ABSTRACT:The relative contributions of inflammation and ischemia to the pathogenesis of periventricular leukomalacia (PVL) have not been elucidated. We hypothesized that fetal cardiovascular function and cerebral blood flow velocity (BFV) would be decreased in a rat model of chorioamnionitis. We also tested whether placental inflammation was related to proximity to the cervix in our model of chorioamnionitis [intracervical lipopolysaccharide (LPS) or vehicle (PBS) injection]. On embryonic d 15, Sprague-Dawley rats underwent baseline maternal and fetal echocardiography, followed by LPS or PBS injection, then serial echocardiographic evaluations until embryonic day (ED) 21. One hour after birth, pups had middle cerebral artery (MCA) BFV measured. Placentas of LPS-exposed pups exhibited uniform, higher inflammation grades (p Ͻ 0.001). All fetal BFVs increased with advancing GA (p Ͻ 0.001) whereas resistance index (RI) decreased (p Ͻ 0.001). There was no difference in fetal BFV between the groups other than a reduced gestationrelated increase in descending aorta BFV in LPS-exposed rats (p Ͻ 0.05). Newborn pups exposed to LPS had lower heart rate (p ϭ 0.006) and MCA BFV (p ϭ 0.024) and higher RI (p ϭ 0.003) and pulsatility index (PI; p ϭ 0.004). In conclusion, intracervical LPS injection produces an inflammation independent of placental position, a blunted increase in gestation-related aortic BFV, and a decrease in MCA BFV in newborn pups. (Pediatr Res 68: 513-518, 2010) P eriventricular leukomalacia (PVL) describes necrosis of the white matter adjacent to the lateral cerebral ventricles, which occurs primarily among premature infants and is strongly associated with the development of cerebral palsy (1,2). Historically, the pathogenesis of PVL was attributed to hypoxia/ischemia of developing oligodendroglia during their most vulnerable period in the late mid-trimester (3). Recently, several epidemiological and experimental studies have implicated chorioamnionitis in the pathogenesis of PVL (1-8). This association suggests that inflammation, rather than hypoxia/ ischemia, may be a primary cause of white matter injury. However, because chorioamnionitis is also associated with hemodynamic alterations in the newborn premature infant (9,10), it remains possible that inflammation and ischemia both contribute to the pathogenesis of PVL in chorioamnionitis-associated preterm brain injury.Several animal models have been developed to study the pathogenesis of chorioamnionitis-associated PVL (11-14). We have shown that intracervical injection of lipopolysaccharide (LPS) to a gravid rat produces PVL-like lesions in the brains of surviving LPS-exposed pups (13,14). The lesions are characterized by apoptosis (measured by TUNEL staining) and inflammation (TNF-␣ staining) (15). Our model (13) allows the investigation of fetal hemodynamics during and after LPS exposure because a majority of the pups survive. Yet, the contribution of ischemia to white matter injury had not been studied previously in this model.The primary objective o...