How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

Abstract

Background: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear.

Methods: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years.

Results: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury.

Conclusion: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes.

Impact: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

Fig. 1. MRI severity of brain injury and Bayley Scales of Infant Development-III (BSID-III) outcomes.

BSID-III a cognitive, b language, and c motor scores at 2 years of age in relation to the severity of MRI brain injury, among survivors of moderate to severe HIE. Blue dots represent mean value. *Indicates that the 95% CI for the mean difference does not contain 0. Mean difference (95% confidence interval), adjusted for site, treatment, and HIE severity as follows: cognitive: mild vs. none: -1.7 (-5.0,1.7); moderate vs. none: -1.4 (-3.6,0.9); and severe vs. none: -8.1 (-10.2, -6.0). Language: mild vs. none: -1.2 (-5.7,3.4); moderate vs. none: -1.6 (-4.5,1.3); and severe vs. none: -7.7 (-10.3, -5.1). motor: mild vs. none: -2.3 (-5.5,0.8); moderate vs. none: -1.9 (-4.1,0.3); and severe vs. none: -9.4 (-11.7,-7.1).

Fig. 2. Thalamic MRS measures of brain injury and Bayley Scales of Infant Development-III (BSID-III) outcomes.

BSID-III 10 a cognitive, b language, and c motor scores at 2 years of age in relation to lactate/NAA and NAA/Cr ratio quartiles in the thalamus among survivors of moderate to severe HIE. Mean change (95% confidence interval) in BSID-III score per 0.1 unit increase in lactate/NAA ratio, adjusted for site, treatment, and HIE severity: cognitive score: -0.7 (-1.1, -0.4); language score -0.8 (-1.3, -0.3); motor score -1.0 (-1.4, -0.5). Mean change (95% confidence interval) in BSID-III score per 0.1 unit increase in NAA/Cr ratio, adjusted for site, treatment, and HIE severity: cognitive score: 3.6 (1.9,5.3); language score 4.7 (2.6,6.8); motor score 4.4 (2.5,6.3).

Fig. 3. Diagnostic AQ11 accuracy of MRI, MRS, and clinical severity of HIE as predictors of death or NDI at 2 years of age, among infants with moderate to severe HIE.

a Any injury is defined as MRI injury score >1; moderate/severe injury is defined as MRI injury score >11. b MRS measures are defined as top quartile of ratio vs. lower 3 quartiles of ratio values.