Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961.

CONTEXT: Schizophrenia is a common major mental disorder. Intrauterine nutritional deficiency may increase the risk of schizophrenia. The main evidence comes from studies of the 1944-1945 Dutch Hunger Winter when a sharp and time-limited decline in food intake occurred. The most exposed cohort conceived during the famine showed a 2-fold increased risk of schizophrenia. OBJECTIVE: To determine whether those who endured a massive 1959-1961 famine in China experienced similar results. DESIGN, SETTING, AND PARTICIPANTS: The risk of schizophrenia was examined in the Wuhu region of Anhui, one of the most affected provinces. Rates were compared among those born before, during, and after the famine years. Wuhu and its surrounding 6 counties are served by a single psychiatric hospital. All psychiatric case records for the years 1971 through 2001 were examined, and clinical and sociodemographic information on patients with schizophrenia was extracted by researchers who were blinded to the nature of exposure. Data on number of births and deaths in the famine years were available, and cumulative mortality was estimated from later demographic surveys. MAIN OUTCOME MEASURES: Evidence of famine was verified, and unadjusted and mortality-adjusted relative risks of schizophrenia were calculated. RESULTS: The birth rates (per 1000) in Anhui decreased approximately 80% during the famine years from 28.28 in 1958 and 20.97 in 1959 to 8.61 in 1960 and 11.06 in 1961. Among births that occurred during the famine years, the adjusted risk of developing schizophrenia in later life increased significantly, from 0.84% in 1959 to 2.15% in 1960 and 1.81% in 1961. The mortality-adjusted relative risk was 2.30 (95% confidence interval, 1.99-2.65) for those born in 1960 and 1.93 (95% confidence interval, 1.68-2.23) for those born in 1961. CONCLUSION: Our findings replicate the Dutch data for a separate racial group and show that prenatal exposure to famine increases risk of schizophrenia in later life.

[Correlations between the hypothalamo-pituitary-adrenal axis and the metabolic syndrome]. / A hypothalamus-hypophysis-mellékvese tengely es a metabolikus szindróma kapcsolata.

The metabolic syndrome has several similarities with Cushing's syndrome (impaired glucose tolerance, hypertension, dyslipidemia, central obesity) suggesting that abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis may have a link with the metabolic syndrome. Several studies suggested an association between the clinical signs of the metabolic syndrome and the increased hypothalamic-pituitary-adrenal axis activity based on increased cortisol concentration at 09.00 a.m. and increased cortisol response to corticotropin. According to the Barker hypothesis the fetal malnutrition could determine adult cardiovascular diseases (coronary heart disease, hypertension), some endocrine and metabolic disorders (obesity, type 2 diabetes and hyperlipidemia). The suggested mechanism of the phenomenon is that the suboptimal fetal nutrition results in glucocorticoid overproduction. The 11beta-hydroxysteroid dehydrogenase (converts biological inactive cortisone to cortisol and vice versa) is an important enzyme in cortisol metabolism. The increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in fat tissue could lead to central obesity and impaired glucose tolerance. The hypothesis that increased corticotropin-releasing hormone production drives the overactive hypothalamo-pituitary-adrenal axis was not proven. Further investigations are needed to identify additional pathogenetic factors and to find new therapeutic possibilities.

Effect of prenatal protein malnutrition on numbers of neurons in the principal cell layers of the adult rat hippocampal formation.

Malnutrition has been associated with a variety of functional and anatomical impairments of the hippocampal formation. One of the more striking of these is widespread loss of hippocampal neurons in postnatally malnourished rats. In the present study we have investigated the effect of prenatal malnutrition on these same neuronal populations, neurons that are all generated during the period of the dietary restriction. In prenatally protein deprived rats, using design-based stereology, we have measured the regional volume and number of neurons in the hilus of the dentate gyrus and the pyramidal cell layers of CA3, CA2, CA1, and the subiculum of 90-day-old animals. These results demonstrated a statistically significant reduction of 20% in neuron numbers in the CA1 subfield, while numbers in the other subfields were unchanged. There was a corresponding significant reduction of 22% in the volume of the CA1 subfield and a significant 14% decrease in the volume of the pyramidal layer of the subiculum. The change in volume of the pyramidal layer of the subiculum without neuron loss may reflect loss of CA1 afferent input to the pyramidal layer. Although the effect of nutritional deprivation on the neuronal population appears to be different in pre- and postnatal malnutrition, both dietary paradigms highlight the vulnerability of key components of the hippocampal trisynaptic circuit (consisting of the dentate granule cell mossy fibers projection to CA3 pyramids and the CA3 projection to the CA1 pyramids), which is an essential circuit for memory and learning.

Intrauterine environmental and genetic influences on the association between birthweight and cardiovascular risk factors: studies in twins as a means of testing the fetal origins hypothesis.

Evidence has accumulated that low birthweight is associated with several risk factors for cardiovascular disease. However, it is not known whether or not these associations are due to a programmed response to intrauterine malnutrition or genetic factors influencing both birthweight and cardiovascular risk factors. Twin studies offer a unique opportunity to distinguish between intrauterine and genetic origins of the association between birthweight and cardiovascular risk. In our twin cohort, low birthweight was associated with insulin resistance, lower HDL and shorter height within both dizygotic and monozygotic twin pairs, suggesting that these associations are, at least in part, independent of genetic factors. In contrast, low birthweight was associated with blood pressure, total and LDL cholesterol, fibrinogen and sympathetic activation within dizygotic twin pairs, but not within monozygotic twin pairs. These differences between dizygotic and monozygotic twins suggest that these associations are, at least in part, due to genetic factors. Therefore, both intrauterine environmental and genetic factors appear to play a role in the association between birthweight and cardiovascular risk factors. In the future, strategies may be developed targeted at improving or preventing impaired intrauterine growth. However, the effects of interventions that comprise changes in environment within the normal range may be limited due to the possible important role of genetic factors.

Microalbuminuria in adults after prenatal exposure to the Dutch famine.

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.

Fetal and childhood onset of adult cardiovascular diseases.

Childhood onset of adult cardiovascular disease has become a significant public health problem. Whether genetic, environmental, or fetal influences are the primary culprits in the epidemic of the cardiovascular disease seen today remains unknown. The benefits of an overall physically active lifestyle that includes weight control, lower blood pressure, avoidance of tobacco use, and consistent exercise are clear and can impact the overall health of children and adolescents. Physicians who care for children and adolescents must begin to incorporate screening of adult cardiovascular disorders into their practice. Better understanding of the etiology of these disease states will bring with it enhanced preventive and targeted therapies.

Programming of obesity and cardiovascular disease.

BACKGROUND: There is evidence that malnutrition in early life induces a growth retardation leading, in adult life, to manifest components of the metabolic syndrome. However, the impact on obesity seems less clearly established. OBJECTIVE: To review the effects of foetal and postnatal malnutrition on the programming of obesity in the context of the metabolic syndrome, as well as the link between central obesity and cardiovascular diseases. METHODS: Included in the review were recent papers exploring the mechanisms linking maternal nutrition with impaired foetal growth and later obesity, cardiovascular disease, hypertension and diabetes in humans and animals. RESULTS: The programming of obesity during foetal and early postnatal life depends of the timing of maternal malnutrition as well as the postnatal environment. Obesity arises principally in offspring submitted to malnutrition during early stages of gestation and which presented early catch-up growth. The programming may involve the dysregulation of appetite control or the hormonal environment leading to a context favourable to obesity development (hypersecretion of corticosteroids, hyperinsulinaemia and hyperleptinaemia and anomalies in the IGF axis). Adipose tissue secretes actively several factors implicated in inflammation, blood pressure, coagulation and fibrinolysis. The programmed development of intra-abdominal obesity after early growth restriction may thus favour higher prevalence of hypertension and cardiovascular diseases. CONCLUSIONS: Abdominal obesity appears in malnourished offspring and is aggravated by early catch-up growth. Higher rates of intra-abdominal obesity observed after growth restriction may participate to hypertension and create atherothrombotic conditions leading to the development of cardiovascular diseases.

Long-term metabolic consequences of being born small for gestational age.

This review highlights the evidence of linking small for gestational age (SGA) with metabolic/cardiovascular disturbances (dysmetabolic syndrome) in later life. The metabolic and cardiovascular complications associated with in utero undernutrition have been identified during the past 10 yr. Reduced fetal growth is independently associated with an increased risk of the development of cardiovascular diseases, the insulin-resistance syndrome, or one of its components: hypertension, dyslipidemia, impaired glucose tolerance, or type 2 diabetes. All of them appear to result from the initial development of insulin-resistance which appears as a key component underlying the metabolic complications. Although the mechanism remains unclear, there is some evidence that argues in favor of an active contribution of the adipose tissue in the emergence of insulin-resistance associated with in utero undernutrition, but this hypothesis remains to be further documented. From a broader point of view, several hypotheses have been proposed over the past 10 yr to understand this unexpected association. Each of them points to either a detrimental fetal environment or genetic susceptibilities or interactions between these two components as playing a critical role in this context. Although not confirmed, the hypothesis suggesting that this association could be the consequence of genetic/environmental interactions remains at the moment the most attractive.