Envoronmental Pre- and Perinatal Influences in Etiology

A few specific pregnancy and perinatal factors were associated with the subsequent development of psychotic disorder, particularly schizophrenia, in early adult life. The association of small size for gestational age and bleeding during pregnancy with increased risk of early onset schizophrenia among males could reflect placental insufficiency.

In the search for the causes of schizophrenia, the preponderance of evidence suggests that genes play a substantial role in the etiology of the disorder. Based on the results from twin, family, and adoption studies, genetic influences account for approximately 80% of the disorder’s etiology. Although schizophrenia appears to be a highly heritable disorder, it is clear that environmental factors also are involved.

Many environmental influences have been investigated as potential contributors to the disorder, such as family environment, socioeconomic status, and substance abuse; however, a repeatedly demonstrated environmental predictor of schizophrenia has been a history of obstetric complications (OCs). OCs constitute a fairly broad class of events, including any deviation from the normal course of pregnancy, labor - delivery, and the early neonatal period, such as low birthweight, prenatal maternal infection, and many others (discussed below).

Such complications are relatively common, occurring in the histories of approximately 20 - 30% of patients with schizophrenia and approximately 5 - 10% of the population overall. In this chapter, we provide an overview of the various OCs that have been linked to schizophrenia, discuss different explanatory models of how OCs operate within the etiology of the disorder, and discuss the potential mechanisms underlying two main classes of OCs associated with schizophrenia: prenatal infection and fetal oxygen deprivation.

Evidence from epidemiological and neuropathological studies indicates that pathogenic processes that culminate in the development of schizophrenia are initiated early in life. The neurodevelopmental hypothesis that schizophrenia has its origins in aberrant brain development receives support from the evidence of an association between obstetric complications and schizophrenia, especially schizophrenia with an early age of onset. However, there is still controversy concerning the specificity of this association for schizophrenia, the existence of specific risk factors, and the possibility of a bias in the literature towards publication of positive findings. In a recent hospital based case-control study of 107 schizophrenic patients with age of onset up to 45 years only aberrations in size at birth remained significantly associated with schizophrenia in a multivariate analysis.

We undertook the present nationwide Swedish study to examine the association between size at birth and other prenatal and perinatal factors and the risk of developing schizophrenia in early adult life. Additionally, we addressed the question of whether disturbance in prenatal development is specific to schizophrenia or whether it also occurs in affective and reactive psychoses.

Christina M Hultman,  Pär Sparén, Noriyoshi Takei, Robin M Murray, Sven Cnattingius

Key messages

  • The role of prenatal and perinatal risk factors in the development of schizophrenia and affective and reactive psychosis in early adult life were investigated by linking individual data from the Swedish birth and inpatient registries
  • Adverse prenatal and perinatal factors were more common in patients with schizophrenia of early onset than in controls and seemed more important in the aetiology of schizophrenia than in that of affective and reactive psychosis
  • Multiparity, bleeding during pregnancy, and small size for gestational age were associated with a threefold to fourfold increased risk for schizophrenia among males
  • There was no support for previous claims that head circumference is small in preschizophrenic infants
  • Late winter birth was associated with increased risk of both schizophrenia and affective psychosis


  • 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.

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