Epidemiological Evidence that Maternal Influenza Contributes to the Aetiology of Schizophrenia

Adams, William Howard; Kendell, R. E.; Hare, E. H.; Munk‐Jørgensen, P.

doi:10.1192/bjp.163.4.522

Cited by 195 publications

(108 citation statements)

References 18 publications

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“…9 This seasonality has sometimes been shown to be linked to influenza epidemics. 10,11 Infectious disease during pregnancy has been found to adversely affect rodent brain development in a manner that can lead to schizophrenia as well as autism. [12][13][14][15][16][17][18] The hypothesis that the seasonality was related to low levels of maternal serum 25-hydroxyvitamin D (calcidiol) was also advanced.…”

Section: Introductionmentioning

confidence: 99%

Epidemiologic evidence for supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism

Grant

Soles²

2009

Dermato-Endocrinology

130

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This study examines whether maternal vitamin D deficiency is a risk factor for infantile autism disease (IAD). We used epidemiologic data seasonal variation of birth rates and prevalence of IAD for cohorts born before 1985. For seven studies reporting spring-to-summer excess birth rates for IAD, the season progressed from broad near 30° N latitude, spring/summer in midlatitudes, to winter at the highest latitude. Also, using data from 10 studies, we found a strong effective latitudinal (related to wintertime solar ultraviolet B radiation) increase in IAD prevalence. These findings are consistent with maternal vitamin D deficiency's being a risk factor for IAD, possibly by affecting fetal brain development as well as possibly by affecting maternal immune system status during pregnancy. Further investigation of this hypothesis is warranted. IntroductionThe etiology of autism is still somewhat of an enigma. Autism is considered an autoimmune disease. 1 It also appears to have important risk factors in utero, as evidenced by a highly significant increased frequency of congenital malformations; 2 and those with autism have several characteristics associated with schizophrenia, 3 which is also linked to in utero risk factors. 4 Perinatal viral infection of mother or infant is a risk factor for both infantile autism and schizophrenia. 5 Also, several studies have reported seasonality in excess births of those with autism, with March being a peak month in Sweden, 6 Denmark 7 and Boston, 8 but without a good explanation for this seasonality.Schizophrenia is another disease that exhibits excess of births in winter and a deficit in summer. 9 This seasonality has sometimes been shown to be linked to influenza epidemics. 10,11 Infectious disease during pregnancy has been found to adversely affect rodent brain development in a manner that can lead to schizophrenia as well as autism. [12][13][14][15][16][17][18] The hypothesis that the seasonality was related to low levels of maternal serum 25-hydroxyvitamin D (calcidiol) was also advanced. 19 Support for the maternal vitamin D deficiency hypothesis has been reported based on rat studies. [20][21][22] It was recently proposed that the annual solar ultraviolet-B (UVB) and vitamin D cycles explained some of the seasonality of epidemic influenza, which peaks in winter. 23 This hypothesis received experimental support in a randomized, prospective, placebo-controlled vitamin D study involving 204 postmenopausal black women living in the state of New York. Those taking 2,000 IU of vitamin D3 per day got 10% as many colds or influenza as those taking the placebo. 24 More support came from a study of meteorological variables associated with incidence of respiratory syncytial virus that found an effect for solar UVB in addition to temperature and relative humidity, with greatest effect at lower latitude. 25 Thus, serum calcidiol levels can affect risk of maternal viral disease during pregnancy.This report examines the evidence supporting the hypothesis that maternal vitamin D deficien...

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Section: Introductionmentioning

confidence: 99%

Epidemiologic evidence for supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism

Grant

Soles²

2009

Dermato-Endocrinology

130

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“…A causal relationship pertaining to disturbed brain ontogenesis and schizophrenia comes from epidemiological studies that have identified several risk factors that, acting during pregnancy, increase the incidence of the disease in offspring. Maternal infection with influenza virus in the second trimester of pregnancy causes a major disorder incidence (Mednick et al 1988;O'Callaghan et al 1991;Adams et al 1993). In addition, a seasonal effect has been also documented, with more persons born in the late winter and early spring months developing schizophrenia (Torrey et al 1977;Mortensen et al 1999).…”

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confidence: 99%

Prenatal Immune Challenge Disrupts Sensorimotor Gating in Adult Rats Implications for the Etiopathogenesis of Schizophrenia

Borrell

Vela²,

Arévalo-Martı́n³

et al. 2002

Neuropsychopharmacology

280

191

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Increasing evidence associates schizophrenia with prenatal exposure to infection. Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) of the acoustic startle reflex. We analyzed the effect of a prenatal immune challenge-peripheral administration of bacterial endotoxin lipopolysaccharide (LPS) to pregnant female rats-upon PPI and immune function in adult offspring. Prenatal LPS treatment disrupted PPI which was reversed by antipsychotics. Serum levels of interleukin-2 and interleukin-6 were increased. In addition, histopathological features in brain areas related with PPI circuitry were observed. These results illustrate the critical influence of prenatal immune events upon adult CNS functioning in association with the putative role of the immune system in (Braff et al. 1978;Kumari et al. 1999). A well-established sensorimotor gating paradigm is the prepulse inhibition (PPI) of the startle response. PPI refers to the reduction in startle reactivity toward an intense pulse stimulus when it is shortly preceded by a weak prepulse stimulus (Hoffman and Ison 1980). It is thought that the prepulse response activates an inhibitory process that attenuates or "gates" the startle response. Because identical stimulus parameters can be used for animal and human studies, it is considered that animal models of PPI disruption represent a promising way to study the neural mechanisms underlying sensorimotor gating dysfunction (Swerdlow et al. 1994(Swerdlow et al. , 1999Swerdlow and Geyer 1998) and as a screening test for potential antipsychotics (Swerdlow et al. 1994;Depoortere et al. 1997). In fact, antipsychotics remove PPI deficits in schizophrenic patients (Kumari et al. 1999;Weike et al. 2000). Nevertheless, it must be taken into consideration that deficiency of PPI has been reported in other selected neuropsychiatric disorders where inability to inhibit movements is involved (Huntington's disease (Swerdlow et al. 1995 Tourette's syndrome (Castellanos et al. 1996)), where inability to control attentional and cognitive processes is involved (obsessive-compulsive disorder (Swerdlow et al. 1993)), or where anxiety and exaggerated startle occur (posttraumatic stress disorder (Grillon et al. 1996)). The focus of schizophrenia research has been turning from studies of structural and functional brain abnormalities to an increasing emphasis on possible etiologic factors. Neurodevelopmental theories of schizophrenia postulate that the psychopathology of schizophrenia may derive from alterations of brain organization secondary to defective ontogenesis (Weinberger 1996;Raedler et al. 1998). A causal relationship pertaining to disturbed brain ontogenesis and schizophrenia comes from epidemiological studies that have identified several risk factors that, acting during pregnancy, increase the incidence of the disease in offspring. Maternal infection with influenza virus in the second trimester of preg...

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“…Among environmental factors that may detrimentally affect neurodevelopment, prenatal exposure to viral infection has been implicated by several large epidemiological studies, indicating that such exposure increases the risk of schizophrenia (Adams et al, 1993;Izumoto et al, 1999;Mednick et al, 1994;O'Callaghan et al, 1994;Torrey et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia

Zuckerman

Rehavi

Nachman

et al. 2003

Neuropsychopharmacol

445

355

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Prenatal exposure to infection is associated with increased liability to schizophrenia, and it is believed that such an association is mediated by the maternal immune response, in particular, the proinflammatory cytokines released by the maternal immune system, which may disrupt fetal brain development. Impaired capacity to ignore irrelevant stimuli is one of the central deficits in schizophrenia, and is manifested, among others, in loss of latent inhibition (LI), a phenomenon whereby repeated inconsequential pre-exposure to a stimulus impairs its subsequent capacity to signal significant consequences. We tested the effects of prenatal immune activation induced by peripheral administration of the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I : C) to pregnant dams, on LI in juvenile and adult offspring. Consistent with the characteristic maturational delay of schizophrenia, prenatal immune activation did not affect LI in the juvenile offspring, but led to LI disruption in adulthood. Both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) reinstated LI in the adult offspring. In addition, prenatal immune activation led to a postpubertal emergence of increased sensitivity to the locomotorstimulating effects of amphetamine and increased in vitro striatal dopamine release, as well as to morphological alterations in the hippocampus and the entorhinal cortex in the adult offspring, consistent with the well-documented mesolimbic dopaminergic and temporolimbic pathology in schizophrenia. These results suggest that prenatal poly I : C administration may provide a neurodevelopmental model of schizophrenia that reproduces a putative inducing factor; mimics the temporal course as well as some central abnormalities of the disorder; and predicts responsiveness to antipsychotic drugs.

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Epidemiological Evidence that Maternal Influenza Contributes to the Aetiology of Schizophrenia

Cited by 195 publications

References 18 publications

Epidemiologic evidence for supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism

Epidemiologic evidence for supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism

Prenatal Immune Challenge Disrupts Sensorimotor Gating in Adult Rats Implications for the Etiopathogenesis of Schizophrenia

Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia

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