This proposal will provide Dr. Yanowitz with concepts and techniques necessary to become an independent clinical investigator with expertise in hemodynamic abnormalities which potentially predispose the premature fetus and newborn to perinatal brain injury. Cerebral palsy is 30 times more common in premature than term infants and may be predicted by periventricular leukomalacia (PVL) on cranial ultrasound. PVL results from susceptibility of developing oligodendroglia to ischemia and/or cytotoxic effects of IL-1beta, IL-6 and TNF-alpha. These cytokines are elevated in cord blood during intra-uterine infection. However, a causal relationship has not been established. This project will test the hypothesis that the predisposition to perinatal brain injury in preterm infants born to mothers with chorioamnionitis results from cytokine-mediated alterations of systemic and cerebral hemodynamics. Dr. Yanowitz will use noninvasive techniques to test whether premature infants born to mothers with chorioamnionitis have 1) decreased cardiac function and middle cerebral artery Doppler blood flow velocity in-utero and after birth; 2) altered cerebral oxygen availability as measured by near infrared spectroscopy (NIRS) after birth; and 3) elevated serum concentrations of IL-1beta, IL-6, and TNF-alpha which can be correlated with the hemodynamic disturbances. Singleton or twin fetuses at risk of delivery less than 32 wk g.a. will undergo fetal echocardiography and middle cerebral artery Doppler examination daily until delivery. Premature newborns will be similarly evaluated at 3q1, 24q2 and 48q4 hr of life. Variability in cerebral cytochrome aa3 and total, oxygenated, and deoxygenated hemoglobin will be determined on newborns using NIRS. Histologic chorioamnionitis (graded by the number of polymorphonuclear leukocytes on ten adjacent 400x fields of an H and E-stained placental membrane roll and umbilical cord) and cord blood concentrations of IL-1beta, IL-6, and TNF-alpha will be determined after the hemodynamic studies are completed in order to avoid investigator bias. Data will be analyzed by repeated measures ANOVA and Kruskal-Wallis tests. Demonstration that cardiac function and/or cerebral hemodynamics are altered by chorioamnionitis and correlate with elevated cytokine concentrations will provide important insight for the prevention of neonatal brain injury. Magee-Womens Research Institute is an ideal environment for Dr. Yanowitz to test her hypothesis and begin her research career. The varied and pertinent expertise of her committee members will make the development phase of her patient-oriented clinical research career a well-rounded and enlightening experience.
