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Evidence Mounts for the Maternal Inflammation Hypothesis of Schizophrenia

July 15, 2014. New data from a Finnish birth cohort link higher serum levels of the maternal inflammatory marker C-reactive protein during pregnancy to an elevated risk of schizophrenia in offspring. The study, led by Alan Brown of Columbia University in New York City and published online June 27 in the American Journal of Psychiatry, provides a big boost to the maternal immune activation/inflammation hypothesis of schizophrenia.

The idea that maternal infection during pregnancy plays a role in the baby's risk of later developing schizophrenia originated from studies reporting an association between epidemics of infections such as influenza and increased incidence of the illness in offspring born shortly after (see SRF related conference report; SRF conference report). More recently, birth cohort studies utilizing serological samples collected during pregnancy have demonstrated that maternal infection with a number of pathogens, including influenza, Toxoplasma gondii, and rubella, is associated with schizophrenia (see SRF related news report; SRF news report).

The diversity of associated pathogens suggests that maternal inflammation, more generally, may be the culprit behind this association, a hypothesis backed by both preclinical studies and findings of increased proinflammatory cytokines in mothers whose children later developed schizophrenia (Brown and Derkits, 2010). In addition, autoimmune diseases characterized by chronic inflammation have also been associated with risk for the illness (see SRF related news report).

Inflammation measurement
In the current study, first author Sarah Canetta and colleagues investigated the link between general inflammation during pregnancy and the offspring's risk of schizophrenia by measuring levels of the inflammatory marker C-reactive protein, which helps mark dead cells and select pathogens for degradation.

The authors used subjects from the Finnish Prenatal Studies, a birth cohort of all individuals born in Finland from 1983 to 1998. Within the larger study, the Finnish Prenatal Study of Schizophrenia includes 1,514 cases of schizophrenia and schizoaffective disorder identified from the country’s hospital discharge and outpatient registry. Of these, 777 had enough maternal sera for the C-reactive protein assay. Each case was matched to a control subject based on sex and residence in Finland.

The researchers found a significant association between increasing levels of maternal C-reactive protein, measured using an immunoassay, and a subsequent diagnosis of schizophrenia (odds ratio = 1.12). An examination of the data revealed that this effect was not due to outliers, as more cases than controls were present in the highest 50 percent of protein values, while the opposite was true in the lowest 50 percent.

To further investigate the relationship between maternal C-reactive protein levels and schizophrenia, the authors analyzed a number of known health and demographic variables obtained from the Finnish Population Registry. Several variables (such as increased maternal age, increased number of earlier births, and rural birth) were significantly associated with elevated levels of C-reactive protein. Others (including urbanicity, province of birth, and singleton births) were significantly associated with schizophrenia, though none were associated with both maternal C-reactive protein and schizophrenia. When the variables were included as co-variates in a second statistical model that adjusted for their effects, the strength of the association between maternal C-reactive protein level and schizophrenia increased (odds ratio = 1.28).

Inflammation mechanism
Canetta and colleagues suggest a few different possibilities for the mechanism underlying the link between maternal inflammation and schizophrenia. Elevated C-reactive protein may reflect increased levels of the inflammatory cytokine interleukin 6 (which leads to the production of C-reactive protein), which animal studies have shown is responsible for producing schizophrenia-associated behaviors such as abnormal sensorimotor gating in adult offspring (Smith et al., 2007). Unfortunately, interleukin 6 levels could not be measured in the current study due to an insufficient amount of maternal sera.

However, the authors also noted that the elevated maternal C-reactive protein levels may not be specific to schizophrenia, and hypothesized that after maternal immune activation “primes” the developing brain for later emergence of psychiatric disorders, “interaction with specific genetic or environmental insults … might then determine the specificity of the later disorder.” In support of this idea, the researchers have recently reported similar elevations in maternal C-reactive protein in members of the Finnish Birth Studies who went on to develop autism (Brown et al., 2014). Canetta and colleagues also noted that, although they have not yet examined the relationship between C-reactive protein and bipolar disorder or depression, the literature suggests that maternal infection and inflammation may play a role in these disorders as well.

Although it is possible that elevated C-reactive protein is not a causative factor in the illness, “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,” conclude the authors.—Allison A. Curley.

Reference:
Canetta S, Sourander A, Surcel HM, Hinkka-Yli-Salomäki S, Leiviskä J, Kellendonk C, McKeague IW, Brown AS. Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort. Am J Psychiatry. 2014 Jun 27. Abstract

 
Comments on News and Primary Papers
Comment by:  Stephen Marder, SRF Advisor
Submitted 10 July 2014 Posted 11 July 2014

Accumulating evidence indicates that activation of the maternal immune system—from infectious and non-infectious sources—increases the risk of schizophrenia. This interesting study using data from the Finnish Prenatal Study of Schizophrenia measured C-reactive protein, a general marker of inflammation, in maternal serum from 777 schizophrenia subjects and an equal number of controls. The importance of this study derives from the size of the sample and the strength of the relationship between immune activation and schizophrenia risk.

View all comments by Stephen Marder


Comment by:  Chris Carter
Submitted 16 July 2014 Posted 16 July 2014
  I recommend the Primary Papers

If the development of schizophrenia depends upon maternal infection, perhaps a large number of susceptibility genes (possibly related to infection susceptibility and the immune system) would be concentrated in maternal alleles, with other maternal/paternal genes contributing later in life, and in different ways, for the offspring.

Have there been , or are there programmed, any genome-wide association studies on non-schizophrenic mothers of schizophrenic patients? A comparison of maternal/paternal genetic donation might perhaps be a useful means of dissecting out the various pathways leading to disease.

View all comments by Chris Carter

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