These methodological shortcomings were the prime motivator for our group and others to initiate birth cohort studies aimed at refining the methodology for testing the infection-schizophrenia hypothesis.2
The study of subjects who were born during a particular period and geographic region, in whom exposure to infection during pregnancy could be acquired, yielded a number of methodological advantages, including prospectively documented maternal infection in individual pregnancies, longitudinal follow-up, accurate assessment of the timing of infection during pregnancy, and control of potential confounding factors. The use of archived biological specimens from the mother or infant has allowed investigators to further capitalize on these birth cohorts because they permit the measurement of biomarkers of infection during pregnancy.
These studies have yielded a series of intriguing associations (reviewed in Brown and Derkits2
) and are briefly summarized here. Our group demonstrated that prenatal exposure to rubella was related to a greater than 5-fold increased risk of nonaffective psychosis during young adulthood12
and in midadulthood over 20% of subjects who were exposed in utero to rubella were diagnosed with schizophrenia or a schizophrenia spectrum disorder.13
Influenza exposure documented by quantification of maternal antibody titers during pregnancy was associated with a 3-fold increased risk of schizophrenia for exposure in mid to late gestation and a 7-fold elevation in risk of the disorder following first trimester exposure.14
Elevated maternal IgG antibodies to Toxoplasma gondii
, an intracellular parasite and a well-known infectious cause of central nervous system (CNS) congenital anomalies,1,15
was related to greater than 2-fold increased risk of schizophrenia,16
a finding which was essentially replicated in a Danish sample that capitalized on filter paper blood spots taken from the infant within the first week of birth.17
In 3 studies, elevated maternal IgG antibody to (HSV-2) was related to an increased risk of psychotic disorders, including schizophrenia,18,19,20
while the finding was not replicated in a different birth cohort.21
Maternal genital/reproductive infections, broadly defined, were, however, associated with a 5-fold increased risk of schizophrenia when the exposure occurred during the periconceptional period.22
Exposure to maternal respiratory infection was related to a 2-fold elevated schizophrenia risk,23
as well as bacterial infections broadly defined.24
In summary, birth cohort studies have provided several key methodological advantages that have allowed for more rigorous testing of relationships between maternal infection and schizophrenia. Birth cohort studies conducted to date have provided further support for the hypothesis that maternal viral, protozoal, and bacterial infections increase the risk for schizophrenia in adult offspring.