An array of models has been proposed to explain how OCs contribute to the causes of schizophrenia. We cover the most prominent models in schizophrenia research and discuss which model is best supported by empirical research.

Some theorists have proposed that there may be a subgroup of patients with schizophrenia who acquire the disorder from entirely nongenetic origins. According to this model, an obstetric insult could cause schizophrenia independently of genetic contributions. If this model were correct, then exposure to OCs (with a given degree of severity and during a sensitive period of gestation) would lead to expression of schizophrenia with a fair degree of reliably. The prevailing evidence suggests that this model is unlikely, because the rate of OCs in the general population is far higher than the rate of schizophrenia (approximately 1% of the population). Even if OCs during particularly critical periods of gestation only were considered, there would likely still be a much higher rate of schizophrenia in the population if OCs were the sole cause of the disease onset. Therefore, there currently is little support for the idea that OCs alone can produce schizophrenia.

Another model, the gene - environment covariation model, posits that OCs are associated with the genes for the disorder, but OCs do not exert any etiological role in the disease. This model predicts an increase in the number of OCs in individuals who carry genes associated with schizophrenia, regardless of whether they develop the disorder. The main support for the gene - environment covariation model comes from studies that found increased birth complications in offspring of mothers with schizophrenia (who carry the disease-producing genes given that they express the disorder phenotypically), but it is inconsistent with the finding that unaffected siblings of patients with schizophrenia do not differ from the general population in the incidence of OCs. Siblings of patients with schizophrenia would be expected to share some of the disease-promoting genes, therefore leading to increased risk of OCs, if the gene - environment covariation model were correct.

In addition, interpretation of increases in OCs among mothers with schizophrenia is complicated by the elevated occurrence of health-risk behaviors during pregnancy among this cohort. Specifically, women with schizophrenia are less likely to receive prenatal care, more likely to be polydrug users, more likely to drink alcohol, more likely to be on psychiatric medications, and more likely to smoke cigarettes than women without schizophrenia, all of which have been associated with increases in OCs. Moreover, discontinuation of antipsychotic medication has been associated with a worsening of symptoms, often leading to psychotic episodes in relatively asymptomatic women. The onset of a psychotic episode likely has many consequences for prenatal health, including increased stress, poor nutrition, poor self-care, suicide attempts, attempts at premature delivery, and other risky behaviors that could lead to deleterious pregnancy and birth outcomes.

Given the limitations of the available data, findings that support the gene - environment covariation model are difficult to interpret.

Most studies support the gene - environment interaction model, which asserts that obstetric influences depend on the presence of disease-promoting genes in the etiology of schizophrenia. According to this model, the occurrence of an OC in a genetically vulnerable individual would increase the likelihood of that individual developing the disorder.

Support for this model comes from studies in which a history of OCs differentiated between siblings with and without schizophrenia, suggesting that this early insult interacted with disease-producing genes to cause the disorder. It also is possible that genetic and obstetric risk factors for schizophrenia occur independently of each other but additively influence risk for disease expression (additive influence model). Both the gene - environment interaction model and the additive influences model predict a relative increase in the rate of OCs among individuals who develop schizophrenia; therefore, the two models are often difficult to separate. Specifically, it is very difficult to examine directly gene - environment interactions or gene - environment aggregations. To do this, it is necessary to measure the environmental influence, as well as the gene, or genes. This may be more feasible now, with the recent availability of serological data from pregnancy and the identification of candidate genes involved in schizophrenia. Nevertheless, only a handful of candidate genes have been identified, and schizophrenia is not caused by one gene, which further complicates the ease of directly testing gene - environment interactions and aggregations.

For our purposes in this chapter, we refer to the gene - environment interaction model, but many of the findings may also fit into the additive influences model.

Last,  it is possible that multiple models are correct and operate simultaneously within the disorder. This possibility has not been explored as extensively, but it will likely gain more attention with the virtual explosion of studies investigating specific genetic variations among patients with schizophrenia, termed polymorphisms, as well as increasing attempts to map out molecular pathways implicated in the disorder. For instance, a genetic polymorphism associated with a magnified inflammatory response has been linked to schizophrenia (discussed further in section on prenatal infection).  In the presence of infection, this genetic polymorphism leads to increased inflammation (gene - environment interaction),  the consequences of which are discussed more extensively below. Interestingly, this polymorphism also is associated with increased incidence of certain OCs, such as preterm delivery (gene - environment covariation); therefore, we can see that a gene associated with schizophrenia could have multiple functions, some others of which may serve to play a role in the causes of the disorder and others of which may be unrelated to the etiology. The relatively new opportunity to investigate directly gene - environment interactions at a molecular level will certainly shed considerable light on how OCs operate within the disorder.

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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