 0.031 kg/m(2), 95% CI 0.019 to 0.043). pBMI was not related to height. CONCLUSIONS: pBMI is an independent determinant of weight and BMI of the child at age 14 months. At least one third of this effect is mediated through birth weight. collapse abstract

Genetic variant in the IGF2BP2 gene may interact with fetal malnutrition to affect glucose metabolism.

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 repli... expand abstractcated 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. collapse abstract

Birth weight and risk of type 2 diabetes: a systematic review.

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... expand abstract 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. collapse abstract

Prenatal exposure to the Dutch famine is associated with a preference for fatty foods and a more atherogenic lipid profile.

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 tha... expand abstractt 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. collapse abstract

Sexual orientation and gender identity after prenatal exposure to the Dutch famine.

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 f... expand abstracteminization 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. collapse abstract

Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life.

OBJECTIVE: Maternal undernutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. We investigated whether these effects may persist in subsequent generations. DESIGN: Historical cohort study. SETT... expand abstractING: Interview during a clinic or home visit or by telephone. POPULATION: Men and women born in the Wilhelmina Gasthuis in Amsterdam between November 1943 and February 1947. METHODS: We interviewed cohort members (F1) born around the time of the 1944-45 Dutch famine, who were exposed or unexposed to famine in utero, about their offspring (F2). MAIN OUTCOME MEASURES: Birthweight, birth length, ponderal index and health in later life (as reported by F1) of the offspring (F2) of 855 participating cohort members, according to F1 famine exposure in utero. RESULTS: F1 famine exposure in utero did not affect F2 (n = 1496) birthweight, but, among the offspring of famine-exposed F1 women, F2 birth length was decreased (-0.6 cm, P adjusted for F2 gender and birth order = 0.01) and F2 ponderal index was increased (+1.2 kg/m(3), P adjusted for F2 gender and birth order = 0.001). The association remained unaltered after adjusting for possible confounders. The offspring of F1 women who were exposed to famine in utero also had poor health 1.8 (95% CI 1.1-2.7) times more frequently in later life (due to miscellaneous causes) than that of F1 unexposed women. CONCLUSIONS: We did not find transgenerational effects of prenatal exposure to famine on birthweight nor on cardiovascular and metabolic disease rates. F1 famine exposure in utero was, however, associated with increased F2 neonatal adiposity and poor health in later life. Our findings may imply that the increase in chronic disease after famine exposure in utero is not limited to the F1 generation but persists in the F2 generation. collapse abstract

The metabolic syndrome in adults prenatally exposed to the Dutch famine.

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 assess... expand abstracted 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. collapse abstract

Maternal nutrition during gestation and carotid arterial compliance in the adult offspring: the Dutch famine birth cohort.

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 ar... expand abstracttery 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. collapse abstract

A possible link between prenatal exposure to famine and breast cancer: a preliminary study.

In a study of 475 women born around the 1944-1945 Dutch famine, women exposed to prenatal famine more often reported a history of breast cancer than nonexposed women (hazard ratio, 2.6; 95% confidence interval, 0.9-7.7). They also had alterations in ... expand abstractreproductive risk factors. Prenatal famine may increase breast cancer incidence. collapse abstract

Cortisol responses to psychological stress in adults after prenatal exposure to the Dutch famine.

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 respo... expand abstractnse 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. collapse abstract

Preconception care: an essential part of the care for mother and child

Blood pressure response to psychological stressors in adults after prenatal exposure to the Dutch famine.

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 histo... expand abstractrical 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. collapse abstract

Cardiovascular health among children born after assisted reproduction.

Reduced intima media thickness in adults after prenatal exposure to the Dutch famine.

BACKGROUND: Restricted prenatal growth is associated with an increased risk of coronary heart disease morbidity and mortality. We studied the effects of exposure to famine during gestation on intima media thickness (IMT) in later life. METHODS AND RE... expand abstractSULTS: We studied 730 people aged 58 years who were born as term singletons around the time of the 1944-45 Dutch famine. Persons exposed to famine during gestation (n=293) had reduced carotid artery IMT compared to people who had not been exposed to famine in utero (n=437) (mean 0.71 mm, S.D. 0.16 mm compared to 0.75 mm, S.D. 0.15 mm, sex adjusted p=0.001). Femoral artery IMT was also thinner among people exposed to famine during gestation compared to people unexposed in utero (mean 0.64 mm, S.D. 0.20mm, compared to 0.68 mm, S.D. 0.24), although the difference did not achieve statistical significance. CONCLUSION: Exposure to famine in utero may reduce IMT. However, it does not reduce the risk of coronary heart disease among famine exposed people. collapse abstract

Impaired insulin secretion after prenatal exposure to the Dutch famine.

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 assoc... expand abstractiation 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. collapse abstract

Early onset of coronary artery disease after prenatal exposure to the Dutch famine.

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 ... expand abstractWorld 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. collapse abstract

Hypothalamic-pituitary-adrenal axis activity in adults who were prenatally exposed to the Dutch famine.

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 ... expand abstractlater 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. collapse abstract

Cardiovascular disease in survivors of the Dutch famine.

The effects of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene on glucoseinsulin metabolism interact with prenatal exposure to famine.

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-act... expand abstractivated 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. collapse abstract

Glucose tolerance at age 58 and the decline of glucose tolerance in comparison with age 50 in people prenatally exposed to the Dutch famine.

AIMS/HYPOTHESIS: People who were small at birth have an increased risk of type 2 diabetes in later life. People who were in utero during the Dutch famine had decreased glucose tolerance and raised insulin concentrations at age 50. We aimed to evaluat... expand abstracte whether prenatal famine exposure leads to more rapid progression of impaired glucose/insulin homeostasis with increasing age. METHODS: We performed an OGTT in 702 men and women at age 50 and in 699 men and women at age 58, all born as term singletons immediately before, during or after the 1944-1945 Dutch famine. RESULTS: People who had been exposed to famine in utero had significantly higher 120-min glucose concentrations at age 58 compared with people who had not been exposed to famine (difference=0.4 mmol/l, 95% CI 0.1 to 0.7, adjusted for sex and BMI). Glucose tolerance deteriorated between the age of 50 and 58. The unadjusted 120-min glucose concentrations rose by 0.2 mmol/l (95% CI 0.0 to 0.4), while 120-min insulin concentrations had increased by 64 pmol/l (95% CI 48 to 82). There were no differences in the rates of glucose and insulin level increase between the famine-exposed group and the unexposed group (p=0.28 for the difference in increase in glucose concentrations and p=0.09 for insulin concentrations). CONCLUSIONS/INTERPRETATION: Although we confirmed that undernutrition during gestation is linked to decreased glucose tolerance, the effect does not seem to become more pronounced at age 58 as compared with age 50. collapse abstract

Adult mortality at age 57 after prenatal exposure to the Dutch 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 du... expand abstractring 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. collapse abstract

Prenatal exposure to the Dutch famine and disease in later life: an overview.

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 singlet... expand abstractons 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. collapse abstract