These results provide the first evidence that fetal exposure to increases in a maternal cytokine is associated with structural neuroanatomic alterations that have been consistently linked to schizophrenia (Wright et al., 2000
). Among schizophrenia cases, increases in maternal IL-8 during the second/third trimesters of pregnancy were related to increases in ventricular CSF. In addition, we observed significant associations between maternal IL-8 and decreases in left entorhinal cortex and right posterior cingulate volumes, and volumetric decreases that approached significance in the right caudate, the putamen bilaterally, and the right superior temporal gyrus among cases.
Ventricular enlargement is arguably the most well-replicated neuromorphologic anomaly in schizophrenia (Wright et al., 2000
). Further, ventricular enlargement has been previously associated with hypoxia-associated OCs, suggesting that this structural change may have risk factors that are neurodevelopmental in origin (Cannon et al., 2002
). Lastly, fetal exposure to activation of proinflammatory cytokines in rodents has been linked to increased ventricular CSF, which is the only known neuromorphologic volumetric finding among animal studies to date (Patterson, 2008
). Cumulatively, these findings suggest that fetal exposure to IL-8 may contribute to the known increases in ventricular volumes in schizophrenia.
Many of the other volumetric changes found in the present study also have been observed in schizophrenia and prodromal populations (Borgwardt et al., 2007
; Pantelis et al., 2003
; Wright et al., 2000
). Specifically, parahippocampal and superior temporal gyrus (STG) volume reductions have been repeatedly found among patients with schizophrenia and these regions have been shown to be decreased in the available prodromal studies, as well (Pantelis et al., 2003
; Wright et al., 2000
). Similar to the present study, in first-episode and prodromal patients basal ganglia volumes were decreased (Corson, Nopoulos, Andreasen, Heckel, & Arndt, 1999
; Pantelis et al., 2003
Interestingly, no significant associations were observed among controls. This pattern of null findings may support the assertion that a genetic or environmental factor associated with schizophrenia is necessary for IL-8 to exert damaging influences on the fetal brain, although studies with larger samples are necessary to confirm this possibility.
IL-8 is a proinflammatory chemokine produced by multiple cells involved in mobilizing, activating and degranulating neutrophils (Janeway, Travers, Walport, & Schlomchik, 2005
). Although IL-8 is integral in the initial immune response to infection, elevations in IL-8 also are sometimes associated with other maternal conditions during pregnancy that increase risk for schizophrenia, such as preeclampsia, obesity and anemia (Basso, Gimenez, & Lopez, 2005
; Dalman, Allebeck, Cullberg, Grunewald, & Koster, 1999
; Fain, 2006
; Insel, Schaefer, McKeague, Susser, & Brown, 2008
; Laskowska, Laskowska, Leszczynska-Gorzelak, & Oleszczuk, 2007
; Schaefer et al., 2000
). It is possible that additional obstetric insults may add to, interact with, or precede the effects of IL-8 to cause disruptions in fetal neuronal development among cases, which should be teased apart in future studies.
There were several limitations in the present study that should be noted. Given the multiple tests conducted in this study, it is possible that spurious findings arose from type I error. It appears unlikely, however, that our results are entirely due to chance, as they are consistent with many previous studies in clinical and preclinical studies of schizophrenia. Further, there is the possibility of Type 2 error, given the modest sample sizes. It should considered, however, that the present study is the first of its kind with access to serological evidence of prenatal events and follow-up brain imaging data. Nevertheless, it will be essential to attempt to replicate the results of the present study with larger samples.
In addition, the sample was limited to slightly more than 25% of cases from the overall cohort, raising the potential for selection bias. However, cases who participated in the DIBS study and cases from the original cohort who were not DIBS subjects did not differ with regard to several demographic variables and IL-8 levels; therefore, it is unlikely that case ascertainment bias accounts for our findings. Bias also would be mitigated by the fact that the sample was derived from a population-based study, in contrast to many clinical imaging studies, which draw upon hospital or clinic-based samples.
Lastly, the use of antipsychotics may have influenced our results. Although this is a possibility, IL-8 values were not significantly related to current antipsychotic use, which significantly decreases the likelihood that medication use confounded our findings. Nonetheless, long-term medication use, which is difficult to assess retrospectively, could have influenced the observed brain volumes.
In conclusion, the present study is the first to suggest that brain anomalies previously associated with schizophrenia may be partially attributable to in utero insults, such as fetal exposure to elevated IL-8. These findings support our previous association between fetal exposure to IL-8 and risk of schizophrenia in this birth cohort (Brown et al., 2004
). Future research is necessary to replicate this finding and to delineate whether fetal exposure to IL-8 interacts with risk genes for schizophrenia. Our findings underscore the potential importance of prenatal contributions to schizophrenia, with implications for prevention, early intervention, and treatment strategies.