Intrauterine infection and the development of cerebral palsy

Cerebral palsy is a serious motor disorder that appears in early life. The expectation that improved obstetrical and neonatal care would decrease the rate of this condition has not been realised. Recent evidence indicates that white matter brain lesions, often termed periventricular leukomalacia (PVL), are the most important identifiable risk factors for the development of cerebral palsy. The hypothesis under examination is that inflammatory cytokines released during the course of intrauterine infection play a central role in the genesis of preterm parturition, fetal PVL, and cerebral palsy. We examined the relationship between umbilical cord plasma concentrations of cytokines at birth and the occurrence of PVL in preterm gestation and demonstrated that umbilical cord plasma concentrations of interleukin (IL)-6 was a significant independent predictor of PVL-associated lesions. We also demonstrated that preterm neonates born to mothers with elevated amniotic fluid concentrations of pro-inflammatory cytokines were at increased risk for the subsequent development of PVL and cerebral palsy. Histological chorioamnionitis and congenital neonatal infection-related morbidity were more common in neonates with PVL than those without PVL in this study. We have also been able to induce PVL-like brain white matter lesions in the fetal rabbit after experimental ascending intrauterine infection. In support of this hypothesis, we were able to demonstrate overexpression of tumour necrosis factor-alpha and IL-6 in histological sections of neonatal brains with PVL. Moreover, the presence of funisitis, a histological counterpart of the fetal inflammatory response syndrome, and elevated concentrations of amniotic fluid IL-6 and IL-8 were strong and independent risk factors for the subsequent development of cerebral palsy at the age of 3 years in our recent study. Therefore, clinical and experimental data provide strong support for the hypothesis. There are significant implications of our findings. First, cytokine determinations in amniotic fluid provide information about the risk of PVL and cerebral palsy before birth. Second, the process responsible for some cases of PVL and cerebral palsy begins during intrauterine life, implying that effective strategies for the prevention of cerebral palsy associated with PVL must begin in utero.