Functional reconstruction of the basal ganglia neural circuit by human striatal neurons in hypoxic-ischaemic injured brain.

Perinatal hypoxic-ischaemic encephalopathy is the leading cause of neonatal death and permanent neurological deficits, while the basal ganglia is one of the major nuclei that is selectively and greatly affected in the brains of hypoxic-ischaemic encephalopathy patients, especially in severe cases. Human embryonic stem cell-derived neurons have shown great potential in different types of brain disorders in adults. However, it remains unknown whether and how grafted human embryonic stem cell-derived neurons can repair immature brains with hypoxic-ischaemic encephalopathy. Here, by administrating genetically labelled human embryonic stem cell-derived striatal neural progenitors into the ipsilateral striatum of hypoxic-ischaemic encephalopathy-injured mice, we found that the grafted cells gradually matured into GABA spiny projection neurons morphologically and electrophysiologically, and significantly rescued the area loss of hypoxic-ischaemic encephalopathy-injured brains. Intriguingly, using immunohistochemical staining combined with enhanced ascorbate peroxidase-based immunoelectron microscopy and rabies virus-mediated trans-synaptic tracing, we show that the grafts start to extend axonal projections to the endogenous target areas (globus pallidus externa, globus pallidus internus, substantia nigra), form synapses with host striatal, globus pallidus and nigra neurons, and receive extensive and stable synaptic inputs as early as 2 months post-transplantation. Importantly, we further demonstrated functional neural circuits re-established between the grafted neurons and host cortical, striatal and substantial nigra neurons at 3-6 months post-transplantation in the hypoxic-ischaemic encephalopathy-injured brain by optogenetics combined with electrophysiological recording. Finally, the transplanted striatal spiny projection neurons but not spinal GABA neurons restored the motor defects of hypoxic-ischaemic encephalopathy, which were reversed by clozapine-N-oxide-based inhibition of graft function. These findings demonstrate anatomical and functional reconstruction of the basal ganglia neural circuit including multiple loops by striatal spiny projection neurons in hypoxic-ischaemic encephalopathy-injured immature brains, which raises the possibility of such a cell replacement therapeutic strategy for hypoxic-ischaemic encephalopathy in neonates.

Apparent diffusion coefficient values can predict neuromotor outcome in term neonates with hypoxic-ischaemic encephalopathy.

AIM: To determine the apparent diffusion coefficient (ADC) in brain structures during the first 2 weeks of life and its relation with neurological outcome for hypoxic-ischaemic encephalopathy (HIE) in term neonates. METHODS: We retrospectively evaluated 56 term-born neonates. The ADC values were measured for 11 brain regions. The clinical outcomes at least 2 years of age were defined as normal outcome, mild disability and severe disability. The area under curves (AUCs) by ROC analysis were performed to predict the neurodevelopmental outcomes. The clinical outcomes were compared between favourable outcome and adverse outcome and also between normal outcome and unfavourable outcome. RESULTS: Thirty-four patients were judged as normal outcome, 10 as mild disability and 12 as severe disability. When the clinical outcomes were compared between favourable outcome and adverse outcome, the AUC on the 1st week was highest value at the thalamus. When the clinical outcomes were compared between normal outcome and unfavourable outcome, the AUC on the 1st week was highest at the thalamus. CONCLUSION: The ADC values in the thalamus in the 1st week can predict the neurological outcome. The ADC values in centrum semiovale on the 2nd week can be used to predict neurodevelopmental outcomes.

Higher parental education was associated with good cognitive outcomes in infants with hypoxic-ischaemic encephalopathy.

AIM: Predicting neurodevelopmental outcomes in hypoxic-ischaemic encephalopathy (HIE) remains imprecise, despite advanced imaging and neurophysiological tests. We explored the predictive value of socio-economic status (SES). METHODS: The cohort comprised 93 infants (59% male) with HIE, who had received therapeutic hypothermia. Patients underwent magnetic resonance imaging, and brain injuries were quantified using the Barkovich scoring system. Family SES was self-reported using a questionnaire. Adverse outcomes were defined as mild to severely delayed development with a score of ≤85 in any domain at 2 years of age, based on the Bayley Scales of Infant Development, Second Edition. Data are presented as odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Multiple regression modelling revealed that higher parental education was strongly associated with good cognitive development, when adjusted for gestational age, serum lactate and brain injuries (OR 2.20, 95% CI 1.16-4.36). The effect size of parental education (ß = 0.786) was higher than one score for any brain injury using the Barkovich scoring system (ß = -0.356). The literacy environment had a significant effect on cognitive development in the 21 infants who had brain injuries (OR 40, 95% CI 3.70-1352). CONCLUSION: Parental education and the literacy environment influenced cognitive outcomes in patients with HIE.

Abnormal expression and role of MicroRNA-214-3p/SLC8A1 in neonatal Hypoxic-Ischaemic encephalopathy.

Neonatal hypoxic-ischaemic encephalopathy (HIE) refers to brain damage caused by intra-uterine distress and asphyxia/hypoxia during the perinatal and neonatal periods. MicroRNA (MiR)-214-3p plays a critical role in cell growth and apoptosis. The aim of this study was to investigate the expression and role of miR-214-3p in neonatal HIE development, and to explore the underlying mechanisms. The expression of miR-214-3p was significantly down-regulated, while that of Slc8a1, a direct target of miR-214-3p, was significantly up-regulated, in the brain tissue of neonatal HIE rats. The over-expression of miR-214-3p promoted the proliferation and inhibited the apoptosis of neurones, while its down-regulation had the opposite effect. Our results indicate that miR-214-3p expression was down-regulated in neonatal HIE rats, and the up-regulation of miR-214-3p expression protected against HIE development by inhibiting neuronal apoptosis.

Outcomes in children after mild neonatal hypoxic ischaemic encephalopathy: A population-based cohort study.

OBJECTIVE: To investigate whether mild neonatal hypoxic ischaemic encephalopathy (HIE) in term born infants is associated with cerebral palsy, epilepsy, mental retardation and death up to 6 years of age. DESIGN: Population-based cohort study. SETTING: Sweden, 2009-2015. POPULATION: Live term born infants without congenital malformations or chromosomal abnormalities (n = 505 075). METHODS: Birth and health data were retrieved from Swedish national health and quality registers. Mild HIE was identified by diagnosis in either the Swedish Medical Birth Register or the Swedish Neonatal Quality Register. Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). MAIN OUTCOME MEASURES: A composite of the outcomes cerebral palsy, epilepsy, mental retardation and death up to 6 years of age. RESULTS: Median follow-up time was 3.3 years after birth. Of 414 infants diagnosed with mild HIE, 17 were classified according to the composite outcome and incidence rates were 12.6 and 2.9 per 1000 child-years in infants with and without HIE respectively. Infants with mild HIE was four times as likely to be diagnosed with the composite outcome (HR 4.42, 95% CI 2.75-7.12) compared with infants without HIE. When analysed separately, associations were found with cerebral palsy (HR 21.50, 95% CI 9.59-48.19) and death (HR 19.10, 95% CI 7.90-46.21). HRs remained essentially unchanged after adjustment for covariates. CONCLUSIONS: Mild neonatal HIE was associated with neurological morbidity and mortality in childhood. Challenges include identifying infants who may develop morbidity and how to prevent adverse outcomes.

Kidney outcomes in early adolescence following perinatal asphyxia and hypothermia-treated hypoxic-ischaemic encephalopathy.

BACKGROUND: Acute kidney injury (AKI) remains common among infants with hypothermia-treated hypoxic-ischaemic encephalopathy (HIE). Little is known about long-term kidney outcomes following hypothermia treatment. We recently reported that 21% of survivors of hypothermia-treated HIE had decreased estimated glomerular filtration rate (eGFR) based on plasma creatinine in early adolescence. Here, we assessed kidney functions more comprehensively in our population-based cohort of children born in Stockholm 2007-2009 with a history of hypothermia-treated HIE. METHODS: At 10-12 years of age, we measured cystatin C (cyst C) to estimate GFR. Children with decreased cyst C eGFR also underwent iohexol clearance examination. We measured urine-albumin/creatinine ratio, blood pressure (BP) and kidney volume on magnetic resonance imaging. Fibroblast growth factor 23 (FGF 23) levels in plasma were assessed by enzyme-linked immunosorbent assay (ELISA). Outcomes were compared between children with and without a history of neonatal AKI. RESULTS: Forty-seven children participated in the assessment. Two children (2/42) had decreased cyst C eGFR, for one of whom iohexol clearance confirmed mildly decreased GFR. One child (1/43) had Kidney Disease Improving Global Outcomes (KDIGO) category A2 albuminuria, and three (3/45) had elevated office BP. Subsequent ambulatory 24-h BP measurement confirmed high normal BP in one case only. No child had hypertension. Kidney volume and FGF 23 levels were normal in all children. There was no difference in any of the parameters between children with and without a history of neonatal AKI. CONCLUSION: Renal sequelae were rare in early adolescence following hypothermia-treated HIE regardless of presence or absence of neonatal AKI. A higher resolution version of the Graphical abstract is available as Supplementary information.

High incidence of poor in-hospital outcomes of term newborns with hypoxic-ischaemic encephalopathy admitted at a regional referral hospital in Dodoma, Tanzania.

AIM: Hypoxic-ischaemic encephalopathy (HIE) is one of the leading causes of neonatal deaths and neurological impairment with the highest impact in resource-limited settings. This study aimed to determine the incidence of poor in-hospital outcomes and related factors among newborns with HIE in Tanzania. METHODS: A prospective observational study in which 170 newborns with HIE (diagnosed using the Thompson clinical score) were followed from 1 September 2020 to 28 February 2021 at the neonatal ward of Dodoma Regional Referral Hospital in Dodoma, central Tanzania, until discharge or death. Clinical parameters were recorded. Multinomial logistic regression analysis was applied to determine factors associated with adverse outcomes. RESULTS: Out of 170 newborns, 44.7% (76/170) had poor outcomes (death 27.1% (46/170); neurological deficits 17.6% (30/170)). Severe HIE (Thompson score > 14) (p < 0.0001), history of aspiration (adjusted odds ratio (AOR) = 3.06, 95% confidence interval (CI) [1.170, 8.014], p = 0.0226) and 5th-min APGAR of <7 (AOR = 2.88, 95% CI [1.133, 7.310], p = 0.0262) were associated with mortality. Severe HIE, delivery at other facilities (AOR = 3.106 CI [1.158, 8.332], p = 0.0244) and abnormal heart rate (<100 or ≥160 beats/min) on admission (AOR = 3.469 [1.200, 10.030], p = 0.0216) predicted neurological impairment at discharge. CONCLUSION: Hypoxic-ischaemic encephalopathy is associated with a high incidence of poor outcomes in resource-limited settings. To improve outcomes newborns with severe HIE, history of aspiration, referred from other facilities, 5th-min APGAR score of <7 and abnormal heart rate need improved quality of neonatal care.

Cooling strategies during neonatal transport for hypoxic-ischaemic encephalopathy.

AIM: We reviewed the literature on cooling methods during transport of newborn infants with hypoxic-ischaemic encephalopathy (HIE) born in a non-tertiary centre and transferred to a neonatal intensive care unit for therapeutic hypothermia. METHODS: The electronic databases CENTRAL, MEDLINE, Embase, CINAHL, and Scopus were searched from inception up to 8 March 2022 for studies comparing cooling versus no cooling, active versus passive cooling, and servo-controlled versus non-servo-controlled cooling. Odds ratio and confidence of interval were calculated for dichotomous outcomes and mean difference and confidence interval for continuous outcomes. RESULTS: The final analysis included 14 studies, 1 randomised and 13 non-randomised, involving 1098 newborn infants. Compared with the other cooling methods, servo-controlled active cooling was more likely to maintain body temperature within the target range of 33°C-34°C on arrival at a neonatal intensive care unit: odds ratio 13.58, 95% confidence interval 4.32-42.66, risk difference 0.33, 95% confidence interval 0.19-0.46; 224 participants; three studies; I2 0%. The certainty of evidence was low. Only five studies reported mortality rates. CONCLUSION: Servo-controlled active cooling may be the preferred method during transport of newborn infants with HIE. A future area of focus should be long-term neurodevelopmental outcomes after servo-controlled active cooling.

Prolonged requirements for mechanical ventilation and tube feeding support predicted 18-month outcomes for neonatal encephalopathy.

AIM: We evaluated the predictive ability of prolonged requirements for mechanical ventilation or tube feeding support for 18-month composite outcomes in infants with hypoxic-ischaemic encephalopathy treated with hypothermia. METHODS: This retrospective, nationwide, observational study focused on newborn infants registered in Japan's Baby Cooling Registry between 1 January 2012 and 31 December 2016. The adverse outcomes were defined as death or survival with cerebral palsy, visual or auditory impairment or the requirement for mechanical ventilation or tube feeding at 18 months of age. RESULTS: Adverse outcomes occurred in 165 (28%) of the 591 children in the final cohort. These were predicted by prolonged dependence on mechanical ventilation or tube feeding for more than seven and more than 14 days. The respective values were positive predictive value 0.34 (95% CI 0.33-0.34) and 0.60 (95% CI 0.56-0.62), negative predictive value 0.97 (95% CI 0.91-0.99) and 0.93 (95% CI 0.90-0.95) and area under the curve 0.59 (95% CI 0.54-0.64) and 0.81 (95% CI 0.77-0.85). CONCLUSION: Prolonged dependence on mechanical ventilation or tube feeding for more than 14 days may be useful in predicting 18-month outcomes in newborn infants who have received therapeutic hypothermia.

Altered biventricular function in neonatal hypoxic-ischaemic encephalopathy: a case-control echocardiographic study.

BACKGROUND: In newborns with hypoxic-ischaemic encephalopathy, more profound altered right and left ventricular function has been associated with mortality or brain injury. Mechanisms underlying cardiac dysfunction in this population are thought to be related to the persistence of increased pulmonary vascular resistance and myocardial ischaemia. We sought to compare cardiac function in newborns with hypoxic-ischaemic encephalopathy to controls using echocardiography. METHODS: We did a retrospective case-control study with moderate or severe hypoxic-ischaemic encephalopathy between 2008 and 2017. Conventional and speckle-tracking echocardiography measures were extracted to quantify right and left ventricular systolic and diastolic function. Fifty-five newborns with hypoxic-ischaemic encephalopathy were compared to 28 controls. RESULTS: Hypoxic-ischaemic encephalopathy newborns had higher estimated systolic pulmonary pressure (62.5 ± 15.0 versus 43.8 ± 17.3 mmHg, p < 0.0001) and higher systolic pulmonary artery pressure/systolic blood pressure ratio [101 ± 16 (iso-systemic) versus 71 ± 27 (2/3 systemic range) %, p < 0.0001]. Tricuspid annular plane systolic excursion was decreased (7.5 ± 2.2 versus 9.0 ± 1.4 mm, p = 0.002), E/e' increased (7.9 ± 3.3 versus 5.8 ± 2.0, p = 0.01), and right ventricle-myocardial performance index increased (68.1 ± 21.5 versus 47.8 ± 9.5, p = 0.0001) in hypoxic-ischaemic encephalopathy. Conventional markers of left ventricle systolic function were similar, but e' velocity (0.059 ± 0.019 versus 0.070 ± 0.01, p = 0.03) and left ventricle-myocardial performance index were statistically different (77.9 ± 26.2 versus 57.9 ± 11.2, p = 0.001). The hypoxic-ischaemic encephalopathy group had significantly altered right and left ventricular deformation parameters by speckle-tracking echocardiography. Those with decreased right ventricle-peak longitudinal strain were more likely to have depressed left ventricle-peak longitudinal strain. CONCLUSION: Newborns with hypoxic-ischaemic encephalopathy have signs of increased pulmonary pressures and altered biventricular systolic and diastolic function.

Predictive utility of the fetal cerebroplacental ratio for hypoxic ischaemic encephalopathy, severe neonatal morbidity and perinatal mortality in late-preterm and term infants.

AIMS: The aim of this study was to evaluate the association of a low cerebroplacental ratio (CPR) with hypoxic ischaemic encephalopathy (HIE), severe neonatal morbidity (SNM) and perinatal mortality (PNM). METHODS: This was a retrospective cohort study of late-preterm and term births at Mater Mothers' Hospital, Brisbane, between 2016 and 2020. Study outcomes were HIE, PNM and SNM (a composite of severe acidosis, Apgar score less than four at 5 min, severe respiratory distress or need for significant cardiopulmonary resuscitation at birth). Univariate and multivariable logistic regressions were used to determine if a low CPR was associated with HIE, SNM or PNM. RESULTS: A total of 51 870 births met the inclusion criteria. Of these, 216 (0.42%) were complicated by HIE, 10 224 (19.7%) had SNM and 251 (0.48%) had PNM. Rates of low CPR (<10th and <5th centile) were significantly higher in the SNM cohort (20.1 and 13.2%, respectively) and PNM cohort (21.1 and 15.1%, respectively) compared to the overall cohort. A low CPR was associated with significantly increased adjusted odds for SNM but not for HIE or PNM. The area under the receiver operating characteristic curve for CPR <10th centile was greatest for SNM (0.768) and lowest for HIE (0.595). Predictive margins of a low CPR for HIE, SNM and PNM were significant only for SNM at late-preterm gestations. CONCLUSIONS: A low CPR is associated with increased odds of SNM in infants born >34 weeks' gestation but not for HIE or PNM.

Perinatal antecedents of moderate and severe neonatal hypoxic ischaemic encephalopathy: An Australian birth cohort study.

BACKGROUND: Neonatal hypoxic ischaemic encephalopathy (HIE) is the most common cause of encephalopathy in the neonatal period and carries a high risk of mortality and long-term morbidity. AIM: The aim of this study was to investigate key antecedents of moderate and severe HIE in a large contemporary birth cohort. METHODS: A retrospective cohort study of births meeting criteria was conducted between 2016 and 2020 at the Mater Mothers' Hospital, Brisbane, Australia. This is a quaternary perinatal centre and Australia's largest maternity hospital. Univariate and multivariate Firth logistic regression were used to account for imbalanced frequency classes between non-HIE and HIE groups. Maternal variables and intrapartum factors were investigated for associations with neonatal moderate and severe HIE. RESULTS: Overall, 133 of 46 041 (0.29%) infants were diagnosed with HIE: 77 (0.17%) with mild HIE and 56 (0.12%) with moderate/severe HIE. Nulliparity, type 1 diabetes mellitus and maternal intensive care unit admission were associated with increased odds of moderate/severe HIE. Intrapartum risk factors included emergency caesarean birth, emergency caesarean for non-reassuring fetal status or failure to process, intrapartum haemorrhage and an intrapartum sentinel event (shoulder dystocia, cord prolapse, uterine rupture and placental abruption). Neonatal risk factors included male sex, late preterm gestation (35+0 -36+6  weeks), Apgar score less than four at 5 min, severe respiratory distress requiring ventilatory support and severe acidosis at birth. CONCLUSIONS: This cohort study identified a series of potentially modifiable maternal and obstetric risk factors for HIE. Risk factors for HIE do not appear to have changed significantly with evolution in modern obstetric care.

Volumetric apparent diffusion coefficient (ADC) histogram analysis of the brain in paediatric patients with hypoxic ischaemic encephalopathy.

Purpose: To evaluate the whole brain, hippocampus, thalamus, and lentiform nucleus by volumetric apparent diffusion coefficient (ADC) histogram analysis in paediatric patients with hypoxic-ischaemic encephalopathy (HIE). Material and methods: This retrospective study included 25 patients with HIE and 50 patients as the control group. Diffusion-weighted imaging was obtained at b-values of 1000 mm2/s. The histogram parameters of ADC values, including the mean, minimum, maximum, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles, as well as skewness, kurtosis, and variance were determined. The interclass correlation coefficient (ICC) was used to assess the inter-observer agreement. Results: ADCmin, ADCmean, and ADCmax, as well as the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of ADC values for the HIE group were all lower than those of the control group (p < 0.001) in the volumetric histogram analysis of the hippocampus, thalamus, and lentiform nucleus. In the whole-brain histogram analysis, ADC min, and the 50th and 75th percentiles of ADC values did not differ significantly, while other parameters were lower in the HIE group. The ROC curve revealed that the ADC histogram parameters of the hippocampus provided the most accurate results for the diagnosis of HIE. The area under the curve (AUC) of the 95th percentile of ADC values was the highest (AUC = 0.915; cut-off 1.262 × 10-3 mm2/s; sensitivity 88% and specificity 84%). Conclusions: Volumetric ADC histogram analysis of the whole brain, hippocampus, thalamus, and lentiform nucleus with b-values of 1000 mm2/s can serve as an imaging marker for determining HIE.

Short-term morbidity and types of intrapartum hypoxia in the newborn with metabolic acidaemia: a retrospective cohort study.

OBJECTIVES: To assess labour characteristics in relation to the occurrence of Composite Adverse neonatal Outcome (CAO) within a cohort of fetuses with metabolic acidaemia. DESIGN: Retrospective cohort study. SETTING: Three Italian tertiary maternity units. POPULATION: 431 neonates born with acidaemia ≥36 weeks. METHODS: Intrapartum CTG traces were assigned to one of these four types of labour hypoxia: acute, subacute, gradually evolving and chronic hypoxia. The presence of CAO was defined by the occurrence of at least one of the following: Sarnat Score grade ≥2, seizures, hypothermia and death <7 days from birth. MAIN OUTCOME MEASURES: To compare the type of hypoxia on the intrapartum CTG traces among the acidaemic neonates with and without CAO. RESULTS: The occurrence of a CAO was recorded in 15.1% of neonates. At logistic regression analysis, the duration of the hypoxia was the only parameter associated with CAO in the case of an acute or subacute pattern (odds ratio [OR] 1.3; 95% CI 1.02-1.6 and OR 1.04; 95% CI 1.0-1.1, respectively), whereas both the duration of the hypoxic insult and the time from PROM to delivery were associated with CAO in those with a gradually evolving pattern (OR 1.13; 95% CI 1.01-1.3 and OR 1.04; 95% CI 1.0-1.7, respectively). The incidence of CAO was higher in fetuses with chronic antepartum hypoxia than in those showing CTG features of intrapartum hypoxia (64.7 vs. 13.0%; P < 0.001). CONCLUSIONS: The frequency of CAO seems related to the duration and the type of the hypoxic injury, being higher in fetuses showing CTG features of antepartum chronic hypoxia. TWEETABLE ABSTRACT: This study demonstrates that in a large population of neonates with metabolic acidaemia at birth, the overall incidence of short-term adverse outcome is around 15%. Such risk seems closely correlated to the duration and the type of hypoxic injury, being higher in fetuses admitted in labour with antepartum chronic hypoxia than those experiencing intrapartum hypoxia.

Review of a frugal cooling mattress to induce therapeutic hypothermia for treatment of hypoxic-ischaemic encephalopathy in the UK NHS.

Hypoxic ischaemic encephalopathy (HIE) is a major cause of neonatal mortality and disability in the United Kingdom (UK) and has significant human and financial costs. Therapeutic hypothermia (TH), which consists of cooling down the newborn's body temperature, is the current standard of treatment for moderate or severe cases of HIE. Timely initiation of treatment is critical to reduce risk of mortality and disability associated with HIE. Very expensive servo-controlled devices are currently used in high-income settings to induce TH, whereas low-income settings rely on the use of low-tech devices such as water bottles, ice packs or fans. Cooling mattresses made with phase change materials (PCMs) were recently developed as a safe, efficient, and affordable alternative to induce TH in low-income settings. This frugal innovation has the potential to become a reverse innovation for the National Health Service (NHS) by providing a simple, efficient, and cost-saving solution to initiate TH in geographically remote areas of the UK where cooling equipment might not be readily available, ensuring timely initiation of treatment while waiting for neonatal transport to the nearest cooling centre. The adoption of PCM cooling mattresses by the NHS may reduce geographical disparity in the availability of treatment for HIE in the UK, and it could benefit from improvements in coordination across all levels of neonatal care given challenges currently experienced by the NHS in terms of constraints on funding and shortage of staff. Trials evaluating the effectiveness and safety of PCM cooling mattresses in the NHS context are needed in support of the adoption of this frugal innovation. These findings may be relevant to other high-income settings that experience challenges with the provision of TH in geographically remote areas. The use of promising frugal innovations such as PCM cooling mattresses in high-income settings may also contribute to challenge the dominant narrative that often favours innovation from North America and Western Europe, and consequently fight bias against research and development from low-income settings, promoting a more equitable global innovation landscape.

Evolution of early cerebral NIRS in hypoxic ischaemic encephalopathy.

AIM: To describe early cerebral oxygenation (cSO2 ) and fractional tissue oxygen extraction (FTOE) values and their evolution over the first days of life in infants with all grades of hypoxic-ischaemic encephalopathy (HIE) and to determine whether cSO2 and FTOE measured early (6 and 12 h) can predict short-term outcome. METHODS: Prospective, observational study of cerebral near-infrared spectroscopy (NIRS) in infants >36 weeks' gestation with HIE. Ten one-hour epochs of cSO2 and FTOE were extracted for each infant over the first 84 h. Infants with moderate and severe HIE received therapeutic hypothermia (TH). Abnormal outcome was defined as abnormal magnetic resonance imaging (MRI) and/or death. RESULTS: Fifty-eight infants were included (28 mild, 24 moderate, 6 severe). Median gestational age was 39.9 weeks (IQR 38.1-40.7) and birthweight was 3.35 kgs (IQR 2.97-3.71). cSO2 increased and FTOE decreased over the first 24 h in all grades of HIE. Compared to the moderate group, infants with mild HIE had significantly higher cSO2 at 6 h (p = 0.003), 9 h (p = 0.009) and 12 h (p = 0.032) and lower FTOE at 6 h (p = 0.016) and 9 h (0.029). cSO2 and FTOE at 6 and 12 h did not predict abnormal outcome. CONCLUSION: Infants with mild HIE have higher cSO2 and lower FTOE than those with moderate or severe HIE in the first 12 h of life. cSO2 increased in all grades of HIE over the first 24 h regardless of TH status.

Profile of minor neurological findings after perinatal asphyxia.

AIM: To characterise the spectrum of findings in sequential neurological examinations, general movements (GM) assessment and magnetic resonance imaging (MRI) of infants with perinatal asphyxia. METHODS: The prospective cohort study of term infants with perinatal asphyxia treated at Helsinki University Hospital's neonatal units in 2016-2020 used Hammersmith Neonatal Neurological Examination (HNNE) and brain MRI at 2 weeks and Hammersmith Infant Neurological Examination (HINE) and GM assessment at 3 months of age. RESULTS: Analysis included 50 infants: 33 displaying perinatal asphyxia without hypoxic-ischaemic encephalopathy (HIE), seven with HIE1 and 10 with HIE2. Of the infants with atypical HNNE findings, 24/25 perinatal asphyxia without HIE cases, 5/6 HIE1 cases and all 10 HIE2 cases showed atypical findings in the HINE. The HINE identified atypical spontaneous movements significantly more often in infants with white matter T2 hyperintensity. CONCLUSION: In this cohort, most infants with perinatal asphyxia, with or without HIE, presented atypical neurological findings in sequential examinations. The profile of neurological findings for children with perinatal asphyxia without HIE resembled that of children with HIE. White matter T2 hyperintensity was associated with atypical spontaneous movements in the HINE and was a frequent MRI finding also in perinatal asphyxia without HIE.

Proteomic profiles in cerebrospinal fluid predicted death and disability in term infants with perinatal asphyxia: A pilot study.

AIM: Perinatal asphyxia, resulting in hypoxic-ischaemic encephalopathy (HIE), has been associated with high mortality rates and severe lifelong neurodevelopmental disabilities. Our aim was to study the association between the proteomic profile in cerebrospinal fluid (CSF) and the degree of HIE and long-term outcomes. METHODS: We prospectively enrolled 18-term born infants with HIE and 10-term born controls between 2000 and 2004 from the Karolinska University Hospital. An antibody suspension bead array and FlexMap3D analysis was used to characterise 178 unique brain-derived and inflammation associated proteins in their CSF. RESULTS: Increased CSF concentrations of several brain-specific proteins were observed in the proteome of HIE patients compared with the controls. An upregulation of neuroinflammatory pathways was also noted and this was confirmed by pathway analysis. Principal component analysis revealed a gradient from favourable to unfavourable HIE grades and outcomes. The proteins that provided strong predictors were structural proteins, including myelin basic protein and alpha-II spectrin. The functional proteins included energy-related proteins like neuron-specific enolase and synaptic regulatory proteins. Increased CSF levels of 51 proteins correlated with adverse outcomes in infants with HIE. CONCLUSION: Brain-specific proteins and neuroinflammatory mediators in CSF may predict HIE degrees and outcomes after perinatal asphyxia.

Acute kidney injury in infants with hypothermia-treated hypoxic-ischaemic encephalopathy: An observational population-based study.

AIM: To describe incidence and outcome of acute kidney injury (AKI) in infants with hypothermia-treated hypoxic-ischaemic encephalopathy (HIE). METHODS: This observational population-based study included all term and near-term infants with hypothermia-treated HIE born between 2007 and 2009 in greater Stockholm. The KDIGO definition modified for neonatal patients was used to identify infants with AKI. We analysed association between AKI and neonatal morbidity/mortality. Furthermore, we calculated estimated glomerular filtration rate (eGFR) at the age of 10-12 years. RESULTS: Out of 83,939 live births in the Stockholm region, 66 infants underwent hypothermia treatment due to HIE. Out of 65 included infants, 45% suffered AKI. Degree of AKI correlated with HIE severity. One infant needed kidney replacement therapy; others were treated conservatively. AKI was associated with increased mortality and need for blood products (p < 0.05). eGFR at age 10-12 years was available for 72% of survivors. Nine children (21%) had subnormal eGFR, with no difference between those with and without a history of neonatal AKI. CONCLUSION: Despite therapeutic hypothermia, AKI remains a common complication in infants with HIE and is associated with increased neonatal mortality. Twenty-one per cent of children had subnormal eGFR at 10-12 years, highlighting the need for long-term follow-up of renal function.

Haemodynamic impact of chest compressions in the delivery room.

Among 65 neonates with encephalopathy undergoing cooling, 30 (46.1%) received chest compressions during delivery room resuscitation. Despite differences in encephalopathy severity, early (<24 hours) biventricular function on echocardiogram (fractional area change, myocardial performance indices, systolic to diastolic duration ratios, tricuspid annular plane systolic excursion) was comparable between groups with and without chest compressions. Epinephrine receipt was associated with abnormal tricuspid annular plane systolic excursion.