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      Acute maternal stress in pregnancy and schizophrenia in offspring: A cohort prospective study

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          Abstract

          Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters. Recent evidence suggests that human vulnerability may be greatest in the first trimester of gestation and rodent experiments suggest sex specificity. We aimed to describe the consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli war of 1967. A priori, we focused on gestational month and offspring's sex.

          In a pilot study linking birth records to Israel's Psychiatric Registry, we analyzed data from a cohort of 88,829 born in Jerusalem in 1964–76. Proportional hazards models were used to estimate the relative risk (RR) of schizophrenia, according to month of birth, gender and other variables, while controlling for father's age and other potential confounders. Other causes of hospitalized psychiatric morbidity (grouped together) were analyzed for comparison.

          There was a raised incidence of schizophrenia for those who were in the second month of fetal life in June 1967 (RR = 2.3, 1.1–4.7), seen more in females (4.3, 1.7–10.7) than in males (1.2, 0.4–3.8). Results were not explained by secular or seasonal variations, altered birth weight or gestational age. For other conditions, RRs were increased in offspring who had been in the third month of fetal life in June 1967 (2.5, 1.2–5.2), also seen more in females (3.6, 1.3–9.7) than males (1.8, 0.6–5.2).

          These findings add to a growing literature, in experimental animals and humans, attributing long term consequences for offspring of maternal gestational stress. They suggest both a sex-specificity and a relatively short gestational time-window for gestational effects on vulnerability to schizophrenia.

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

          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. To determine whether those who endured a massive 1959-1961 famine in China experienced similar results. 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. Evidence of famine was verified, and unadjusted and mortality-adjusted relative risks of schizophrenia were calculated. 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. 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.
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            Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology.

            Epidemiological evidence suggests that an adverse prenatal environment permanently 'programs' physiology and increases the risk of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood. Prenatal stress or exposure to excess glucocorticoids might provide the link between fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress, glucocorticoid exposure and inhibition (or knockout of) 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2)--the fetoplacental barrier to maternal glucocorticoids--reduce birth weight and cause increases in adult blood pressure, glucose levels, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviors. In humans, mutations in the gene that encodes 11beta- hydroxysteroid dehydrogenase type 2 are associated with low birth weight. Babies with low birth weight have higher plasma cortisol levels throughout life, which indicates HPA-axis programming. In human pregnancy, severe maternal stress affects the offspring's HPA axis and is associated with neuropsychiatric disorders; moreover, maternal glucocorticoid therapy alters offspring brain function. The molecular mechanisms that underlie prenatal programming might reflect permanent changes in the expression of specific transcription factors, including the glucocorticoid receptor; tissue specific effects reflect modification of one or more of the multiple alternative first exons or promoters of the glucocorticoid receptor gene. Intriguingly, some of these effects seem to be inherited by subsequent generations that are unexposed to exogenous glucocorticoids at any point in their lifespan from fertilization, which implies that these epigenetic effects persist.
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              The potential influence of maternal stress hormones on development and mental health of the offspring.

              Recent studies in humans suggest that alterations in the activity of the neuroendocrine system mediate the effects of psychosocial stress on fetal development and birth outcome. Chronic maternal distress compromises the normal regulation of hormonal activity during pregnancy and elevates free circulating corticotrophin-releasing hormone (CRH), probably of placental origin, before the normal increase occurs at term. Excess CRH, and other hormones like cortisol and met-enkephalin that pass through the placenta, could precipitate preterm labor, reduce birth weight and slow growth rate in prenatally stressed infants. CRH and/or cortisol have also been associated with impaired fetal habituation to stimuli and temperamental difficulties in infants. These changes may result from actions of the hormones on their receptors in the fetal limbic system. In the rat, gestational stress and excess maternal and fetal plasma corticosterone cause downregulation of fetal glucocorticoid (GR) and mineralocorticoid (MR) receptors and impair the feedback regulation of the hypothalamic-pituitary adrenal (HPA) axis in infancy and adulthood. The impairment in HPA axis activity can be prevented by maternal adrenalectomy and mimicked by administration of glucocorticoids. Gestational stress also increases CRH activity in the amygdala and the incidence of anxiogenic and depressive-like behavior in rats and non-human primates, which can be ameliorated by CRH antagonists. Excess amounts of CRH and cortisol reaching the human fetal brain during periods of chronic maternal stress could alter personality and predispose to attention deficits and depressive illness through changes in neurotransmitter activity.
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                Author and article information

                Journal
                BMC Psychiatry
                BMC Psychiatry
                BioMed Central
                1471-244X
                2008
                21 August 2008
                : 8
                : 71
                Affiliations
                [1 ]Department of Psychiatry, New York University School of Medicine, New York, NY, USA
                [2 ]Department of Psychiatry, Columbia University, New York, NY, USA
                [3 ]New York State Psychiatric Institute, New York, NY, USA
                [4 ]Shalvata Mental Health Center, Ramat Gan, Israel
                [5 ]Sackler School of Medicine, Tel Aviv University, Israel
                [6 ]Department of Information and Evaluation, Ministry of Health, Jerusalem, Israel
                [7 ]Braun School of Public Health, Hebrew University of Jerusalem, Israel
                [8 ]Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
                Article
                1471-244X-8-71
                10.1186/1471-244X-8-71
                2546388
                18717990
                fe39dbd5-c868-4419-a9a3-4e9f8faae3dc
                Copyright © 2008 Malaspina et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 February 2008
                : 21 August 2008
                Categories
                Research Article

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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