Serologic Evidence of Prenatal Influenza in the Etiology of Schizophrenia

Although numerous studies have reported an increased risk of schizophrenia in persons exposed to influenza, some rigorously designed efforts have shown no evidence of such an association. Imprecise measurements of exposure, based on dates of epidemics and maternal recall of infection, may be at least partly responsible. The present investigators conducted a nested case–control study of a cohort of 12,094 infants born in the years 1959–1966 whose members were followed up for psychiatric disorder after 30 to 38 years. This study appears to be the first to use maternal influenza antibody levels to document exposure. Cases included 64 members of the birth cohort who were diagnosed as having schizophrenia spectrum disorders (SSD), chiefly schizophrenia and schizoaffective disorder. The control group included 125 individuals matched with the cases for date of birth, sex, length of time in the cohort, and availability of maternal serum. Among participants tested in the first trimester of pregnancy, 25% of SSD cases and 11% of controls had been exposed to influenza. In the second and third trimesters, the findings in the SSD and control groups were very similar. Analyses controlling for matched-set membership showed that first-trimester exposure was associated with a 7-fold increase in the risk of SSD, not a statistically significant result. No substantial increase in risk was found for the second and third trimesters. The findings were essentially the same with conditional logistic regression analysis that adjusted for maternal and paternal ages, maternal education, and maternal ethnicity. The population-attributable risk associated with influenza was 21% for the first trimester and 14% for the first half of pregnancy. This study, using serologic methods, showed that exposure to influenza during early to midpregnancy may play a part in the development of schizophrenia. The possibility of routinely vaccinating nonpregnant women may be worth considering.