Background: Hypoxia/ischemia and inflammation are two major mechanisms for cerebral palsy (CP) in preterm infants. Objective: To investigate whether hypoxia/ischemia- and infection-related events in the perinatal and neonatal periods had cumulative effects on CP risk in very-low-birth-weight (VLBW) premature infants. Methods: From 1995 to 2005, 5,807 VLBW preterm infants admitted to Taiwan hospitals were enrolled. The cumulative effects of hypoxic/ischemic and infectious events during the perinatal and neonatal periods on CP risk at corrected age 24 months were analyzed. Results: Of the 4,355 infants with 24-month follow-up, 457 (10.5%) had CP. The CP group had significantly higher incidences of hypoxia/ischemia-related events in the perinatal and neonatal periods, and sepsis in the neonatal period than the normal group. Three hypoxic/ischemic events, including birth cardiopulmonary resuscitation (OR 2.25; 95% CI 1.81-2.82), patent ductus arteriosus (PDA) ligation (2.94; 1.35-5.75) and chronic lung disease (3.14; 2.61-3.85) had the most significant contribution to CP. Relative to CP risk for infants with neither the three hypoxic/ischemic events nor sepsis, the CP odds increased 1.98-, 2.26- and 2.15-fold for infants with birth cardiopulmonary resuscitation, PDA ligation and chronic lung disease, respectively; while the combination with sepsis further increased the odds to 3.18-, 3.83- and 3.25-fold, respectively. Using the three hypoxic/ischemic events plus sepsis, CP rates were 10.0, 16.7, 26.7, 40.0 and 54.7% for infants with none, one, two, three and four events, respectively. Conclusions: Hypoxic/ischemic and infectious events across the perinatal and neonatal periods exerted cumulative effects on CP risk in VLBW premature infants.

1.
Khwaja O, Volpe JJ: Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 2008;93:F153-F161.
2.
O'Shea TM: Cerebral palsy in very preterm infants: new epidemiological insights. Ment Retard Dev Disabil Res Rev 2002;8:135-145.
3.
Vincer MJ, Allen AC, Joseph KS, Stinson DA, Scot H, Wood E: Increasing prevalence of cerebral palsy among very preterm infants: a population-based study. Pediatrics 2006;118:e1621-e1626.
4.
Beaino G, Khoshnood B, Kaminski M, Pierrat V, Marret S, Matis J, Ledesert B, Thiriez G, Fresson J, Roze JC, Zupan-Simunek V, Arnaud C, Burguet A, Larroque B, Breart G, Ancel PV: Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. Dev Med Child Neurol 2010;52:e119-e125.
5.
McElrath TF, Allred EN, Boggess KA, Kuban K, O'Shea TM, Paneth N, Leviton A: Maternal antenatal complications and the risk of neonatal cerebral white matter damage and later cerebral palsy in children born at an extremely low gestational age. Am J Epidemiol 2009;170:819-828.
6.
Schlapbach LJ, Aebischer M, Adams M, Natalucci G, Bonhoeffer J, Latzin P, Nelle M, Bucher HU, Latal B: Impact of sepsis on neurodevelopmental outcome in a Swiss national cohort of extremely premature infants. Pediatrics 2011;128:e348-e357.
7.
Yanowitz TD, Jordan JA, Gilmour CH, Towbin R, Bowen A, Roberts JM, Brozanski BS: Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations. Pediatr Res 2002;51:310-316.
8.
Wong FY, Silas R, Hew S, Samarasinghe T, Walker AM: Cerebral oxygenation is highly sensitive to blood pressure variability in sick preterm infants. PLoS One 2012;7:e43165.
9.
Kaukola T, Herva R, Perhomma M, Paakko E, Kingsmore S, Vainionpaa L, Hallman M: Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurological outcome in very preterm, extremely low birth weight infants. Pediatr Res 2006;59:478-483.
10.
Wang LW, Chang YC, Lin CY, Hong JS, Huang CC: Low-dose lipopolysaccharide selectively sensitizes hypoxic ischemia-induced white matter injury in the immature brain. Pediatr Res 2010;68:41-47.
11.
Wang LW, Wang ST, Huang CC: Preterm infants of educated mothers have better outcome. Acta Paediatr 2008;97:568-573.
12.
Kuban K, Allred EN, O'Shea M, Paneth N, Pagano M, Leviton A: An algorithm for identifying and classifying cerebral palsy in young children. J Pediatr 2008;153:466-472.
13.
Schmidt B, Asztalos EV, Roberts RS, Robertson CMT, Sauve RS, Whitfield MF: Impact of bronchopulmonary dysplasia, brain injury and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months. JAMA 2003;289:1124-1129.
14.
Girard S, Kadhim H, Roy M, Lavoie K, Brochu ME, Larouche A, Sebire G: Role of perinatal inflammation in cerebral palsy. Pediatr Neurol 2009;40:168-174.
15.
Wyckoff MH, Salhab WA, Heyne RJ, Kendrick DE, Stoll BJ, Laptook AR: Outcome of extremely low birth weight infants who received delivery room cardiopulmonary resuscitation. J Pediatr 2012;160:239-244.
16.
Gonzalez A, Sosenko IRS, Chandar J, Hummler H, Claure N, Bancalari E: Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1,000 g or less. J Pediatr 1996;128:470-478.
17.
Chock VY, Ramamoorthy C, Van Meurs KP: Cerebral oxygenation during different treatment strategies for a patent ductus arteriosus. Neonatology 2011;100:233-240.
18.
Bose CL, Laughon MM, Allred EN, O'Shea TM, Van Marter LJ, Ehrenkranz RA, Fichorova RN, Leviton A: Systemic inflammation associated with mechanical ventilation among extremely preterm infants. Cytokine 2013;61:315-322.
19.
Bassler D, Stoll BJ, Schmidt B, Asztalos EV, Roberts RS, Robertson CMT, Sauve RS: Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics 2009;123:313-318.
20.
Martin RJ, Wang K, Koroglu O, Di Fiore J, Kc P: Intermittent hypoxic episodes in preterm infants: do they matter? Neonatology 2011;100:303-310.
21.
Van Marter LJ, Dammann O, Allred EN, Leviton A, Pagano M, Moore M, Martin C: Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002;140:171-176.
22.
Shim SY, Jeong HJ, Son DW, Jeong JS, Oh SH, Park SY, Ryu TH, Kim YB, Cho ZH: Altered microstructure of white matter except the corpus callosum is independent of prematurity. Neonatology 2012;102:309-315.
23.
Oskoui M, Coutinho F, Dykeman J, Jette N, Pringsheim T: An update on the prevalence of cerebral palsy: a systemic review and meta-analysis. Dev Med Child Neurol 2013;55:509-519.
24.
Farooqi A, Hagglof B, Sedin G, Serenius F: Impact at age 11 years of major neonatal morbidities in children born extremely preterm. Pediatrics 2011;127:e1247-e1257.
25.
Doyle LW, Anderson PJ: Pulmonary and neurological follow-up of extremely preterm infants. Neonatology 2010;97:388-394.
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