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Preterm Birth: Causes, Consequences, and Prevention
of research (Dammann and Leviton, 1998; Grether and Nelson, 1997; Leviton, 1993). A growing body of evidence suggests that maternal genital tract infections, particularly intrauterine and intra-amniotic infections, may be important and potentially preventable causes of periventricular white matter damage and cerebral palsy. The association between intrauterine infection and cerebral palsy is supported by human observational studies and animal experimental studies. Bejar and colleagues (1988) observed that the risk of cerebral white matter damage was 9.4-fold greater among preterm neonates with purulent amniotic fluid than among those with nonpurulent fluid. Similarly, Grether and Nelson (1997) observed cerebral white matter damage in association with maternal intrapartum fever or chorioamnionitis. A recent meta-analysis of 30 human observational studies by use of a random-effects model reported that clinical chorioamnionitis was significantly associated with both cerebral palsy (relative risk [RR] 1.9; 95% confidence interval [CI] 1.4–2.5) and periventricular leukomalacia (RR 3.0; 95% CI 2.2–4.0) in preterm infants (Wu and Colford, 2000). Among term infants, a significant association was also found between clinical chorioamnionitis and cerebral palsy (RR 4.7; 95% CI 1.3–16.2) Clinical studies have reported elevated concentrations of proinflammatory cytokines, including IL-6, IL-1, and TNF-α, in amniotic fluid and elevated concentrations of IL-6 in umbilical cord plasma among neonates with periventricular leukomalacia or cerebral palsy (Nelson et al., 1998; Yoon et al., 1996, 1997a); increased expression of IL-6 and TNF-α within the brain lesions of infants who died with periventricular leukomalacia has also been reported (Yoon et al., 1997b).
Animal models consisting of pregnant rabbits with experimental intrauterine infection have demonstrated brain white matter lesions characterized by increased karyorrhexis, rarefaction, disorganization of the white matter, and increased apoptosis in the cerebral cortex (Yoon et al., 1997c). Finally, in a feline model of Escherichia coli endotoxin-induced cerebral white matter injury, daily intraperitoneal injections of endotoxin resulted in injury of the telencephalic white matter of newborn kittens (Gilles et al., 1976). One shortcoming of these animal studies is a lack of detailed monitoring of adverse systemic events associated with endotoxin, including hypoglycemia, acidosis, and hypotension. Subsequent studies with rabbit pups (Ando et al., 1988) and neonatal dogs (Young et al., 1983) demonstrated that cerebral white matter lesions occurred within 1 to 3 days of endotoxin exposure in the setting of transient acute arterial hypotension. Hence, the diverse forms of white matter pathology induced by endotoxin or infection might be due, at least in part, to systemic vascular effects.