Blood Biomarkers and 6- to 7-Year Childhood Outcomes Following Neonatal Encephalopathy

Abstract

Objective This study aimed to profile the cytokine/chemokine response from day 0 to 7 in infants (≥36 weeks of gestational age) with neonatal encephalopathy (NE) and to explore the association with long-term outcomes. Study Design This was a secondary study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network randomized controlled trial of whole body hypothermia for NE. Eligible infants with moderate–severe NE were randomized to cooling or normothermia. Blood spots were collected on days 0 to 1, 2 to 4, and 6 to 7. Twenty-four cytokines/chemokines were measured using a multiplex platform. Surviving infants underwent neurodevelopmental assessment at 6 to 7 years. Primary outcome was death or moderate–severe impairment defined by any of the following: intelligence quotient <70, moderate–severe cerebral palsy (CP), blindness, hearing impairment, or epilepsy. Results Cytokine blood spots were collected from 109 participants. In total 99 of 109 (91%) were assessed at 6 to 7 years; 54 of 99 (55%) developed death/impairment. Neonates who died or were impaired had lower early regulated upon activation normal T cell expressed and secreted (RANTES) and higher day 7 monocyte chemotactic protein (MCP)-1 levels than neonates who survived without impairment. Though TNF-α levels had no association with death/impairment, higher day 0 to 1 levels were observed among neonates who died/developed CP. On multiple regression analysis adjusted for center, treatment group, sex, race, and level of hypoxic ischemic encephalopathy, higher RANTES was inversely associated with death/impairment (odds ratio (OR): 0.31, 95% confidence interval [CI]: 0.13–0.74), while day seven MCP-1 level was directly associated with death/impairment (OR: 3.70, 95% CI: 1.42–9.61). Targeted cytokine/chemokine levels demonstrated little variation with hypothermia treatment. Conclusion RANTES and MCP-1 levels in the first week of life may provide potential targets for future therapies among neonates with encephalopathy. Key Points

Relationship Between TNF-α and the Risk of Cerebral Palsy: A Systematic Review and Meta-Analysis

“…After screening the titles and abstracts and excluding duplicates, 22 remaining records seemed to be relevant to this study. After reviewing the full-text articles, nine articles ( 5 – 11 , 14 , 15 ) were included in this meta-analysis. The flowchart for the search and selection results is shown in Figure 1 .…”

“…In total 1,117 cases and 3,563 controls were eligible and included in this study; the sample size ranged from 74 participants ( 6 ) to 1,741 participants ( 15 ). All included studies were observational in nature, including three cohort studies ( 6 , 7 , 10 ), four case-control studies ( 5 , 8 , 9 , 14 ) and one randomized controlled trial ( 11 , 13 ). Four studies were conducted in the United States ( 8 , 10 , 11 , 14 ), two studies were conducted in Europe ( 6 , 7 ), one study was conducted in Australia, ( 15 ) and the others were conducted in China ( 5 , 9 ).…”

“…All included studies were observational in nature, including three cohort studies ( 6 , 7 , 10 ), four case-control studies ( 5 , 8 , 9 , 14 ) and one randomized controlled trial ( 11 , 13 ). Four studies were conducted in the United States ( 8 , 10 , 11 , 14 ), two studies were conducted in Europe ( 6 , 7 ), one study was conducted in Australia, ( 15 ) and the others were conducted in China ( 5 , 9 ). Of the five studies conducted at the beginning of the neonatal period before the diagnosis of CP, two collected blood samples from cord blood ( 6 , 14 ) and three from venous blood ( 8 , 10 , 11 ), and all four infant studies collected venous blood samples ( 5 , 7 , 9 , 15 ).…”

“…Four studies were conducted in the United States ( 8 , 10 , 11 , 14 ), two studies were conducted in Europe ( 6 , 7 ), one study was conducted in Australia, ( 15 ) and the others were conducted in China ( 5 , 9 ). Of the five studies conducted at the beginning of the neonatal period before the diagnosis of CP, two collected blood samples from cord blood ( 6 , 14 ) and three from venous blood ( 8 , 10 , 11 ), and all four infant studies collected venous blood samples ( 5 , 7 , 9 , 15 ). The methods used to assess TNF-α differed among the studies, two studies used Enzyme-linked Immunoassay (ELISA) ( 5 , 14 ), three studies used SNP analysis ( 7 , 9 , 15 ) and four used cytometry techniques, including Cytometric Bead Array (CBA) ( 6 ), Meso Scale Discovery (MSD) electrochemiluminescence system ( 8 , 10 ), Multiplex Luminex Assay ( 11 ).…”

“…The meta-analysis was performed with a random-effects model, and the pooled OR suggested a significant positive relationship between blood TNF-α levels and the risk of CP in children (pooled crude OR 1.82, 95% CI: 1.25–2.66, z = 3.11, p = 0.002) with high heterogeneity among the studies ( I 2 = 81.2%, p = 0.000) ( Figure 2 ). Nine studies evaluated the relationship between TNF-α and the risk of CP in children ( 5 – 11 , 14 , 15 ), and two reported no significant association ( 14 , 15 ).…”