Alterations in the Stool Microbiome in Newborns Undergoing Mild Therapeutic Hypothermia after Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is associated with brain injury in newborns and may lead to disability or death. Mild therapeutic hypothermia (TH) is an effective neuroprotective intervention and an established standard of care in western countries. The gut microbiome, the genomic and physicochemical contribution of the gut microbiota, serves important functions and is increasingly recognized as a major influencer on development. The impact of HIE and TH on the evolving gut microbiota of the newborn remains to be elucidated. OBJECTIVE: The objective of this study was to carry out an exploratory study on the effects of HIE and TH on the gut microbiome in term neonates. METHODS AND RESULTS: Stool samples were obtained from 28 newborns with HIE (median age 68 h) undergoing TH on the neonatal unit (HIE TH group), with a follow-on stool sample available for 20 of these babies (median age 151 h). For comparison, a single stool specimen was obtained from 19 healthy newborns on the postnatal ward (median age 34 h). The microbiota composition was determined using established microbial DNA extraction and 16S rRNA gene sequencing methodology. There was no difference in the mode of delivery or the method of feeding the newborns, once established, between the 2 groups. All the infants in the HIE TH group had received antibiotics compared to only one of the controls. A lower α-diversity, quantified by the Shannon diversity index, was noted in the microbiota of the HIE TH group in comparison to the control group. The HIE TH group had a higher mean relative abundance (MRA) of facultative anaerobes and aerobes such as Staphylococcus species and a lower MRA of strict anaerobes, such as members of the Bacteroides genus, compared to the control. Also, there was a significant reduction in the MRA of the genus Bifidobacterium in the HIE TH group. Although the mode of delivery exerts a profound influence on the gut microbiota of the newborn, distance-based redundancy analysis showed that TH may exert an independent influence. This study could not determine the independent contribution of the use of antibiotics or the neonatal intensive care unit environment. CONCLUSION: In this study, we demonstrate an alteration in the microbiota composition in newborns undergoing TH for HIE.

In clinical practice, cerebral MRI in newborns is highly predictive of neurodevelopmental outcome after therapeutic hypothermia.

OBJECTIVE: In the trials, a substantial proportion of newborns who underwent therapeutic hypothermia (TH) had an adverse outcome after hypoxic-ischaemic encephalopathy (HIE). Cooled babies were noted to have fewer cerebral lesions on MRI but when present lesions were predictive of adverse outcome. We investigate the predictive value of cerebral MRI in babies who undergo cooling in the clinical setting outside of the clinical trials in a prospective UK cohort. RESULTS: Of 75 babies recruited from four centres, neurodevelopment was available for 69 (92%) with 29% (20/69) being abnormal. The unfavourable MRI group (n = 22) had significantly lower motor (p < 0.001), language (p < 0.001) and cognition (p < 0.001) scores on Bayley-III assessment, compared to the favourable MRI group (n = 47). On multiple regression there was a significant relationship between basal ganglia and thalami abnormality and motor (p = 0.002), cognition (p = 0.011) and language (p = 0.013) outcomes. Half of the babies who had an MRI predictive of adverse outcome (11/22) had highest grade cerebral palsy. Cerebral MRI had 95% sensitivity, 94% specificity, 91% PPV and 98% NPV in predicting neurodevelopment. CONCLUSIONS: In this clinical cohort, fewer children had adverse neurodevelopment after TH compared to the TH trials. However, half the children who had an MRI predictive of adverse ND outcome had the most severe form of cerebral palsy. In this cohort, cerebral MRI was found to be highly predictive of neurodevelopmental outcome.

WITHDRAWN: In clinical practice, cerebral MRI in newborns is highly predictive of neurodevelopmental outcome after therapeutic hypothermia.

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Raised Plasma Neurofilament Light Protein Levels Are Associated with Abnormal MRI Outcomes in Newborns Undergoing Therapeutic Hypothermia.

AIMS AND HYPOTHESIS: 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. METHODS: 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. RESULTS: 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%). INTERPRETATION OF RESEARCH: 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.

Validation study of the accuracy of echocardiographic measurements of systemic blood flow volume in newborn infants.

BACKGROUND: The echocardiographic assessment of circulatory function in sick newborn infants has the potential to improve patient care. However, measurements are prone to error and have not been sufficiently validated. Phase-contrast magnetic resonance imaging (MRI) provides highly validated measures of blood flow and has recently been applied to the newborn population. The aim of this study was to validate measures of left ventricular output and superior vena caval flow volume in newborn infants. METHODS: Echocardiographic and MRI assessments were performed within 1 working day of each other in a cohort of newborn infants. RESULTS: Examinations were performed in 49 infants with a median corrected gestational age at scan of 34.43 weeks (range, 27.43-40 weeks) and a median weight at scan of 1,880 g (range, 660-3,760 g). Echocardiographic assessment of left ventricular output showed a strong correlation with MRI assessment (R(2) = 0.83; mean bias, -9.6 mL/kg/min; limits of agreement, -79.6 to +60.0 mL/kg/min; repeatability index, 28.2%). Echocardiographic assessment of superior vena caval flow showed a poor correlation with MRI assessment (R(2) = 0.22; mean bias, -13.7 mL/kg/min; limits of agreement, -89.1 to +61.7 mL/kg/min; repeatability index, 68.0%). Calculating superior vena caval flow volume from an axial area measurement and applying a 50% reduction to stroke distance to compensate for overestimation gave a slightly improved correlation with MRI (R(2) = 0.29; mean bias, 2.6 mL/kg/min; limits of agreement, -53.4 to +58.6 mL/kg/min; repeatability index, 54.5%). CONCLUSIONS: Echocardiographic assessment of left ventricular output appears relatively robust in newborn infant. Echocardiographic assessment of superior vena caval flow is of limited accuracy in this population, casting doubt on the utility of the measurement for diagnostic decision making.