THE ROLE OF SUBCLINICAL INFECTION AND CYTOKINES IN PRETERM PARTURITION

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The goal of this project is to explore the relationship between sub-clinical intra-amniotic infection, preterm parturition and the complications of prematurity. This year the Branch focused specifically on the relationship between sub-clinical intrauterine infection and periventricular leukomalacia. Periventricular leukomalacia (PVL), a cerebral lesion characterized by foci of necrosis in the white matter near the lateral ventricles is found in 7-26 % of neonates with a birth weight under 1,500 g. Between 47% and 80% of these infants developed abnormalities of neuromuscular tone and posture (i.e. cerebral palsy) , and often cognitive impairment. Inflammatory cytokines released during the course of intrauterine infections have been implicated in the genesis of brain white matter lesions and subsequent CP. The Branch completed a study to determine if fetuses who subsequently were diagnosed to have periventricular brain white matter lesions within the first seven days of life could be identified by determining the concentrations of inflammatory cytokines in amniotic fluid. Women with complicated preterm gestations underwent amniocentesis for clinical indications. Amniotic fluid concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and the natural interleukin-1 receptor antagonist (IL-1ra) were determined by immunoassay. Periventricular white matter lesions of the neonate were diagnosed by neurosonography. Ninety-four women and their neonates were included in the study; white matter lesions were diagnosed in 24% (23/94) of the newborns. The mothers of newborns with brain white matter lesions had higher median concentrations of TNF-alpha, IL-1beta, and IL-6 (but not IL-1ra) in amniotic fluid than those who delivered newborns without white matter lesions (P<0.01 for each). Acute histologic chorioamnionitis was more common in the placentas of neonates with white matter lesions than in those without these lesions (P=0.001). Neonates with white matter lesions were delivered at a lower mean gestational age and birth weight and had a higher rate of significant complications (including respiratory distress syndrome, intraventricular hemorrhage, infection-related complications) than those without white matter lesions. The differences in median IL-1beta and IL-6 between these two groups remained significant after adjusting for gestational age and birth weight (IL-6: odds ratio, 5.7; 95% confidence interval, 1.3 to 24.4; IL-1beta: odds ratio, 4.4; 95% confidence interval, 1.1 to 17.0). Of the 94 newborns included in this study, 11 died before six months of age and seven developed severe spastic paresis of at least one lower extremity; all seven had white matter lesions and elevated cytokines in amniotic fluid. These data provides strong support for the hypothesis that inflammatory cytokines released during the course of intrauterine infection play a role in the genesis of brain white matter lesions.