Maternal infection during pregnancy and schizophrenia.

For the 2007–2008 season, the Canadian National Advisory Committee on Immunization has for the first time recommended that all pregnant women be vaccinated against influenza. In the United States, the Centers for Disease Control and Prevention have recommended influenza vaccination for pregnant women in the second and third trimester of pregnancy since 1997; in 2004, this recommendation was revised to include pregnant women in all trimesters (see Mak and colleagues for further discussion of current policies on influenza vaccination during pregnancy in other countries). Although the decision to vaccinate is based mainly on the increased risk in pregnant women for acute cardiopulmonary complications due to influenza, increased influenza vaccination during pregnancy could have implications for the development of schizophrenia. For a few decades now, maternal infection during pregnancy has been considered a plausible risk factor for schizophrenia. The story essentially began in Finland with the publication in 1988 of a paper by Mednick and colleagues reporting an increased risk for schizophrenia in people who were fetuses during the 1957 influenza epidemic. The story has continued up to the publication in December 2007 of a study coming again from Scandinavia, this time from Denmark. Using a much more sophisticated database (i.e., a national longitudinal registry of health records), this study again showed an increased risk for schizophrenia associated with maternal influenza during pregnancy. During the intervening 20 years, more than 25 epidemiologic studies have examined this issue, using various sources for information on the infection, ranging from simple correlation with known dates of epidemics to maternal recall, hospital records and national registry records on documented influenza occurrence. About one-half have replicated the finding, and about one-half have not. These failures to replicate could be due to inaccurate information on infection or other factors, or they may represent true findings of no association between maternal influenza and schizophrenia in some populations. Interestingly, increased rates of diagnosis for major affective disorder have also been reported following exposure to an influenza epidemic during the second trimester, indicating that effects may not be specific for schizophrenia. In addition to influenza, a wide variety of other maternal infections during pregnancy have been reported to be associated with increased risk for schizophrenia. These include maternal infections with other viruses (measles, rubella, varicella-zoster, polio) as well as maternal bronchopneumonia (which is largely bacterial), maternal infection with the parasite causing toxoplasmosis and infections of the maternal genital and reproductive systems. The rubella study is particularly striking in that up to 20% of subjects exposed to rubella (serologically confirmed) in the first trimester developed adult schizophrenia. Thus it appears that maternal infection with a wide variety of agents might potentially increase risk for schizophrenia, suggesting that factors common to many infections may be mechanistically responsible. More recently, some laboratories have attempted to confirm maternal infection more precisely by analyzing antibodies for viral infection in maternal serum that had been stored from 30 to 40 years until offspring had grown and developed schizophrenia. As can be appreciated, these are very challenging studies with limits in the sample size due to limited availability of stored serum, questions about storage and stability of samples, etc. Studies by Brown and colleagues found an association between schizophrenia spectrum disorders and maternal influenza during the first trimester of pregnancy that just missed statistical significance (p = 0.08) and during the first half of pregnancy that also barely missed significance (p = 0.052). Interestingly, while earlier epidemiologic studies had quite consistently implicated influenza in the second trimester of pregnancy, Brown and colleagues’ studies with archived maternal serum have implicated the first third to half of pregnancy. It has been pointed out that, if the association between maternal influenza and schizophrenia holds, then maternal influenza could account for an