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Bad Timing: Prenatal Exposure to Maternal STDs Raises Risk of Schizophrenia

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 fetal brain development, dual first authors of the second paper, Urs Meyer and Myriel Nyffeler used a mouse model of acute inflammation during pregnancy that results in behavioral deficits in the offspring (Shi et al., 2003; Meyer et al., 2005). In this model, injecting pregnant mice with a synthetic analog of double-stranded RNA (polyI:C) elicits a strong but transient inflammatory response, and allows studies on the effects on offspring through postnatal life.

By dosing at two different gestational stages, the investigators found distinct patterns of psychopathological outcomes, cytokine production, and brain neuropathology as a result of the timing of inflammation. When they treated with polyI:C at gestational day 9 (thought to be in the vicinity of the first-to-second trimester transition in humans: Kaufman, MH [2003] The atlas of mouse development. London: Academic), the offspring showed significantly reduced exploratory behavior in an open field test as young adolescents. Offspring of mothers who were dosed at day 17 (equivalent to human second-to-third trimester transition) also showed a decrease in exploratory behavior in an open field, but it was much smaller and not statistically significant. The later-treated animals did show significant behavioral changes by a different measure, a reversal-of-choice task, where they took longer to learn the new choice. This perseverative behavior is proposed to model the lack of behavioral flexibility seen in schizophrenia and several other disorders, including autism and obsessive-compulsive disorder.

The neuropathological correlates of these behavioral changes were different in the offspring from earlier or later-treated mouse dams. Gross brain morphology was unaltered, but a closer look showed that the mice that were exposed on P9, and thus experienced inflammation at mid-gestation, had reduced reelin-positive cells in the hippocampus. The mice that experienced inflammation later showed reductions in reelin-expressing cells that were not as severe. Both groups had a loss of newly born neurons in the dentate gyrus of the hippocampus, but only the mice treated later in gestation displayed significantly elevated levels of caspase activation and apoptosis of neurons. The mice also showed different patterns of maternal and fetal production of proinflammatory and anti-inflammatory cytokines, depending on the timing of polyI:C injection.

These results suggest that the same inflammatory stimulus, when present at different gestational stages, can interfere with distinct developmental pathways via stimulation of varying cytokine profiles. If these results translate to humans, then timing of infection and the cytokines induced should be a critical determinant of the type of pathology that shows up in adulthood. This jibes with the current epidemiological study, and previous ones using the same group of patients (Brown et al., 2001; Brown et al., 2004), that link the risk for schizophrenia to infections occurring in a window of vulnerability in early to mid-pregnancy.—Pat McCaffrey.

References:
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract

Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract

 
Comments on News and Primary Papers
Comment by:  Paul Patterson
Submitted 22 May 2006 Posted 22 May 2006

Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory...  Read more


View all comments by Paul Patterson

Comment by:  Jürgen Zielasek
Submitted 3 June 2006 Posted 3 June 2006

Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.

Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and...  Read more


View all comments by Jürgen Zielasek

Primary Papers: The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology.

Comment by:  Akira Sawa, SRF Advisor
Submitted 5 June 2006 Posted 5 June 2006

I was greatly interested to read the recent article by Benjamin Yee and colleagues. In this article, the authors hypothesized that cytokine-associated inflammatory responses would be important for maternal infection-induced neuropsychiatric conditions. Thus, the authors administered the viral mimic polyriboinosinic-polyribocytidylic acid (polyI:C) into pregnant mouse dams on gestational day 9 or day 17 and examined the effects in the offspring. It is very impressive that an acute insult, depending on the embryonic day, leads to varied brain changes, as well as behavioral alterations, even in adulthood.

One important lesson from this study is how critical it is to use appropriate molecular markers (in this case, caspase-3, reelin, etc.) in dissecting anatomical and histological changes that may potentially occur in animal models for psychiatric conditions. The data clearly indicate that classic Nissl staining is insufficient to detect important molecular changes that may underlie behavioral alterations in these animals. Many laboratories are now generating and...  Read more


View all comments by Akira Sawa
Comments on Related Papers
Related Paper: Prenatal determinants of schizophrenia: what we have learned thus far?

Comment by:  Patricia Estani
Submitted 27 May 2006 Posted 27 May 2006
  I recommend this paper
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