Prenatal inflammation is an established risk factor for schizophrenia. However, the specific inflammatory pathways that mediate this association remain unclear. Potential candidate systems include inflammatory markers produced by microglia, such as cytokines and complement. Accumulating evidence suggests that these markers play a role in typical neurodevelopmental processes, such as synapse formation and interneuron migration. Rodent models demonstrate that altered marker levels during the prenatal period can cause lasting deficits in these systems, leading to cognitive deficits that resemble schizophrenia. This review assesses the potential role of prenatal cytokine and complement elevations on the etiology of schizophrenia. The current neurobiological understanding of the development of schizophrenia is reviewed to identify candidate cellular mechanisms that may be influenced by prenatal inflammation. We discuss the functions that cytokines and complement may play in prenatal neurodevelopment, review evidence that links exposure to these factors with risk for schizophrenia, and consider how these markers may interact with genetic vulnerabilities to influence the neurodevelopment of schizophrenia. We consider how prenatal inflammatory exposure may influence childhood and adolescent developmental risk trajectories for schizophrenia. Finally, we identify areas of further research needed to support the development of anti-inflammatory treatments to prevent the development of schizophrenia in at-risk neonates.

Although animal models and correlational studies support a model of fetal programming as a mechanism in the transmission of risk for psychopathology from parents to children, the experimental studies that are required to empirically test the model with the human prenatal dyad are scarce. With a systematic review and meta-analysis of the literature, we critically examined the evidence regarding the neurobiological and behavioral changes in infants as a function of randomized clinical trials to prevent or reduce maternal depression during pregnancy, treating randomized clinical trials as experiments testing the fetal programming model. Based on 25 articles that met inclusion criteria, we found support for interventions designed to change maternal prenatal mood being associated with changes in offspring functioning, but with a very small effect size. Effect sizes ranged broadly, and were higher for younger children. The findings enhance understanding of putative mechanisms in the transmission of risk from women's prenatal depression to infants’ vulnerabilities to, and early signs of, the development of psychopathology. We note limitations of the literature and suggest solutions to advance understanding of how preventing or treating depression in pregnant women might disrupt the transmission of risk to the infants.