22 May 2006. Chasing down environmental risk factors for schizophrenia has led researchers back to the womb, to the very beginning of brain development in fetal life. Epidemiological data point to a mother’s exposure to a range of pathogens as a risk factor for several neuropsychiatric illnesses in her grown children. In particular, research has linked maternal exposure to influenza virus, toxoplasmosis, and rubella to an increased incidence of schizophrenia in adults.
Much of this work has been done by Alan Brown and colleagues at Columbia University in New York, and they can now add to that list a wide range of sexually transmitted microbes. In a paper appearing in the May issue of the American Journal of Psychiatry, Brown and colleagues report that children born to mothers who experienced genital/ reproductive infections around the time of conception or in the first few weeks of pregnancy displayed a five times higher risk of schizophrenia as adults. The time window of susceptibility was quite narrow, as no elevated risk was associated with maternal infection at later gestational times.
One possible explanation of the results is that stimulation of the maternal immune system, rather than direct fetal infection with a particular organism, affects brain development, leading to later problems. Just how that might happen is the subject of another paper, this from the lab of Benjamin Yee at the Swiss Federal Institution of Technology Zurich (Switzerland). Writing in the May 3 issue of the Journal of Neuroscience, Yee and colleagues show that elevation of maternal inflammatory cytokines at different stages of pregnancy in mice causes distinct neurodevelopmental abnormalities in the offspring. By tying maternal and fetal cytokine profiles to changes in neurogenesis, neuronal apoptosis, and adult behavior, this line of research provides a mechanistic footing for the epidemiological work. It is also possible that some individual infections may operate by unique effects to disrupt fetal brain development and increase risk for schizophrenia.
In the first study, lead author Vicki Babulas and her Columbia colleagues searched for a connection between infections of the reproductive tract and schizophrenia in a sampling of mothers and their (now adult) children, in a birth cohort in northern California. Of the 7,794 offspring in the study, 71 were diagnosed with schizophrenia spectrum disorders. To determine the frequency of maternal infection, the researchers reviewed the mothers’ medical records for physician documentation of any of eight diagnoses, including endometritis, cervicitis, pelvic inflammatory disease, vaginitis, gonorrhea, syphilis, condylomata, or venereal disease during four pregnancy intervals—periconception and first, second, or third trimester.
Their results show that when the mother was exposed during the periconceptional period (from 30 days before the last menstrual period to 30 days after), the rate ratio for schizophrenia in the offspring was 5.03 (95 percent CI 2.00-12.64, p = .001), compared to unexposed pregnancies and adjusted for maternal race, education, age, and mental illness. The incidence of rates of schizophrenia did not differ between the offspring of exposed versus unexposed mothers at any other time during pregnancy.
Additional, larger studies will be needed to confirm these findings and clarify which of the many infectious agents involved contribute most to the prenatal risk identified in this study. But if the results are replicated, it opens the possibility that treating and preventing STDs before and during pregnancy could have an immediate impact on the children of infected mothers. The authors write, “It is conceivable that a reduction in the incidence of schizophrenia may be brought about by readily available pharmacotherapeutic and other public health measures.”
Effects of in utero cytokines depend on time of exposure
Infection of mothers might affect development of their babies via changes in both maternal and fetal cytokine levels. To look directly at the effect of maternal cytokines on