Chronic Exposure to Intra-Amniotic Lipopolysaccharide Affects the Ovine Fetal Brain

OBJECTIVE: Fetal brain injury is associated with chorioanmionitis, which is often present without signs of overt infection or fetal compromise. We aimed to determine if prolonged exposure to intrauterine inflammation caused by intra-amniotic infusion of lipopolysaccharide (LPS) would affect the fetal brain.METHODS: At 80 days of pregnancy ewews bearing singletons had osmotic pumps implanted intra-omniotically to infuse Eschericia coli LPS (055:B5; n=8) or saline (n=7) for 28 days. At delivery (110 days), umbilical arterial blood and chorioamnion were assessed for inflammation; cytokine concentration (interleukin [IL]-6 and IL-8) in amnitotic fluid and fetal and maternal plasma were measured. The fetal cerebral hemispheres were examined for gross anatmmoical changes and for the number of activated microaglia/mamacrophages, astrocytes, and oligodendroctes estimated after immunohistochemical staining.RESULTS: Intra-amniotic administration of LPS caused chorioamnioitis, fetal leucocytosis, and a moderate to extensice infiltration of activated microalgia/macrophages in the subcortical white matter in six of the eight fetuses; the remaining two fetuses were less affected. Within these focal regions of damage there was an attenuation of astrocytic processes, axonal injury, and a reduction in the number of 2', 3'-cyclic nucletide 3'-phosphodiesterase (CNPase) immunreactive oligodendroctes in areas of extensive focal damage. In control fetuses there was a mild (3/7) or no inflitration of activated microalgia/macrophages in the subcortical white matter. Overall the infiltration of activated microalgia/macrophages in the white matter was significantly greater in the LPS-exposed fetuses compared to controls. In regions devoid of injury, the number of oligodendrocytes and astrocytes was not differenbt between groups, nor was there a difference in the volume of cerebral white matter or density of blood vessels withing the white matter. Amniotic fluid IL-6 and IL-8, and maternal plasma IL-8concentrations were significantly increased by LPS infusion.CONCLUSIONS: An increase in inflammatory cells and axonal disruption in the subcortical white matter of the fetal brain can accompany chorioamnioitis induced by intra-amniotic administration of LPS, but cystic lesions do not occur. Thus, the effect on the fetal brain is milder than that reported from animal models of acute fetal/intrauterine infection. (J Soc Gynecol Investig 2006; 13:239- 47) Copyright (c) 2006 by the Society for Gynecologic Investigation.