Abstract
Hypoxic-ischemic encephalopathy (HIE) remains an important cause of death and disability in newborns. Mild therapeutic hypothermia (TH) is safe and effective; however, there are no tissue biomarkers available at the bedside to select babies for treatment. The aim of this study was to show that it is feasible to study plasma neurofilament light (NfL) levels from newborns and to evaluate their temporal course. Hypothesis: Raised plasma NFL protein levels from newborns who undergo TH after HIE are associated with abnormal MRI outcomes. Between February 2014 and January 2016, term newborns with HIE treated with TH for 72 h had plasma samples taken at three time points: (i) after the infant had reached target temperature, (ii) prior to commencing rewarming, and (iii) after completing rewarming. Infants with mild HIE who did not receive TH had a single specimen taken. NfL protein was analyzed using an enzyme-linked immunosorbent assay. Twenty-six newborns with moderate-severe HIE treated with TH were studied. Half of these had cerebral MRI predictive of an unfavorable outcome. Plasma NfL levels were significantly higher in the TH group with unfavorable outcome (median age 18 h) compared to levels from both the mild HIE group and TH group with favorable outcome (F = 25.83, p < 0.0001). Newborns who had MRIs predictive of unfavorable outcome had significantly higher NfL levels compared to those with favorable outcomes, at all three time points (mixed models, F = 27.63, p < 0.001). A cutoff NfL level >29 pg/mL at 24 h is predictive of an unfavorable outcome [sensitivity 77%, specificity 69%, positive predictive value (PPV) 67%, negative predictive value (NPV) 72%] with increasing predictive value until after rewarming (sensitivity 92%, specificity 92%, PPV 92%, NPV 86%). Plasma NfL protein levels may be a useful biomarker of unfavorable MRI outcomes in newborns with moderate-severe HIE and may assist in selecting newborns for adjunctive neuroprotective interventions. Larger studies with NfL testing at earlier time points are required.
Highlights
Perinatal asphyxia in the newborn remains an important cause of death and of disability in survivors
We have investigated only the neurofilament light (NfL) subunit because researchers from our institution and others have shown that NfL levels are raised in neurologic conditions in which neuronal and axonal injury is important [11,12,13]
Our data suggest that plasma NfL is a potentially useful biomarker for predicting unfavorable MRI outcomes in newborns with moderate–severe hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH)
Summary
Perinatal asphyxia in the newborn remains an important cause of death and of disability in survivors. The resulting brain dysfunction and neonatal encephalopathy occurs in up to 4 per 1,000 live births in western countries [1, 2]. Mild therapeutic hypothermia (TH) treatment started within 6 h after birth, has been shown to be safe and effective in reducing death and disability, with numbers needed to treat (NNT) of 7–9 [3, 4]. Various compounds have been studied in the plasma, urine, and cerebrospinal fluid (CSF) as potential early biomarkers of CNS injury [8]. There are no established blood biomarkers available to assist early cot side identification of babies most likely to benefit from neuroprotection. A number of babies with hypoxic-ischemic encephalopathy (HIE) who do not fulfill empirical criteria and who do not receive TH are noted to have adverse outcomes [9]
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