This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Numerous studies have identified Grades 3-4 intraventricular hemorrhage (IVH) as a significant cause of adverse outcome for very low birthweight (VLBW) neonates. IVH, or hemorrhage into the germinal matrix tissues of the developing brain, is believed to be secondary to changes in cerebral blood flow to the immature germinal matrix microvasculature and secondary periventricular venous infarction. Over 12% of all VLBW infants experience Gr. 3-4 IVH, and three quarters of these develop mental retardation, cerebral palsy and/or seizures. Based on data from the U.S. Census Bureau, the NICHD Neonatal Network and the CDC, there are over 3600 new cases of mental retardation attributable to Gr. 3-4 IVH in the U.S. each year, and the lifetime care costs for these children exceed 3.6 billion dollars. Preterm birth represents a unique environment for the developing brain;many factors such as inflammation, hypotension and hypoxemia that contribute to IVH have been identified. The incidence of Gr. 3-4 IVH has not changed, however, over the past ten years. Until recently, there has been limited information on whether genetic factors play a role in the pathogenesis of Gr. 3-4 IVH. New data, however, strongly suggest familial susceptibility for IVH in VLBW twins, and several studies have investigated the role of thrombophilia, inflammatory and vascular genes in the genesis of Gr. 3-4 IVH. We hypothesize that for VLBW infants, Gr. 3-4 IVH is attributable to both environmental and genetic actors. The genetic factors are alleles and haplotypes of as yet unidentified genes that render VLBW infants susceptible to Gr. 3-4 IVH. It is likely that many are part of inflammatory, vascular, oxidative and/or coagulation pathways. To accomplish these aims, this randomized, multi-center study, in aggregate, will collect DNA from 1000 neonates of 500-1250g birthweight with Gr. 3-4 IVH and 1000 matched control preterm infants with normal cranial ultrasounds and no evidence for IVH. The genetic analyses will include a whole genome association study of 500,000 markers distributed throughout the genome and candidate pathway gene studies targeting genes that encode proteins known to subserve vascular, inflammatory, oxidative and/or coagulation pathways. In order to determine the contribution of environmental factors to Gr. 3-4 IVH, pre-, peri- and neo-natal data will be collected;using multivariate analyses, the relative contribution of genetic and environmental factors to the susceptibility to IVH will be assessed. This is an NIH funded, randomized multi-center trial, of which Baylor College of Medicine is one of 14 participating institutions. The total number of study infants will be 1000 with Grade 3 or 4 IVH and 1000 matched controls. Enrollment will take place over the first four years of the study. Our site plans to enroll at total of 248 infants (124 with Gr 3 or 4 IVH and 124 matched controls) over the four year grant period.
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