Inflammation in Pregnancy Strongly Linked to Schizophrenia

Caroline Cassels

September 04, 2014

Elevated levels of C-reactive protein in pregnant women are strongly linked to an increased risk for schizophrenia in offspring, new research shows.

A nested case-control study showed that increasing maternal levels of C-reactive protein, a well-established and reliable marker of inflammation, were associated with a nearly 60% increased risk for schizophrenia in children. The finding remained significant after adjusting for a wide range of potential confounders, including parental history of mental illness.

"This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implication for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders," the authors, led by Sarah Cannetta, PhD, Columbia University and New York State Psychiatric Institute in New York City, write.

The study is published in the September issue of the American Journal of Psychiatry.

"Priming" the Brain

A growing body of epidemiologic and preclinical evidence suggests that infection and subsequent immune activation play a role in the etiology of schizophrenia, the researchers note.

"The most convincing epidemiologic studies were based on birth cohorts in which maternal biomarkers of infection and inflammation were assayed from prospectively archived maternal serologic specimens drawn during pregnancy. These studies revealed associations between offspring with schizophrenia and elevated maternal antibody to influenza, rubella, toxoplasma gondii, and herpes simplex virus type 2," the authors write.

To investigate whether maternal inflammation during pregnancy is linked to schizophrenia in offspring, the researchers examined C-reactive protein levels in prospectively collected and archived serum samples of pregnant women and validated offspring diagnoses from all schizophrenia cases in Finland via national registries.

They point out that "to our knowledge no previous study has examined maternal C-reactive protein in relation to schizophrenia in offspring...."

A total of 777 schizophrenia patients (schizophrenia, n = 630; schizoaffective disorder, n = 147) with maternal serum samples were identified and matched to 777 control persons.

Results revealed that 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) and that the risk remained significant after adjusting for potential confounders.

Overall, the median maternal C-reactive protein level for case patients was 2.47 mg/L. The median level for control individuals was 2.17 mg/L.

The investigators found that for every 1 mg/L increase in maternal C-reactive protein, the risk for schizophrenia was increased by 28%.

Although the precise mechanism is not known, the investigators speculate that "maternal inflammation during pregnancy may 'prime' the brain to broadly increase the risk for the later development of different types of psychiatric syndromes."

They note that their previous research in this same Finnish national birth cohort "demonstrated a significant increase in maternal C-reactive protein levels in pregnancies that gave rise to childhood autism."

Clinical Implications for Psychiatrists Too

In an accompanying editorial, Mary Cannon, MD, PhD, and colleagues from the Departments of Psychiatry and Psychology, Royal College of Surgeons in Dublin, Ireland, emphasize that the findings are clinically relevant for all clinicians managing pregnant women, including psychiatrists.

At first glance, they note, protecting women from infection and stress might seem to be "beyond the province of most psychiatrists. Indeed, infection during pregnancy is an increasing concern of obstetricians, since recent evidence indicates that pregnant women are particularly vulnerable to certain infections."

"Nevertheless," they add, "stress management, and treatment of depression and anxiety, does encompass the responsibilities of psychiatrists who work with pregnant women. Comprehensive psychiatric and psychological treatment for expectant mothers, as well as physical monitoring, would now seem indicated not only for the health of the mother but also to thereby decrease the longer-term risk for mental illness in her child."

The authors and editorialists report no relevant financial relationships.

Am J Psychiatry. 2014;171:960-968, 901-905. Abstract, Editorial

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