There have now been multiple reviews (see References and Recommended Readings) that show that fetal hypoxia is likely involved in a variety of OCs associated with schizophrenia. Specifically, OCs associated with schizophrenia, such as emergency caesarian section, bleeding during pregnancy, and preeclampsia, have all been associated with fetal hypoxia. To test the strength of the relationship between hypoxia-associated OCs and schizophre- nia onset in offspring, two studies used a hypoxia-associated OCs scale, including both indirect and direct indicators of hypoxia. Direct hypoxia-associated complications included events such as blue at birth, required resuscitation, neonatal cyanosis, and neonatal apnea. Indirect complications were selected based on validation with direct measures of hypoxia from previous studies and included abnormalities of fetal heart rate or rhythm, umbilical cord knotted or wrapped tightly around neck, third trimester bleeding, placental hemorrhaging or infarcts, an excessive amount of amniotic fluid (polyhydramnios), meconium1 in amniotic fluid, and breech presentation. Both studies found that hypoxia-associated OCs were associated with schizophrenia outcome in offspring, especially when patients exhibited disease onset at an early age. Hypoxia-associated OCs also have been found to differentiate between siblings with and without schizophrenia, suggesting that in the presence of a common genetic background (i.e., sibship), fetal hypoxia increases the likelihood of later developing schizophrenia. Nevertheless, fetal hypoxia is unlikely to lead to schizophrenia on its own; therefore, a genetic factor associated with schizophrenia likely renders the fetal brain particularly vulnerable to the effects of hypoxia. This hypothesis is supported by brain imaging studies, in which hypoxia-associated OCs predicted ventricular enlargement in patients with schizophrenia but not among their unaffected siblings and controls at low genetic risk for schizophrenia. Similarly, one study compared hippocampal volumes of patients with schizophrenia, their unaffected siblings, and nonschizophrenia comparison subjects, and found a stepwise decrease in hippocampal volumes with increased genetic liability for the disorder. A history of hypoxia-associated OCs led to further reductions in hippocampal volumes among patients with schizophrenia, suggesting that genetic contributions to hippocampal volume reductions in patients with schizophrenia were worsened by a history of fetal hypoxia. The aforementioned studies support a gene - environment interaction model, in which an early hypoxic event adds to or interacts with a genetic vulnerability for schizophrenia, leading to a form of schizophrenia characterized by earlier age of onset and greater neuroanatomical abnormalities. Independently of a genetic liability for schizophrenia, fetal hypoxia has been found to 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. In sheep, fetal hypoxia has been found to disrupt neuronal development and connections in the hippocampus, cerebellum, and visual cortex. When the duration of the hypoxia was increased to 20 days during late gestation, abnormalities were found in the cerebellum, as well as white matter lesions. Shorter periods of hypoxia during midgestation were associated with 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 showed myelination deficits in multiple brain regions, including the hippocampus and cerebellum, suggesting that hypoxia may also affect neuronal signal speed. In addition, findings from rat studies have linked perinatal oxygen insufficiency with dopamine abnormalities in the prefrontal cortex, nucleus accumbens, and striatum. In humans, fetal hypoxia has been linked to a series of motor and cognitive deficits in children. Children exposed to mild fetal hypoxia exhibited no detectable motor or cognitive deficits later in childhood; however, exposure to moderate fetal hypoxia led to speech, language, motor, verbal, and overall cognitive deficits. Furthermore, survivors of moderate hypoxia were more likely to be behind more than one grade level compared to children in their age group. The more severe cases of fetal hypoxia often lead to neonatal death or cerebral palsy. Thus, infants exposed to moderate and severe fetal hypoxia are at risk for physical and mental impairment, as well as worsened school performance even in the absence of a genetic vulnerability for schizophrenia.