Umbilical cord blood biomarkers of neurologic injury and the risk of cerebral palsy or infant death

To evaluate the association between cerebral palsy (CP) or infant death and putative cord blood biomarkers of neurologic injury, we performed a nested case–control secondary analysis of a multicenter randomized trial of magnesium sulfate (MgSO4) versus placebo to prevent CP or death among offspring of women with anticipated delivery from 24 to 31 weeks’ gestation. Cases were infants who died by 1 year (n = 25) or developed CP (n = 16), and were matched 1:2 to a control group (n = 82) that survived without developing CP. Umbilical cord sera concentrations of S100B, neuron‐specific enolase (NSE) and the total soluble form of the receptor for advanced glycation end‐products (sRAGE) were measured by ELISA in duplicates. Maternal characteristics were similar between the 2 groups. Cases were born at a lower gestational age (GA) and had lower birth weight compared with controls. There were no differences in concentrations of the three biomarkers and the composite outcome of CP or infant death. However, S100B was higher (median 847.3 vs. 495.7 pg/ml; P = 0.03) in infants who had CP and total sRAGE was lower (median 1259.3 vs. 1813.1 pg/ml; P = 0.02) in those who died compared with the control group. When corrected for delivery GA and treatment group, both differences lost statistical significance. In conclusion, cord blood S100B level may be associated with CP, but this association was not significant after controlling for GA and MgSO4 treatment.

[1]  G. Hankins,et al.  Antenatal antecedents and the impact of obstetric care in the etiology of cerebral palsy. , 2008, Clinical obstetrics and gynecology.

[2]  M. Lotze,et al.  The grateful dead: damage‐associated molecular pattern molecules and reduction/oxidation regulate immunity , 2007, Immunological reviews.

[3]  K. Himmelmann,et al.  The changing panorama of cerebral palsy in Sweden. X. Prevalence and origin in the birth‐year period 1999–2002 , 2010, Acta paediatrica.

[4]  C. Müller,et al.  Early Biochemical Indicators of Hypoxic-Ischemic Encephalopathy after Birth Asphyxia , 2001, Pediatric Research.

[5]  M. Cavaglià,et al.  Peripheral markers of blood-brain barrier damage. , 2004, Clinica chimica acta; international journal of clinical chemistry.

[6]  F. Michetti,et al.  Amniotic fluid S100B protein in mid-gestation and intrauterine fetal death , 2004, The Lancet.

[7]  J. Schiettecatte,et al.  Elevated serum levels of S-100&bgr; protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock* , 2006 .

[8]  M. Yeargin-Allsopp,et al.  Trends in the prevalence of cerebral palsy in a population-based study. , 2002, Pediatrics.

[9]  B. Acunaş,et al.  Neuron-specific enolase as a marker of the severity and outcome of hypoxic ischemic encephalopathy , 2004, Brain and Development.

[10]  F. Michetti,et al.  Circulating S100β Protein Is Increased in Intrauterine Growth-Retarded Fetuses , 2002, Pediatric Research.

[11]  S. Kingsmore,et al.  Cerebral palsy is characterized by protein mediators in cord serum , 2004, Annals of neurology.

[12]  B Hagberg,et al.  Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991–94 , 2001, Acta paediatrica.

[13]  F. Michetti,et al.  S100B Protein in Urine of Preterm Newborns with Ominous Outcome , 2005, Pediatric Research.

[14]  F. Michetti,et al.  S100B protein in biological fluids: a tool for perinatal medicine. , 2002, Clinical chemistry.

[15]  V. Félix,et al.  [Blood neuronal specific enolase in newborns with perinatal asphyxia]. , 2001, Revista de neurologia.

[16]  P. Rogalla,et al.  Tissue-specific expression patterns of the RAGE receptor and its soluble forms--a result of regulated alternative splicing? , 2003, Biochimica et biophysica acta.

[17]  K. Maršál,et al.  S100 Protein in Serum as a Prognostic Marker for Cerebral Injury in Term Newborn Infants with Hypoxic Ischemic Encephalopathy , 2004, Pediatric Research.

[18]  D. Rouse,et al.  Magnesium sulfate for the prevention of cerebral palsy. , 2009, American journal of obstetrics and gynecology.

[19]  S. Takasawa,et al.  Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. , 2003, The Biochemical journal.

[20]  A. Frigiola,et al.  Perinatal asphyxia in preterm neonates leads to serum changes in protein S-100 and neuron specific enolase. , 2009, Current Neurovascular Research.

[21]  Saroj Saigal,et al.  An overview of mortality and sequelae of preterm birth from infancy to adulthood , 2008, The Lancet.

[22]  M. Kiely,et al.  Descriptive epidemiology of cerebral palsy. , 1984, Public health reviews.

[23]  Ben Vandermeer,et al.  Systematic review of biomarkers of brain injury in term neonatal encephalopathy. , 2009, Pediatric neurology.

[24]  Adriana B Ferreira,et al.  S100β Induces Neuronal Cell Death Through Nitric Oxide Release from Astrocytes , 1997, Journal of neurochemistry.

[25]  F. Michetti,et al.  Measurement of urinary S100B protein concentrations for the early identification of brain damage in asphyxiated full-term infants. , 2003, Archives of pediatrics & adolescent medicine.

[26]  R. Medzhitov Origin and physiological roles of inflammation , 2008, Nature.

[27]  R. Romero,et al.  Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. , 2000, American journal of obstetrics and gynecology.

[28]  F. Michetti,et al.  Urinary S100B protein measurements: A tool for the early identification of hypoxic-ischemic encephalopathy in asphyxiated full-term infants , 2004, Critical care medicine.

[29]  R. Ehrenkranz,et al.  Characterization of RAGE, HMGB1, and S100beta in inflammation-induced preterm birth and fetal tissue injury. , 2009, The American journal of pathology.

[30]  Chang-il Park,et al.  Over-expression of S100B protein in children with cerebral palsy or delayed development , 2004, Brain and Development.

[31]  T. Beems,et al.  Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury , 2004, Neurology.

[32]  F. Malone,et al.  A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. , 2008, The New England journal of medicine.

[33]  Dong Zhou,et al.  Umbilical artery blood S100β protein: a tool for the early identification of neonatal hypoxic-ischemic encephalopathy , 2008, European Journal of Pediatrics.

[34]  J. Perlman,et al.  Intervention strategies for neonatal hypoxic-ischemic cerebral injury. , 2006, Clinical therapeutics.