Psychological Medicine

Original Articles

Prenatal maternal immune disruption and sex-dependent risk for psychoses

J. M Goldsteina1a2a3 c1, S. Cherkerziana1a2, L. J. Seidmana3a4, J.-A. L. Donatellia5, A. G. Remingtona1, M. T. Tsuanga6a7a8, M. Horniga9a10 and S. L. Bukaa5

a1 Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA

a2 Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA, USA

a3 Division of Psychiatric Neuroscience, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

a4 Harvard Medical School, Department of Psychiatry, Massachusetts Mental Health Center; Division of Public Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA

a5 Department of Epidemiology, Brown University, Providence, RI, USA

a6 Beth Israel Deaconess Hospital, Department of Psychiatry, Division of Public Psychiatry, Massachusetts Mental Health Center and Harvard Medical School, Boston, MA, USA

a7 Center for Behavioral Genomics, Department of Psychiatry; Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA

a8 Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard School of Public Heath, Boston, MA, USA

a9 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

a10 Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA


Background. Previous studies suggest that abnormalities in maternal immune activity during pregnancy alter the offspring's brain development and are associated with increased risk for schizophrenia (SCZ) dependent on sex.

Method. Using a nested case–control design and prospectively collected prenatal maternal sera from which interleukin (IL)-1β, IL-8, IL-6, tumor necrosis factor (TNF)-α and IL-10 were assayed, we investigated sex-dependent associations between these cytokines and 88 psychotic cases [SCZ = 44; affective psychoses (AP) = 44] and 100 healthy controls from a pregnancy cohort followed for > 40 years. Analyses included sex-stratified non-parametric tests adjusted for multiple comparisons to screen cytokines associated with SCZ risk, followed by deviant subgroup analyses using generalized estimating equation (GEE) models.

Results. There were higher prenatal IL-6 levels among male SCZ than male controls, and lower TNF-α levels among female SCZ than female controls. The results were supported by deviant subgroup analyses with significantly more SCZ males with high IL-6 levels (>highest quartile) compared with controls [odd ratio (OR)75 = 3.33, 95% confidence interval (CI) 1.13–9.82], and greater prevalence of low TNF-α levels (<lowest quartile) among SCZ females compared with their controls (OR25 = 6.30, 95% CI 1.20–33.04) and SCZ males. Higher levels of IL-6 were only found among SCZ compared with AP cases. Lower TNF-α levels (non-significant) also characterized female AP cases versus controls, although the prevalence of the lowest levels was higher in SCZ than AP females (70% v. 40%), with no effect in SCZ or AP males.

Conclusions. The results underscore the importance of immunologic processes affecting fetal brain development and differential risk for psychoses depending on psychosis subtype and offspring sex.

(Received November 09 2012)

(Revised February 11 2014)

(Accepted February 15 2014)

(Online publication March 26 2014)

Key words

  • Fetal programming;
  • inflammation;
  • psychoses;
  • schizophrenia;
  • sex differences


c1 Address for correspondence: Dr J. M. Goldstein, Brigham and Women's Hospital, One Brigham Circle, Division of Women's Health, 1620 Tremont Street, 3rd Floor, Boston, MA 02120, USA. (Email: