Abnormal fetal growth and development

Low birth weight has been associated with schizophrenia throughout each era of investigation, but this association is not invariably found, and there was significant heterogeneity in the estimate for low birth weight (<2500 g) in this meta-analysis. The concept of a "population shift" in birth weight may account for this heterogeneity, and investigators using an arbitrary cutoff for low birth weight (i.e., <2500 g) will find inconsistent associations depending on the power of the study. Using a quantitative approach, Wahlbeck et al. found that the risk of schizophrenia decreases in a linear fashion with increasing birth weight, increasing length at birth, and increasing placental weight. Low birth weight is usually due to prematurity or intrauterine growth retardation.

The lack of a significant association between risk of schizophrenia and prematurity in our meta-analysis indicates that the low birth weight is most likely due to intrauterine growth retardation (although there was no association between risk of schizophrenia and being small for gestational age). However, almost any factor adversely affecting the fetus will retard its growth, so these findings do not appreciably narrow our search. Low birth weight may be a proxy variable for some other adverse influence or influences on the developing fetus, whether of genetic or environmental origin. Women with schizophrenia or who later develop schizophrenia have been shown to be at increased risk of behaviors during pregnancy - such as smoking, taking medication, or poor attendance at antenatal clinics - that are associated with low birth weight outcomes.

The increased prevalence of congenital malformations found in this meta-analysis echoes the extensive literature on minor physical abnormalities and schizophrenia and further implicates pregnancy as a time when potential etiological factors may be operating.

Complications of delivery

The common mechanism for the delivery complications of asphyxia, uterine atony, and emergency Cesarean section found in our meta-analysis appears to be fetal hypoxia or anoxia. This is by no means a new idea, as anoxia has been mentioned since the earliest days of this literature. Geddes and colleagues concluded that the underlying mechanism for all the complications associated with schizophrenia in their meta-analysis was likely to involve fetal hypoxia but that a "more specific measure of exposure to hypoxia" was required. The pooled estimate for asphyxia in our meta-analysis demonstrated significant heterogeneity, possibly due to the different definitions of asphyxia used.

Three population-based studies that could not be included in the meta-analysis but that fulfilled three of the four inclusion criteria provide additional support for the involvement of fetal hypoxia or asphyxia in the etiology of schizophrenia . Individuals from the National Collaborative Perinatal Project with three or more hypoxia-related obstetric complications were more than five times more likely to develop schizophrenia than individuals with no hypoxia-related obstetric complications, and this finding was particularly marked among patients with early-onset schizophrenia. Siblings of schizophrenic subjects were no more likely to experience these complications than were comparison subjects.