Psychological Medicine

Review Article

Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies

G. M. Khandakera1a2 c1, J. Zimbrona1a2, G. Lewisa3 and P. B. Jonesa1a2

a1 Department of Psychiatry, University of Cambridge, UK

a2 Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK

a3 Academic Unit of Psychiatry, University of Bristol, UK

Abstract

Background Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies.

Method Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review.

Results Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia.

Conclusions Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a ‘sensitive period’ during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.

(Received December 07 2011)

(Revised March 09 2012)

(Accepted March 12 2012)

(Online publication April 16 2012)

Key words

  • Cytokines;
  • infection;
  • neurodevelopment;
  • pregnancy;
  • schizophrenia

Correspondence:

c1 Address for correspondence: Dr G. M. Khandaker, Department of Psychiatry, University of Cambridge, Box 189, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. (Email: gmk24@medschl.cam.ac.uk)

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