A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring

Background: Several studies have implicated early infections, including maternal infection with herpes simplex virus 2 (HSV-2), as an environmental risk factor for schizophrenia. Methods: A case-control study nested within the national Danish birth cohort constituted by the PKU Biobank covering all children born in Denmark since 1981. 602 cases of schizophrenia (ICD-10 F20) were ascertained in the Danish Psychiatric Central Register, covering all in- and out-patient contacts in Denmark, and 602 controls were matched individually on gender, exact date of birth and living in Denmark on the date the case became a case.Incidence rate ratio for schizophrenia was estimated using conditional logistic regression. Main exposure was HSV-2 IgG antibody levels. Confounders and potential interacting factors included family history of mental illness, place of birth and gestational age at time of birth. Results: Elevated levels of maternal HSV-2 IgG were associated with schizophrenia risk (IRR 1.56; 95% CI 1.17-2.07, p = 0.002). This association was not confounded by a maternal or sibling history of psychiatric illness, place of birth, parental age, gestational age, or immigrant status of the parents. However, adjustment for paternal psychiatric history reduced risk slightly (IRR 1.43; 95% CI 1.06-1.92, p = 0.02). Conclusions: The study replicates an association between maternal HSV-2 IgG levels and schizophrenia risk. Since the confounding by familial risk factors is confined to paternal mental illnesses not belonging to the schizophrenia spectrum, we hypothesize that this confounding may be partly due to other risk factors, e.g., other sexually transmitted infections, rather than reflecting variations in genetic liability to develop schizophrenia.