Can Parasite in Mothers Lead To Schizophrenia?

If the long and still-unfinished search for the origins of schizophrenia is like building a house, then Alan S. Brown, M.D., and his colleagues from the Prenatal Determinants of Schizophrenia Study are among the bricklayers. With other researchers around the world, they are amassing evidence bit by bit to pin down the causes of the disease.

Brown, an associate professor of clinical psychiatry and clinical epidemiology at the New York State Psychiatric Institute and the Mailman School of Public Health at the College of Physicians and Surgeons of Columbia University, and his coauthors have published the latest in a series of reports on the relation of the presence of toxoplasmosis antibodies during pregnancy to the prevalence of schizophrenia in the offspring.

Brown has also studied the connection between elevated maternal cytokine interleukin-8 and increased risk of schizophrenia in the offspring and also how serologically documented maternal influenza and rubella relate to schizophrenia. Other research has sought to connect schizophrenia with exposure in the womb to diseases like herpes simplex, polio, or varicella-zoster or to environmental agents like lead.

Toxoplasma gondii is a protozoan parasite that can be passed to humans who eat infected, undercooked meat or through exposure to cat litter or soil containing oocysts of the organism. Infected pregnant women can pass the parasite to their fetus.

Primary Infection Not Likely

The current report in the April American Journal of Psychiatry is based on data gathered four decades ago. The Prenatal Determinants of Schizophrenia Study draws on the Child Health and Development Study cohort initiated by Jacob Yerushalmy at the University of California at Berkeley in 1959, in collaboration with Kaiser Permanente Medical Care Plan in Northern California.

The Child Health and Development study included almost all pregnant women in the Kaiser Foundation Health Plan from 1959 to 1967. Researchers back then took serum samples from these women and froze them for later study. Of the 19,044 children born to these women, 12,094 were available for follow-up between 1981 and 1997. Within that group, there were 183 who screened positive for schizophrenia spectrum disorders, of whom 146 were available for follow-up.

The Prenatal Determinants of Schizophrenia researchers tested the serum for Toxoplasma gondii using immunoassays for immunoglobulin G antibody (IgG), which can persist for years in the bloodstream and is associated with“ both severe and subtle neuropsychiatric abnormalities.” Serum immunoglobulin M antibody (IgM) indicates only recent infection, but was not found in the mothers of the offspring with schizophrenia.

They divided IgG titers into three groups, negative (<1:16), moderate (1:16 to 1:64), and high (1:128 to 1:1024). They found an association between high maternal antibody titers and schizophrenia or schizophrenia spectrum disorders among the children (odds ratio 2.61, p=0.051). Although the results fell slightly short of significance, prenatal exposure to toxoplasmosis is a plausible risk factor for schizophrenia, they said. No association was found with lower antibody levels.

The research adds to evidence connecting prenatal toxoplasmosis infection and congenital brain abnormalities, as seen on postmortem and neuroimaging studies. Primary infection was unlikely to be a cause of schizophrenia in the Kaiser cohort because samples were negative for IgM, said Brown. The high IgG antibody levels could be an immune response to an old infection or a re-emergence of the infection from dormant cysts in the body.

Hypotheses other than simple infection have been proposed to connect toxoplasmosis and problems with fetal brain development. One suggests that a known toxin produced by the parasite causes congenital abnormalities in laboratory animals. Alternatively, given the persistence of IgG antibodies, toxoplasma IgG antibody, rather than the organism or a toxin, may cross the placenta and damage the developing fetal brain.

Methodology Advances

Brown said that research has moved from simply noting maternal exposure to an epidemic to collecting and analyzing serum samples of cytokines and antibodies.

“Our methodology is improving,” said Brown in an interview.“ Of course, it's essential to replicate these findings, but at least it points to a role for prenatal infections as risk factors for adult schizophrenia.”

Research elsewhere may be adding more bricks to the wall. A Danish team recently reported that elevated toxoplasma IgG antibody in newborns was associated with an increased risk of adult schizophrenia in those individuals.

Brown and his colleagues are now doing brain-imaging studies in the schizophrenic offspring of mothers with high toxoplasmosis antibodies, comparing those with risk factors for developing schizophrenia with unaffected matched controls. He also hopes to collect DNA samples from cohort members. Other researchers are working on other large datasets, like the National Collaborative Prenatal Project, covering women pregnant in 1959 to 1966.

Work is also continuing on animal models, said Brown. Animals do not develop schizophrenia, but analogues may be available. Humans with schizophrenia have deficits in their prepulse inhibition to a second startle response, for instance. Mice whose mothers were exposed to influenza virus while pregnant exhibit similar prepulse inhibition deficits, according to California Institute of Technology biology professor Paul H. Patterson, Ph.D.:“ Maternal viral infection has a profound effect on the behavior of adult offspring, probably via an effect of the maternal immune response on the fetus.”

The current study adds some weight to a role for prenatal infection or environmental exposure, but the full story will likely be complicated by interaction with inherited influences, too.

“The effect sizes we're observing are comparable to, and in some cases stronger than, at least some of the effects of individual genes, although the largest single risk factor for schizophrenia remains a family history of the illness,” said Brown.

A call for more definitive research may be the right conclusion now, said Brown, but it doesn't rule out action to minimize risk. Inexpensive measures to prevent infections known to disrupt fetal development of the central nervous system are already available and can be implemented now.

The Centers for Disease Control and Prevention recommends that pregnant women take steps to avoid toxoplasmosis by cooking meat thoroughly, washing or peeling fruits and vegetables, wearing gloves while gardening, and avoiding changing cat litter, if possible.

This research is funded by grants from the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, the Lieber Center for Schizophrenia Research, and the National Institute for Child Health and Development.

“Maternal Exposure to Toxoplasmosis and Risk of Schizophrenia in Adult Offspring” is posted at<http://ajp.psychiatryonline.org/cgi/content/full/162/4/767>. The CDC report, “Preventing Congenital Toxoplasmosis,” is posted at<www.cdc.gov/mmwr/preview/mmwrhtml/rr4902a5.htm>.▪

Am J Psychiatry 2005 162 767