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Alan S. Brown, MD; Melissa D. Begg, ScD; Stefan Gravenstein, MD; Catherine A. Schaefer, PhD; Richard J. Wyatt, MD; Michaeline Bresnahan, PhD; Vicki P. Babulas, MPH; Ezra S. Susser, MD, DrPH

Arch Gen Psychiatry. 2004;61:774-780.

Context  Some, but not all, previous studies suggest that prenatal influenza exposure increases the risk of schizophrenia. These studies used dates of influenza epidemics and maternal recall of infection to define influenza exposure, suggesting that discrepant findings may have resulted from exposure misclassification.

Objective  To examine whether serologically documented prenatal exposure to influenza increases the risk of schizophrenia.

Design  Nested case-control study of a large birth cohort, born from 1959 through 1966, and followed up for psychiatric disorders 30 to 38 years later.

Setting  Population-based birth cohort.

Participants  Cases were 64 birth cohort members diagnosed as having schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls were 125 members of the birth cohort, had not been diagnosed as having a schizophrenia spectrum or major affective disorder, and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum.

Main Outcome Measures  Archived maternal serum was assayed for influenza antibody in pregnancies giving rise to offspring with schizophrenia and matched control offspring.

Results  The risk of schizophrenia was increased 7-fold for influenza exposure during the first trimester. There was no increased risk of schizophrenia with influenza during the second or third trimester. With the use of a broader gestational period of influenza exposure—early to midpregnancy—the risk of schizophrenia was increased 3-fold. The findings persisted after adjustment for potential confounders.

Conclusions  These findings represent the first serologic evidence that prenatal influenza plays a role in schizophrenia. If confirmed, the results may have implications for the prevention of schizophrenia and for unraveling pathogenic mechanisms of the disorder.

From the College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York (Drs Brown and Susser and Ms Babulas); Departments of Biostatistics (Dr Begg) and Epidemiology (Drs Bresnahan and Susser), Mailman School of Public Health of Columbia University, New York; Department of Internal Medicine, Eastern Virginia Medical School, Norfolk (Dr Gravenstein); Division of Research, Kaiser Permanente, Oakland, Calif (Dr Schaefer); and National Institute of Mental Health, Bethesda, Md (Dr Wyatt).
Dr Wyatt is deceased.

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