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Background: The development of periventricular white matter injury (PWMI) in the preterm neonate is the most common insult portending neurologic impairment and is linked with the later development of cerebral palsy. The pathogenesis of PWMI targets premyelinating oligodendrocytes of the periventricular region secondary to free radicals, cytokine toxicity, and excitatory neurotransmitters. The primitive nature of the vasculature in the developing fetal cortex lends to its predilection to PWMI and cerebral ischemia with less arterial anastomoses at arterial border zones and failure to compensate for global hypotension, termed the "pressure-passive" circulation., Objective: Our objective is to determine the relative risk (RR) of fetal metabolic acidosis and perinatal infection in the development of PWMI in very low birthweight (VLBW) (<1500 g) neonates., Study Design: This is a cohort study of all VLBW neonates admitted to our neonatal intensive care unit from April 2009 through December 2014, comparing those who developed PWMI on neonatal head ultrasound at 6 weeks of life to those who did not. Neonates with chromosomal or major congenital abnormalities were excluded. Generalized linear modeling, adjusting for variables significantly different on bivariate analysis, was conducted., Results: During this 5-year and 8-month period there were 374 VLBW neonates admitted; 35 (9.4%) had PWMI. VLBW neonates without PWMI were significantly more likely to have intrauterine growth restriction (2.9% PWMI, 21.5% no PWMI; P = .006), while those neonates with PWMI had a significantly lower gestational age (26.3 ± 2.2 vs 28.0 ± 2.5 weeks; P < .001) and birthweight (868 ± 237 vs 993 ± 276 g; P = .009). There was no significant difference in umbilical arterial pH (7.25 ± 0.15 vs 7.27 ± 0.09; P = .34), base deficit (4.6 ± 6.0 vs 3.4 ± 3.3 mmol/L; P = .11), or pH <7.0 or base deficit >12 mmol/L at birth (10.7% vs 3.2%; P = .09). On bivariate analysis neonates with PWMI had a significant increase in positive cerebrospinal fluid (CSF) cultures (22.9% vs 1.5%; P < .001). The initial lumbar puncture was performed at a similar day of life, and neonates with PWMI had significantly elevated CSF white blood cell counts (5%, 50%, and 95%; 16, 175, and 709/mm(3); 1, 3, and 27/mm(3); P = .008). Generalized linear modeling, adjusted for gestational age and the presence of intrauterine growth restriction, showed that fetal metabolic acidosis had RR 2.59 (95% confidence interval, 1.14-5.92; P = .02) and neonatal CSF infection had RR 4.94 (95% confidence interval, 2.4-10.3; P < .001) for association with PWMI., Conclusion: The RR of neonatal CSF infection being associated with PWMI was 2-fold greater than metabolic acidosis at the time of birth. Decreasing the incidence of CSF infections would have a greater impact on preventing PWMI, a precursor of cerebral palsy., (Copyright © 2016 Elsevier Inc. All rights reserved.)