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Schizophrenia Risk Factor Found in Maternal Blood

An elevated prenatal blood level of homocysteine may double the risk of having a child who will develop schizophrenia. But rubella and flu infections during pregnancy seem to be even larger risks.

Some people mine for gold. Others dig for archeological remains. Yet Alan Brown, M.D., an associate professor of clinical psychiatry and clinical epidemiology at Columbia University, and his colleagues plumb prenatal blood for factors that contribute to schizophrenia.

During the past several years, for example, Brown and his coworkers have used frozen blood from pregnant women to find a link between schizophrenia and toxoplasmosis infections during pregnancy and between schizophrenia and influenza infections during pregnancy (Psychiatric News, May 6, 2005; May 21, 2004). And now they have used such archived blood to make a connection between schizophrenia and high levels of the amino acid homocysteine during pregnancy.

Their findings were published in the January Archives of General Psychiatry.

The study was based on blood that had been collected from some 12,000 women during pregnancy and on a follow-up evaluation of their offspring to see whether any of them developed schizophrenia. Brown and his group then selected 63 offspring who had been diagnosed for schizophrenia or another schizophrenia-spectrum disorder and matched them with 122 offspring who had not developed such illnesses. Cases and controls were matched on age, gender, maternal age, maternal race, and maternal smoking status.

The stored maternal blood samples from all 185 subjects were then analyzed for levels of homocysteine, which has been identified as a plausible risk factor for schizophrenia. For instance, a wealth of evidence has linked glutamate dysfunction with schizophrenia. Abnormalities in the glutamate NMDA receptor have been noted in schizophrenia, and homocysteine is known to influence that receptor. Moreover, high homocysteine levels have been associated with abnormal placental function and pregnancy complications.

Finally, Brown and his group compared the levels of homocysteine in the maternal blood samples taken from the schizophrenia subjects with the levels taken from the control subjects.

The levels of homocysteine in first-trimester maternal blood samples were higher for the schizophrenia cohort than for the control one, but the difference was not statistically significant. However, the levels of homocysteine in third-trimester maternal blood samples were twice as high for the schizophrenia cohort as for the control cohort—a significant difference. Thus, "elevated third-trimester homocysteine levels may be a risk factor for schizophrenia," Brown and his team concluded in their report. "Elevated third-trimester homocysteine levels may elevate schizophrenia risk through developmental effects on brain structure and function and/or through subtle damage to the placental vasculature that compromises oxygen delivery to the fetus."

Findings May Have Clinical Implications

The results also have some potential clinical implications, Brown and his group added. "If future studies both replicate this association and support a causal link, then the use of folic acid supplementation would merit evaluation as a strategy for prevention of schizophrenia in offspring."

Supplementation with folic acid would merit evaluation, they explained, because "this B vitamin donates a methyl group to homocysteine, permitting its transformation to methionine, and folate levels are inversely related to homocysteine levels. [Also] human pregnancy is a period of increased susceptibility to folate deficiency because of an increased maternal requirement, particularly in later gestation."

Psychiatric News asked Brown which of the prenatal factors that have been linked with schizophrenia most likely contributes to the illness. "That's a tough one [to answer]," he replied, "and it depends on what criteria you use."

For example, the only prenatal biomarker that has been independently replicated is an elevated level of IgG antibodies against the parasite that causes toxoplasmosis. Various studies have linked prenatal hypoxia or paternal age with schizophrenia, but there are no known biomarkers for these risks. Rubella infection during pregnancy has been associated with a 10- to 15-fold greater risk than normal of having a child with schizophrenia, but rubella exposure during pregnancy is not common, so it probably can't be blamed for the bulk of schizophrenia cases. In contrast, influenza infection during pregnancy is more common and has been tied to a 3- to 7-fold increased risk of having a child with schizophrenia.

"So I think it's premature to say that there is one leading prenatal factor," Brown said. "From a public health stand-point, it would be most important to try to replicate, using prenatal biomarkers, those exposures that are most common in the population, such as influenza, toxoplasmosis IgG, and folate/B12 deficiency [as evidenced by high homocysteine]."

Pregnant Women Can Lower Risk

Although it's too early to make public health recommendations about preventing schizophrenia, Brown continued, there are steps pregnant women can take to try to safeguard their unborn children from schizophrenia. "Eating a well-balanced diet and vitamin supplementation recommended by current obstetric guidelines is always a good idea. This will almost always normalize homocysteine, and folic acid supplementation is known to prevent against neural tube defects.

"Vaccination against influenza for women who are of reproductive age and sexually active makes sense. It isn't clear yet whether influenza vaccination during pregnancy could be helpful or harmful," Brown added. "One needs to weigh the benefit of protecting the woman and fetus from influenza against the potential risk of a vaccine-induced antibody elevation that could conceivably predispose to schizophrenia."

Brown added that "the usual recommendation for pregnant women regarding the avoidance of changing cat-litter boxes and hand washing after handling cats is also a good idea because it is known to protect the fetus from a variety of severe and subtle congenital anomalies. If our finding on toxoplasmosis is replicated further, these measures may also prevent against schizophrenia in their offspring."

The study was funded by the national institutes of Health and NARSAD.

An abstract of "Elevated Prenatal Homocysteine Levels as a Risk Factor for Schizophrenia" is posted at <http://archpsyc.ama-assn.org/cgi/content/abstract/64/1/31>.

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