Infection early in life and risk of non-affective psychosis

In light of the increasing, but insufficient, evidence that various infections and immunological processes during brain development are associated with psychotic disorder, the aim of this thesis was to investigate infection during foetal life and childhood on the risk of developing non-affective psychosis later in life. We conducted two population-based birth cohort studies using linkages to several nationwide registers as well as two studies on a subset of cases and controls in which biological samples were examined.

In Study I, the association between specific chronic maternal infections during pregnancy and non-affective psychoses in the offspring was assessed. For that purpose we analysed levels of antibodies in neonatal dried blood samples (NDBS) directed at four neurotropic agents; Toxoplasma gondii (T. gondii), cytomegalovirus (CMV) as well as herpes simplex virus type 1 and 2. Maternal T. gondii and CMV infections were found to be associated with schizophrenia.

In Study II, chronic maternal infection during pregnancy, neonatal immune markers, and subsequent non-affective psychosis were investigated. NDBS were analysed to determine levels of antibodies directed at T. gondii and three herpes viruses as well as levels of acute phase proteins (APPs; immune markers). Maternal infection with T. gondii and CMV was associated with a change in APPs among controls but not among individuals who later develop non-affective psychosis. Furthermore, interaction between maternal infection and low levels of APP in the development of psychotic disorder was indicated.

In Study III, the association between hospital admission for infection during childhood (0-13 years of age) and the risk of developing non-affective psychosis was examined. Additionally, possible vulnerable ages, and type of infection (virus and bacteria as well as infection of the central nervous system (CNS)) were scrutinized. Any infection during childhood was modestly associated with non-affective psychosis later in life. The strongest estimates were found for bacterial infection and infection of the CNS during pre-adolescence (10-13 years of age).

In Study IV, the association between maternal infection during pregnancy and non-affective psychosis was investigated. We found no evidence of such association. However, maternal infection during pregnancy and maternal psychiatric disorder interacted in the development of psychosis among offspring. Additionally, associations between maternal infection during pregnancy and offspring childhood infection were investigated. Maternal infection increased the relative risk of offspring childhood infection, two factors that interacted in the development of non-affective psychosis.

In conclusion, there were no strong associations between infection during foetal life or childhood and non-affective psychosis overall. However, neonates with mothers exposed to T. gondii and CMV infection had substantial increased relative risks of developing psychosis, especially in conjunction with an altered immune response. The interactions between infection during foetal life and genetic vulnerability, neonatal immune alterations as well as with childhood infections in the development of non-affective psychosis indicate that maternal infection during pregnancy does play an important role in the aetiology.

List of scientific papers

I. Blomström Å, Karlsson H, Wicks S, Yang, S, Yolken, RH, Dalman C. Maternal antibodies to infectious agents and risk for non-affective psychoses in the offspring-a matched case-control study. Schizophr Res. 2012 Sep;140(1-3):25-30.
https://doi.org/10.1016/j.schres.2012.06.035

II. Blomström Å, Gardner RM, Dalman C, Yolken RH, Karlsson H. Influence of maternal infections on neonatal acute phase proteins and their interaction in the development of non-affective psychosis. Transl Psychiatry. 2015 Feb 3;5:e502.
https://doi.org/10.1038/tp.2014.142

III. Blomström Å, Karlsson H, Svensson A, Frisell T, Lee BK, Dal H, Magnusson C, Dalman C. Hospital admission with infection during childhood and risk for psychotic illness--a population-based cohort study. Schizophr Bull. 2014 Nov;40(6):1518-25.
https://doi.org/10.1093/schbul/sbt195

IV. Blomström Å, Karlsson H, Gardner RM, Jörgensen L, Magnusson C, Dalman C. Associations between maternal infection during pregnancy, childhood infection and the risk of subsequent psychotic disorder – a Swedish cohort of nearly 2 million individuals. [Manuscript]