title: The role of complement in neurodevelopmental impairment following neonatal hypoxic-ischemic encephalopathy.
abstract: Evidence has accumulated implicating complement activation in the pathogenesis of acute post-hypoxic-ischemic cerebral injury in infants who develop hypoxic-ischemic encephalopathy (HIE). However, the relationship between complement activation and subsequent neurological impairment is not known. We tested the hypothesis that in human neonates, post-hypoxic-ischemic complement activation within the central nervous system is positively associated with the acquisition of subsequent neurodevelopmental abnormalities. This prospective study included 18 full-term infants diagnosed with HIE following resuscitation at birth and seven control infants. Cerebrospinal fluid (CSF) samples were obtained from all infants in the first 24 hours of life as part of routine investigations to exclude sepsis and meningitis. Concentrations of terminal complement complexes (TCC), complement component 9 (C9), and albumin were quantified by enzyme-linked immunosorbent assay in all CSF samples. Neurological examination and Denver Developmental Screening Test II were performed at 6 and 12 months of life. Of the 18 HIE subjects, nine died, six survived with significant neurological impairment, and three had normal neurological outcomes. In the CSF of the 15 HIE infants who died or survived with abnormal outcomes, the mean concentration of TCC was increased compared with controls (p = 0.026) and the mean C9 concentration appeared to be decreased but the difference was not statistically significant (p = 0.056). Similar to the TCC concentration, the concentration of albumin in the CSF was significantly increased in infants with abnormal outcomes (p = 0.005). This study indicates that complement activation following resuscitation at birth, as manifested by increased TCC in the CNS, is positively correlated with the combination of the development of subsequent neurological sequelae and death. Further study incorporating larger sample sizes will be required to confirm this association. This step is essential before clinical trials of complement inhibitors can be justified in human neonates who suffer birth asphyxia.
authors.affiliation: Department of Pediatrics, George Washington University and Children's National Medical Center, Washington, DC, USA. haly@mfa.gwu.edu
authors.forename: Hany
authors.initials: H
authors.lastname: Aly
authors.forename: Mohamed T
authors.initials: MT
authors.lastname: Khashaba
authors.forename: Ayman
authors.initials: A
authors.lastname: Nada
authors.forename: Bothina M
authors.initials: BM
authors.lastname: Hasanen
authors.forename: Robert
authors.initials: R
authors.lastname: McCarter
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Schultz
authors.forename: Laura
authors.initials: L
authors.lastname: Gordon
authors.forename: Pamela W
authors.initials: PW
authors.lastname: Feldhoff
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Lassiter
mesh_terms: D000704:Analysis of Variance; D001238:Asphyxia Neonatorum / Q000150:complications* / Q000175:diagnosis / Q000401:mortality / Q000628:therapy; D015415:Biomarkers / Q000032:analysis; D002493:Central Nervous System Diseases / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology; D003167:Complement Activation; D003182:Complement C5; D003186:Complement C9; D003165:Complement System Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism*; D002658:Developmental Disabilities / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000175:diagnosis / Q000401:mortality / Q000628:therapy; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008297:Male; D009460:Neurologic Examination; D011446:Prospective Studies; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D047929:Term Birth
chemical_list: D015415:Biomarkers; D003182:Complement C5; D003186:Complement C9; D003165:Complement System Proteins