Joint Effects of Exposure to Prenatal Infection and Peripubertal Psychological Trauma in Schizophrenia

Context: Prenatal infection and traumatizing experiences have both been linked with schizophrenia, but none of these factors seem sufficient to cause the disorder. However, recent evidence suggests that these environmental insults act in synergy to increase schizophrenia risk.

Objective: To estimate the independent and joint effects of exposure to prenatal infection and peripubertal psychological trauma on the risk of schizophrenia.

Design: Danish nationwide registers were linked in this prospective cohort study. We used survival analysis to report incidence rate ratios (IRRs) and corresponding 95% confidence intervals (95% CIs). Analyses were adjusted for age and calendar period and stratified by sex.

Participants: A total of 979701 persons born between 1980 and 1998 were followed up from January 1, 1995 through December 31, 2013, with 9656 having a hospital contact for schizophrenia.

Results: Females exposed to prenatal infection had a significantly increased risk of schizophrenia (IRR: 1.61, 95% CI: 1.30-2.00), but not males (IRR: 0.99, 95% CI: 0.77-1.28). Peripubertal trauma was associated with increased risk in both sexes. Males, however, had a significantly higher risk of schizophrenia after exposure to both prenatal infection and peripubertal psychological trauma (IRR: 2.85, 95% CI: 2.32-3.51), with significant interaction between infection and peripubertal trauma on the multiplicative scale (P = .007).

Conclusions: Our study demonstrated for the first time that prenatal infection and psychological trauma in peripubertal life can act in synergy to increase the risk of schizophrenia, with a potentially stronger susceptibility in males.