Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies.
BACKGROUND
Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies.


METHODS
Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review.


RESULTS
Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia.


CONCLUSIONS
Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a 'sensitive period' during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.
Department of Psychiatry, University of Cambridge, UK. gmk24@medschl.cam.ac.uk
G M
GM
Khandaker
J
J
Zimbron
G
G
Lewis
P B
PB
Jones
D000328:Adult; D000818:Animals; D015551:Autoimmunity; D001921:Brain / Q000002:abnormalities* / Q000503:physiopathology; D015986:Confounding Factors, Epidemiologic; D016207:Cytokines / Q000378:metabolism; D016206:Databases, Bibliographic; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000453:epidemiology* / Q000276:immunology; D011264:Pregnancy Trimesters; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology* / Q000209:etiology / Q000276:immunology
D016207:Cytokines