CLINICAL HANDBOOK OF SCHIZOPHRENIA

7. Environmental Pre- and Perinatal Influences in Etiology 69hippocampal volumes among patients with schizophrenia, suggesting that genetic contributionsto hippocampal volume reductions in patients with schizophrenia were worsenedby a history of fetal hypoxia. The aforementioned studies support a gene–environment interactionmodel, in which an early hypoxic event adds to or interacts with a genetic vulnerabilityfor schizophrenia, leading to a form of schizophrenia characterized by earlierage of onset and greater neuroanatomical abnormalities.Independently of a genetic liability for schizophrenia, fetal hypoxia has been foundto affect many of the same neural substrates implicated in schizophrenia, depending onthe severity and duration of the hypoxic event, as well as the period of gestation. Insheep, fetal hypoxia has been found to disrupt neuronal development and connections inthe hippocampus, cerebellum, and visual cortex. When the duration of the hypoxia wasincreased to 20 days during late gestation, abnormalities were found in the cerebellum, aswell as white matter lesions. Shorter periods of hypoxia during midgestation were associatedwith reductions in cortical white matter, as well as hippocampal density reductions.Brains of rat pups exposed to perinatal hypoxia during the last day of gestation showedmyelination deficits in multiple brain regions, including the hippocampus and cerebellum,suggesting that hypoxia may also affect neuronal signal speed. In addition, findings fromrat studies have linked perinatal oxygen insufficiency with dopamine abnormalities in theprefrontal cortex, nucleus accumbens, and striatum.In humans, fetal hypoxia has been linked to a series of motor and cognitive deficitsin children. Children exposed to mild fetal hypoxia exhibited no detectable motor or cognitivedeficits later in childhood; however, exposure to moderate fetal hypoxia led tospeech, language, motor, verbal, and overall cognitive deficits. Furthermore, survivors ofmoderate hypoxia were more likely to be behind more than one grade level compared tochildren in their age group. The more severe cases of fetal hypoxia often lead to neonataldeath or cerebral palsy. Thus, infants exposed to moderate and severe fetal hypoxia are atrisk for physical and mental impairment, as well as worsened school performance even inthe absence of a genetic vulnerability for schizophrenia.Infection during PregnancyThe role of prenatal infection in the etiology of schizophrenia has been repeatedly documentedthrough a series of epidemiological and, more recently, serological studies. Seasonof birth, especially during winter–spring months, has been consistently linked withschizophrenia outcome, and these months are typically associated with a higher incidenceof infection. Among epidemiological studies, various prenatal infections, including influenzaand rubella exposure, have been linked to schizophrenia outcome, although therehave been some conflicting findings.More recently, serological data confirming maternal infection during pregnancy haveemerged in schizophrenia research. These studies provide major methodological advancementsover previous investigations, given that biological indicators of infection can providea better estimation of positive cases, as well as assess the timing and severity of theinfection. These data have come from banked maternal sera from two large birth cohortstudies in the United States that followed women throughout the prenatal period andsubsequently 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 schizophreniaspectrum disorders. Prenatal exposure to the parasitic infection Toxoplasma gondii waslinked to schizophrenia in one study, but another study failed to replicated this finding,