growth lower than average birth weight has been one of the most consistent findings, indicating slowed fetal growth possibly mediated by genetic effects. in the first and only prospective study of the low birthweight, schizophrenia, and enlargement of brain ventricles suggestive of cerebral atrophy, leigh silverton and colleagues found that low birthweight (measured prospectively with regard to psychopathology) was associated with enlarged ventricles on ct scans in a sample at risk for schizophrenia over 30 years later. these signs suggestive of cerebral atrophy were associated with schizophrenia symptoms. in a follow up study, silverton et al. noted an interaction between genetic risk for schizophrenia and low birthweight. the risk of enlarged ventricles on brain scan (associated with schizophrenia symptoms and biologically suggestive of emil kraepelin's dementia praecox) was greatly increased if the subjects had both a higher genetic load for schizophrenia and lower birthweight. the investigators suggested that in utero insults may specifically stress those with a schizophrenia diathesis, supporting a "diathesis-stress" etiological model for a subset of schizophrenia (that kraepelin identified) with early abnormalities suggesting brain atrophy. some investigators have noted, however, that any factor adversely affecting the fetus will affect growth rate. some believe that this association may not be particularly informative with regard to causation. in addition, the majority of birth cohort studies have failed to find a link between schizophrenia and low birth weight or other signs of slowed growth. the majority of studies do not measure the interaction of genetic risk with birthweight as was done in the studies by silverton et al. hypoxia it has been hypothesized since the 1970s that brain hypoxia (low oxygen levels) before, at or immediately after, birth may be a risk factor for the development of schizophrenia. hypoxia is demonstrated as relevant to schizophrenia in animal models, molecular biology and epidemiology studies. one study was able to differentiate 90% of cases of schizophrenia from controls based on hypoxia and metabolism. hypoxia has been described as one of the most important of the external factors that influence susceptibility, although studies have been mainly epidemiological. such studies place a high degree of importance on hypoxic insult, but given the pattern of the illness in some families, they propose a genetic basis as well; stopping short of concluding that hypoxia is a sole cause on its own. fetal hypoxia, in the presence of certain unidentified genes, has been correlated with reduced volume of the hippocampus, which is in turn correlated with schizophrenia. although most studies have interpreted hypoxia as causing some form of neuronal dysfunction or even subtle damage, it has been suggested that the physiological hypoxia that prevails in normal embryonic and fetal development, or pathological hypoxia or ischemia, may exert an effect by regulating or dysregulating genes involved in neurodevelopment. a literature review judged that over 50% of the candidate genes for susceptibility to schizophrenia met criteria for "ischemia–hypoxia regulation or vascular expression" even though only 3.5% of all genes were estimated to be involved in hypoxia/ischemia or the vasculature. a longitudinal study found that obstetric complications involving hypoxia were one factor associated with neurodevelopmental impairments in childhood and with the later development of schizophreniform disorders. fetal hypoxia has been found to predict unusual movements at age 4 (but not age 7) among children who go on to develop schizophrenia, suggesting that its effects are specific to a stage of neurodevelopment. a japanese case study of monozygotic twins discordant for schizophrenia (one has the diagnosis while the other does not) draws attention to their different weights at birth and concludes hypoxia may be the differentiating factor. the unusual functional laterality in speech production (e.g. right hemisphere auditory processing) found in some individuals with schizophrenia could be due to aberrant neural networks established as a compensation for left temporal lobe damage induced by pre- or perinatal hypoxia. prenatal and perinatal hypoxia appears to be important as one factor in the neurodevelopmental model, with the important implication that some forms of schizophrenia may thus be preventable. research on rodents seeking to understand the possible role of prenatal hypoxia in disorders such as schizophrenia has indicated that it can lead to a range of sensorimotor and learning/memory abnormalities. impairments in motor function and coordination, evident on challenging tasks when the hypoxia was severe enough to cause brain damage, were long-lasting and described as a "hallmark of prenatal hypoxia". several animal studies have indicated that fetal hypoxia can affect many of the same neural substrates implicated in schizophrenia, depending on the severity and duration of the hypoxic event as well as the period of gestation, and in humans moderate or severe (but not mild) fetal hypoxia has been linked to a series of motor, language and cognitive deficits in children, regardless of genetic vulnerability to schizophrenia. one paper restated that cerebellum neurological disorders were frequently found in those with schizophrenia and speculated hypoxia may cause the subsequent cognitive dysmetria whereas most studies find only a modest effect of hypoxia in schizophrenia, a longitudinal study using a combination of indicators to detect possible fetal hypoxia, such as early equivalents of neurologic soft signs or obstetric complications, reported that the risk of schizophrenia and other nonaffective psychoses was "strikingly elevated" (5.75% versus 0.39%). although objective estimates of hypoxia did not account for all cases of schizophrenia; the study revealed increasing odds of schizophrenia according to graded increase in severity of hypoxia. infections and immune system a number of viral exposures during prenatal development, have been associated with an increased risk of schizophrenia. schizophrenia is somewhat more common in those born in winter to early spring, when such infections are more common. influenza has long been studied as a possible factor. a 1988 study found that individuals who were exposed to the asian flu in the second trimester were at increased risk of later developing schizophrenia. this result was corroborated by a later british study of the same pandemic, but not by a 1994 study of the pandemic in croatia. a japanese study also found no support for a link between schizophrenia and birth after an influenza epidemic. polio, measles, varicella-zoster, rubella, herpes simplex, maternal genital infections, borna disease virus, and toxoplasma gondii have been correlated with the later development of schizophrenia. psychiatrists e. fuller torrey and r.h. yolken have hypothesized that the latter, a common parasite in humans, contributes to some cases of schizophrenia. in a meta-analysis of several studies, they found moderately higher levels of toxoplasma antibodies in those with schizophrenia and possibly higher rates of prenatal or early postnatal exposure to toxoplasma gondii, but not acute infection. however, in another study of postmortem brain tissue, the authors have reported equivocal or negative results, including no evidence of herpes virus or t. gondii involvement in schizophrenia. there is some evidence for the role of autoimmunity in the development of some cases of schizophrenia. a statistical correlation has been reported with various autoimmune diseases and direct studies have linked dysfunctional immune activation to some of the clinical features of schizophrenia. this is known as the pathogenic theory of schizophrenia or germ theory of schizophrenia. it is a pathogenic theory of disease in which it is thought that a proximal cause of certain cases of schizophrenia is the interaction of the developing fetus with pathogens such as viruses, or with antibodies from the mother created in response to these pathogens (in particular, interleukin 8). substantial research suggests that exposure to certain illnesses (e.g., influenza) in the mother of a fetus (especially at the end of the second trimester) causes defects in neural development, which may emerge as a predisposition to schizophrenia around the time of puberty or later, as the brain grows and further develops. other factors there is an emerging literature on a wide range of prenatal risk factors, such as prenatal stress, intrauterine (in the womb) malnutrition, and prenatal infection. increased paternal age has been linked to schizophrenia, possibly due to "chromosomal aberrations and mutations of the aging germline." maternal-fetal rhesus or genotype incompatibility has also been linked, via increasing the risk of an adverse prenatal environment. also, in mothers with schizophrenia, an increased risk has been identified via a complex interaction between maternal genotype, maternal behavior, prenatal environment and possibly medication and socioeconomic factors.