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Articles   |    
Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort
Sarah Canetta, Ph.D.; Andre Sourander, M.D.; Heljä-Marja Surcel, Ph.D.; Susanna Hinkka-Yli-Salomäki, Ph.Lic.; Jaana Leiviskä, Ph.D.; Christoph Kellendonk, Ph.D.; Ian W. McKeague, Ph.D.; Alan S. Brown, M.D., M.P.H.
Am J Psychiatry 2014;171:960-968. doi:10.1176/appi.ajp.2014.13121579
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Dr. Kellendonk has received research support from Forest. All other authors report no financial relationships with commercial interests.

Supported by grants R01 MH-082052-05 and K02 MH-065422-09 (to Dr. Brown) from NIMH and the State Research Institute and grant T32 MH-16434-31 (to Dr. Canetta) from NIMH and the Sackler Institute Fellowship.

From the Departments of Psychiatry and Pharmacology, Columbia University Medical Center, New York State Psychiatric Institute, New York; the Department of Child Psychiatry, Faculty of Medicine, University of Turku, Turku, Finland; the Department of Child Psychiatry, Turku University Hospital, Turku, Finland; the National Institute for Health and Welfare, Oulu, Finland; the Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; and the Departments of Biostatistics and Epidemiology, Columbia University Mailman School of Public Health, New York.

Address correspondence to Dr. Brown (asb11@columbia.edu).

Copyright © 2014 by the American Psychiatric Association

Received December 3, 2013; Revised March 28, 2014; Accepted April 11, 2014.

Abstract

Objective  The objective of the present study was to investigate an association between early gestational C-reactive protein, an established inflammatory biomarker, prospectively assayed in maternal sera, and schizophrenia in a large, national birth cohort with an extensive serum biobank.

Method  A nested case-control design from the Finnish Prenatal Study of Schizophrenia cohort was utilized. A total of 777 schizophrenia cases (schizophrenia, N=630; schizoaffective disorder, N=147) with maternal sera available for C-reactive protein testing were identified and matched to 777 control subjects in the analysis. Maternal C-reactive protein levels were assessed using a latex immunoassay from archived maternal serum specimens.

Results  Increasing maternal C-reactive protein levels, classified as a continuous variable, were significantly associated with schizophrenia in offspring (adjusted odds ratio=1.31, 95% confidence interval=1.10–1.56). This finding remained significant after adjusting for potential confounders, including maternal and parental history of psychiatric disorders, twin/singleton birth, urbanicity, province of birth, and maternal socioeconomic status.

Conclusions  This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implications for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders.

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FIGURE 1. Distribution of Maternal C-Reactive Protein Levels in Case and Control Subjectsa

a The graph shows the frequency of case and control subjects with maternal C-reactive protein values (mg/L) in the given intervals.

FIGURE 2. Median Maternal C-Reactive Protein Levels in Case and Control Subjects by Gestational Week of the Blood Drawa

a The graph shows the median maternal C-reactive protein value (mg/L) for case and control subjects with maternal serum obtained in the indicated range of gestational weeks.

Anchor for Jump
TABLE 1.Relationship Between Covariates and Maternal C-Reactive Protein Levels (≥/< Median) in Control Subjects
Table Footer Note

a Data are missing for 105 control subjects (≥median, N=46; <median, N=59).

Table Footer Note

b Data are missing for four control subjects (≥median, N=2; <median, N=2).

Table Footer Note

c Diagnoses were defined in accordance with the following ICD codes: ICD 10: F20–25, F28–29; ICD 9: 295, 297, 298.9X, 301.2C; ICD 8: 295, 297, 298.20, 298.30, 298.99, 299.

Table Footer Note

d Diagnoses were defined in accordance with the following ICD codes: ICD 10: F30–34, F38–39; ICD 9: 296, 300.4, 298.8A; ICD 8: 296, 298.00, 298.10, 300.41.

Table Footer Note

e Diagnoses were defined in accordance with the following ICD codes, in addition to the codes used in c and d: ICD 10: F84, F40–45, F48, F50–53, F55, F59–66, F68–69, F99, F10–19; ICD 9: 299, 300–300.3, 300.5–301.1, 301.2 excluding 301.2C, 301.3–301.9, 302, 307.1A, 307.4A, 307.4F, 307.4H, 307.5A, B, C and E, 307.8A, 307.9X, 309–309.1, 309.2 excluding A and B, 309.2D, E and F, 309.3–309.9 excluding 309.3A and 309.4A, 312.0A, 312.1–312.2, 312.3 excluding 312.3D, 312.4–312.9, 291–292, 303–305; ICD 8: 308, 300.0–300.3, 300.4, 300.5–302.9, 305, 306.40, 306.50, 306.98, 307.99, 291, 303–304.

Anchor for Jump
TABLE 2.Relationship Between Covariates and Schizophrenia in Case and Control Subjects
Table Footer Note

a Data are missing for 212 subjects (case subjects, N=107; control subjects, N=105).

Table Footer Note

b The odds ratio is 1 by definition because the groups are matched on sex.

Table Footer Note

c Data are missing for 10 subjects (case subjects, N=4; control subjects, N=6).

Table Footer Note

d Data are missing for eight subjects (case subjects, N=4; control subjects, N=4).

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1.
What type of epidemiologic study design was used in this investigation?
2.
For every 1 mg/L increase in C-reactive protein level, the risk of schizophrenia was increased by what percentage?
3.
In a previous study from the same Finnish national birth cohort as in the present study, elevated C-reactive protein levels were associated with which psychiatric disorder:
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