Infection during Pregnancy

The role of prenatal infection in the etiology of schizophrenia has been repeatedly documented through a series of epidemiological and, more recently, serological studies. Season of birth,  especially during winter - spring months,  has been consistently linked with schizophrenia outcome, and these months are typically associated with a higher incidence of infection. Among epidemiological studies, various prenatal infections, including influenza and rubella exposure, have been linked to schizophrenia outcome, although there have been some conflicting findings. More recently, serological data confirming maternal infection during pregnancy have emerged in schizophrenia research. These studies provide major methodological advancements over previous investigations, given that biological indicators of infection can provide a better estimation of positive cases, as well as assess the timing and severity of the infection. These data have come from banked maternal sera from two large birth cohort studies in the United States that followed women throughout the prenatal period and subsequently followed their offspring during the 1950s and 1960s. Among these studies, herpes simplex virus - 2 (HSV-2), influenza, maternal genital and reproductive infection (including endometritis, cervicitis, pelvic inflammatory disease, vaginitis, syphilis, condylomata, “venereal disease,” and gonorrhea) antibodies have been linked to schizophrenia spectrum disorders. Prenatal exposure to the parasitic infection Toxoplasma gondii was linked to schizophrenia in one study, but another study failed to replicated this finding, which may have been due to a relatively small sample size (including 27 psychotic offspring, only 13 of whom were diagnosed with schizophrenia). With the exception of the parasite T. gondii, viral infections rarely cross the placenta; therefore, the damaging effects of fetal exposure to most viral infections likely involve multiple molecular pathways, a primary one being the mother’s immune response to viral infections. During pregnancy, many immunological changes to protect the fetus from the mother mounting an immune response to a genetically dissimilar entity. Many of these changes involve signaling proteins called cytokines, which are considered the hormones of the immune system and, among other functions, are essential in combating infections. Although there are exceptions, there seems to be a shift in immune functioning during pregnancy, with preferential production of helper T cell (Type 2) Th2 cytokines, such as interleukin - 4 (IL-4), interleukin - 5 (IL-5), and interleukin - 10 (IL-10), that are mainly involved in the stimulation of B cells and antibody responses. The relative increase in Th2 cytokines during pregnancy has been associated with a down-regulation of Th1 cytokines, such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin - 2 (IL-2), which are involved in cell-mediated immunity and inflammation (proinflammatory cytokines), thereby potentially decreasing the mother’s ability to respond to viral infection. In addition to the possibility that the fetus is more vulnerable to infection due to a shift in maternal immune functioning, studies suggest that the maternal antiviral response may contribute directly to the neuronal abnormalities found in offspring exposed prenatally to infection, with particular importance placed on the role of proinflammatory cytokines. Pregnant mice injected with a sham virus, capable of producing an antiviral reaction, had offspring with cognitive deficits similar to those found among patients with schizophrenia,  such as deficits in prepulse inhibition (thought to be a measure of sensorimotor gating). In concert with these findings, rats prenatally exposed to proinflammatory cytokines have a multitude of brain abnormalities similar to those found among patients with schizophrenia, such as abnormalities in the hippocampus and cortex. In humans, exposure to elevated cytokines during pregnancy has been associated with neurodevelopmental damage, such as periventricular leukomalacia, cerebral palsy, and mental retardation. In summary, these findings suggest that neuronal abnormalities associated with prenatal infection may be related to elevated proinflammatory cytokine production, even in the absence of a genetic diathesis for schizophrenia. In addition to the direct neurotoxic effects of proinflammatory cytokines, growing evidence suggests a causal relationship between inflammation and multiple OCs found in the histories of patients with schizophrenia, including preterm delivery, preeclampsia, and fetal oxygen deprivation (hypoxia). As discussed earlier, fetal hypoxia leads to a series of neuronal abnormalities found among patients with schizophrenia, even in the absence of infection and in individuals at low genetic risk for schizophrenia.  Therefore,  fetal neuronal damage following exposure to inflammation may be in part a result of the damaging effects of fetal hypoxia. Given the aforementioned studies, it is not surprising that investigators have begun to explore the possible relationship between fetal exposure to proinflammatory cytokines and schizophrenia outcome. This area of research is somewhat complicated by the dynamic nature of the immune system. Specifically, cytokines typically aggregate around the site of infection and/or injury; therefore, cytokine levels in blood serum typically do not accurately reflect either the constantly changing state of the immune system or the interactions between the mother’s immune system and the developing fetus. Nevertheless, two studies have linked markers of inflammation from maternal serum to psychotic outcome in offspring.  Specifically,  interleukin-8 (IL-8)  during second and third trimesters and TNF-alpha at the time of birth (both proinflammatory cytokines) have been linked to increased incidence of psychosis in offspring. In addition to the direct neurotoxic effects of fetal exposure to proinflammatory cytokines, emerging evidence suggests that genetic polymorphisms found in schizophrenia populations may make certain individuals more susceptible to the negative effects of infection and inflammation. TNF-a (promoter region A2) and IL-1 complex [IL-1-alpha (-889) allele 2, IL-1-beta (-511) allele 1, and IL-1RA allele 1] genetic polymorphisms have been associated with schizophrenia outcome. These polymorphisms typically lead to both production of proinflammatory cytokines without any known infection (i.e., basal levels) and overproduction of proinflammatory cytokines in response to infection. Although individuals with these polymorphisms do not always develop schizophrenia, they appear to be more vulnerable to multiple diseases and infections. Therefore, it is possible that carriers of genetic polymorphisms associated with inflammation could be more vulnerable to the damaging effects of prenatal infection, thus increasing the likelihood of psychotic onset in adulthood; however, no studies have directly tested this gene - environment interaction. Cumulatively,  studies implicate a series of prenatal infections in the etiology of schizophrenia. Nevertheless, it appears as though the deleterious effects of exposure to prenatal infection may be more related to maternal immune responses to infection than to the direct effects of the pathogen, given that most pathogens do not cross the placenta. Specifically, prenatal exposure to maternal proinflammatory cytokines has been found to alter multiple areas of the brain that have been implicated in schizophrenia, and these cytokines have been linked to psychotic outcome in offspring.  In addition,  genetic polymorphisms associated with overproduction of proinflammatory cytokines have been found in patients with schizophrenia,  suggesting that individuals who later develop schizophrenia may be particularly vulnerable to infection and other prenatal insults. Last, both infection and proinflammatory cytokines have been linked to increased fetal hypoxia, which has been associated with schizophrenia and many of the brain abnormalities linked to the disorder. The availability of studies using serological data and the possibility of examining direct gene - environment interactions likely will lead to a much better understanding of the molecular pathways linking OCs to schizophrenia outcome, which is the starting point for developing treatment and early intervention strategies. KEY POINTS

• OCs have been found to be repeatedly associated with schizophrenia outcome, occurring in the histories of 20 - 30% of patients with schizophrenia and 5 - 10% of the overall population.
• Of the prevailing explanatory models, the majority of evidence supports the gene - environment interaction model, which asserts that OCs interact with genes associated with schizophrenia to increase risk for the disorder.
• Many OCs have been associated with schizophrenia, including complications during pregnancy, fetal and infant underdevelopment, and birth complications.
• Lack of oxygen to the fetus, termed fetal hypoxia, likely is involved in many OCs associated with schizophrenia.
• A history of hypoxia-associated OCs differentiates between patients with schzophrenia and their nonschizophrenic siblings, and leads to a form of schizophrenia characterized by earlier age of onset and greater neuroanatomical abnormalities.
• Infection during pregnancy has been repeatedly associated with schizophrenia in offspring. More recent studies using serological confirmation of infection have found an association between HSV-2, influenza, genital and reproductive infection, and T. gondii exposure during pregnancy and schizophrenia spectrum disorders in offspring.
• Most prenatal infections do not cross the placenta; therefore, the damaging effects to the fetus seem to be partially related to the mother's immune response to infection, particularly involving inflammation.
• Genetic polymorphisms that amplify the inflammatory response to infection have been found among patients with schizophrenia, suggesting that genetic factors may confer heightened sensitivity to infection and other prenatal insults.
• Both infection and proinflammatory cytokines have been linked to increased fetal hypoxia, which has been associated with schizophrenia and many of the brain abnormalities linked to the disorder.
• Some theorists propose that schizophrenia arises due excessive reduction in the connections throughout the brain (synaptic pruning), leading to problems in most areas of functioning. OCs fit within this model by further reducing the amount of connections in the brain, leading to an earlier age of onset and worsened clinical outcome.

LAUREN M. ELLMAN
TYRONE D. CANNON

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