Placental contribution to neonatal encephalopathy.

Placental assessment, although currently underused, can inform our understanding of the etiology and timing of Neonatal Encephalopathy (NE). We review our current understanding of the links between placental dysfunction and NE and how this information may inform clinical decisions, now and in the future, emphasizing the four major placental lesions associated with NE. In addition, we discuss maternal and fetal factors that are hypothesized to contribute to specific placental pathologies, especially innate or acquired thrombophilias. We outline the importance of assessing placenta across trimesters and after delivery. As this field continues to evolve, currently available placental histopathological examination methods may need to be combined with advanced prenatal molecular and imaging assessments of placenta and be applied in well-designed studies in large representative populations to better define the links between placental dysfunction and NE.

Neonates with hypoxic-ischemic encephalopathy treated with hypothermia: Observations in a large Canadian population and determinants of death and/or brain injury.

BACKGROUND: Birth asphyxia in term neonates remains a serious condition that causes significant mortality and long-term neurodevelopmental sequelae despite hypothermia treatment. The objective of this study was to review therapeutic hypothermia practices in a large population of neonates with hypoxic-ischemic encephalopathy (HIE) across Canada and to identify determinants of adverse outcome. METHODS: Our retrospective observational cohort study examined neonates≥36 weeks, admitted to the Canadian Neonatal Network NICUs between 2010 and 2014, diagnosed with HIE, and treated with hypothermia. Adverse outcome was defined as death and/or brain injury. Maternal, birth, and postnatal characteristics were compared between neonates with adverse outcome and those without. The association between the variables which were significantly different (p < 0.05) between the two groups and adverse outcome were further tested, while adjusting for gestational age, birth weight, gender, and initial severity of encephalopathy. RESULTS: A total of 2187 neonates were admitted for HIE; 52% were treated with hypothermia and 40% developed adverse outcome. Initial severity of encephalopathy (moderate, p = 0.006; severe, p < 0.0001), hypotension treated with inotropes (p = 0.001), and renal failure (p = 0.007) were significantly associated with an increased risk of death and/or brain injury. CONCLUSIONS: In asphyxiated neonates treated with hypothermia, not only their initial severity of encephalopathy on admission, but also their cardiac and renal complications during the first days after birth were significantly associated with risk of death and/or brain injury. Careful monitoring and cautious management of these complications is warranted.

Brain Temperature Is Increased During the First Days of Life in Asphyxiated Newborns: Developing Brain Injury Despite Hypothermia Treatment.

BACKGROUND AND PURPOSE: Therapeutic hypothermia is the current treatment for neonates with hypoxic-ischemic encephalopathy. It is believed to work by decreasing the brain temperature and reducing the baseline metabolism and energy demand of the brain. This study aimed to noninvasively assess brain temperature during the first month of life in neonates with hypoxic-ischemic encephalopathy treated with hypothermia. MATERIALS AND METHODS: Neonates with hypoxic-ischemic encephalopathy treated with hypothermia and healthy neonates were enrolled prospectively. MR imaging was used to identify the presence and extent of brain injury. MR imaging multivoxel spectroscopy was used to derive brain temperatures in the basal ganglia and white matter at different time points during the first month of life. Brain temperature measurements were compared between neonates with hypoxic-ischemic encephalopathy and healthy neonates. RESULTS: Forty-three term neonates with hypoxic-ischemic encephalopathy treated with hypothermia had a total of 74 spectroscopy scans, and 3 healthy term neonates had a total of 9 spectroscopy scans during the first month of life. Brain temperatures were lower in neonates with hypoxic-ischemic encephalopathy during hypothermia, compared with the healthy neonates (respectively, on day 1 of life: basal ganglia, 38.81°C ± 2.08°C, and white matter, 39.11°C ± 1.99°C; and on days 2-3 of life: basal ganglia, 38.25°C ± 0.91°C, and white matter, 38.54°C ± 2.79°C). However, neonates with hypoxic-ischemic encephalopathy who developed brain injury had higher brain temperatures during hypothermia (respectively, on day 1 of life: basal ganglia, 35.55°C ± 1.31°C, and white matter, 37.35°C ± 2.55°C; and on days 2-3 of life: basal ganglia, 35.20°C ± 1.15°C, and white matter, 35.44°C ± 1.90°C) compared with neonates who did not develop brain injury (respectively, on day 1 of life: basal ganglia, 34.46°C ± 1.09°C, and white matter, 33.97°C ± 1.42°C; and on days 2-3 of life: basal ganglia, 33.90°C ± 1.34°C, and white matter, 33.07°C ± 1.71°C). Also, brain temperatures tended to remain slightly higher in the neonates who developed brain injury around day 10 of life and around 1 month of age. CONCLUSIONS: Therapeutic hypothermia using current guidelines decreased the brain temperature of neonates with hypoxic-ischemic encephalopathy during the first days of life but did not prevent an early increase of brain temperature in neonates with hypoxic-ischemic encephalopathy who developed brain injury despite this treatment.

Children born at 32 to 35 weeks with birth asphyxia and later cerebral palsy are different from those born after 35 weeks.

OBJECTIVE: The objectives of this study were to (1) establish the proportion of cerebral palsy (CP) that occurs with a history suggestive of birth asphyxia in children born at 32 to 35 weeks and (2) evaluate their characteristics in comparison with children with CP born at ⩾36 weeks with such a history. STUDY DESIGN: Using the Canadian CP Registry, children born at 32 to 35 weeks of gestation with CP with a history suggestive of birth asphyxia were compared with corresponding ⩾36 weeks of gestation children. RESULTS: Of the 163 children with CP born at 32 to 35 weeks and 738 born at ⩾36 weeks, 26 (16%) and 105 (14%) had a history suggestive of birth asphyxia, respectively. The children born at 32 to 35 weeks had more frequent abruptio placenta (35% vs 12%; odds ratio (OR) 4.1, 95% confidence interval (CI) 1.5 to 11.2), less frequent neonatal seizures (35% vs 72%; OR 0.20, 95% CI 0.08 to 0.52), more frequent white matter injury (47% vs 17%; OR 4.3, 95% CI 1.3 to 14.0), more frequent intraventricular hemorrhage (IVH) (40% vs 6%; OR 11.2, 95% CI 3.4 to 37.4) and more frequent spastic diplegia (24% vs 8%; OR 1.8, 95% CI 1.2 to 12.2) than the corresponding ⩾36 weeks of gestation children. CONCLUSIONS: Approximately 1 in 7 children with CP born at 32 to 35 weeks had a history suggestive of birth asphyxia. They had different magnetic resonance imaging patterns of injury from those born at ⩾36 weeks and a higher frequency of IVH. Importantly, when considering hypothermia in preterm neonates with suspected birth asphyxia, prospective surveillance for IVH will be essential.

Macrosomia and haemodynamic instability may represent risk factors for subcutaneous fat necrosis in asphyxiated newborns treated with hypothermia.

AIM: To identify additional risk factors other than asphyxia and hypothermia in newborns developing subcutaneous fat necrosis (SCFN). METHODS: We conducted a prospective cohort study of all term asphyxiated newborns treated with hypothermia from 2008 to 2015. The presence and location of SCFN were recorded at the time of discharge or at follow-up visits. To identify the risk factors for developing SCFN, we compared the perinatal characteristics of those newborns who developed SCFN with those who did not. RESULTS: The newborns developing SCFN had significantly higher birthweights compared with those newborns who did not develop SCFN. Among the newborns with a birthweight equal or superior to the 90th percentile, those who developed SCFN had a significantly higher use of inotropic support and higher maximum troponin levels during their initial hospitalisation. CONCLUSION: A higher birthweight represented an independent risk factor for developing SCFN in asphyxiated newborns treated with hypothermia. When macrosomia is present, other risk factors related to haemodynamic instability during the initial hospitalisation may also increase the risk of developing SCFN.

Injury to the Cerebellum in Term Asphyxiated Newborns Treated with Hypothermia.

BACKGROUND AND PURPOSE: Until now, most studies of brain injury related to term neonatal encephalopathy have focused on the cerebrum and ignored the cerebellum. We sought to evaluate whether cerebellar injury occurs in term asphyxiated neonates. MATERIALS AND METHODS: Asphyxiated neonates treated with hypothermia were enrolled prospectively. Severity of brain injury in the cerebrum was scored on each MR imaging obtained during the first month of life; cerebellar injury was recorded when mentioned in the imaging or autopsy report. In addition, for some of the neonates, the ADC and fractional anisotropy were measured in 4 regions of interest in the cerebellum. RESULTS: One hundred seventy-two asphyxiated neonates met the criteria for hypothermia. Cerebellar injury was visible only on conventional imaging of 4% of the neonates for whom brain imaging was available, but it was reported in the autopsy report of 72% of the neonates who died. In addition, 41 of the asphyxiated neonates had a total of 84 ADC and fractional anisotropy maps. Neonates with brain injury described only in the cerebrum demonstrated ADC and fractional anisotropy changes similar to those of the neonates with brain injury in the cerebrum and cerebellum--increased ADC around day 10 of life and decreased fractional anisotropy on day 2-3 of life, around day 10 of life, and around 1 month of age. CONCLUSIONS: The cerebellum may be injured in term neonates after birth asphyxia. These cerebellar injuries are only rarely visible on conventional imaging, but advanced neuroimaging techniques may help to identify them.

Placental pathology in asphyxiated newborns treated with therapeutic hypothermia.

OBJECTIVE: To describe the placental findings in asphyxiated newborns treated with hypothermia and to determine their association with the presence and severity of later brain injury. METHODS: Prospective cohort study of the placentas of asphyxiated newborns treated with hypothermia, in whom later brain injury was defined by brain imaging and/or autopsy results. RESULTS: Of the 142 asphyxiated newborns meeting the criteria for hypothermia, 73% had placenta and brain MRI/autopsy available for analysis. Fifty-one percent of these newborns developed brain injury. Sixty-five percent had microscopic placental findings involving the fetal vascular supply, which were comparable in asphyxiated newborns developing or not developing brain injury. Among the asphyxiated newborns with normal placental growth, the placental microscopic findings tended to be more common in those developing brain injury compared to those who did not: chorionic plate meconium in 50% compared to 36%, chorioamnionitis in 75% compared to 44%, and villitis of unknown etiology in 67% compared to 33%, but this did not reach statistical significance. CONCLUSIONS: Antenatal placental processes are common in term asphyxiated newborns treated with hypothermia. The placenta of each asphyxiated term newborn treated with hypothermia should be carefully examined to better understand its role in the progression from perinatal depression to brain injury.

Near-infrared spectroscopy versus magnetic resonance imaging to study brain perfusion in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

BACKGROUND: The measurement of brain perfusion may provide valuable information for assessment and treatment of newborns with hypoxic-ischemic encephalopathy (HIE). While arterial spin labeled perfusion (ASL) magnetic resonance imaging (MRI) provides noninvasive and direct measurements of regional cerebral blood flow (CBF) values, it is logistically challenging to obtain. Near-infrared spectroscopy (NIRS) might be an alternative, as it permits noninvasive and continuous monitoring of cerebral hemodynamics and oxygenation at the bedside. OBJECTIVE: The purpose of this study is to determine the correlation between measurements of brain perfusion by NIRS and by MRI in term newborns with HIE treated with hypothermia. DESIGN/METHODS: In this prospective cohort study, ASL-MRI and NIRS performed during hypothermia were used to assess brain perfusion in these newborns. Regional cerebral blood flow (CBF) values, measured from 1-2 MRI scans for each patient, were compared to mixed venous saturation values (SctO2) recorded by NIRS just before and after each MRI. Analysis included groupings into moderate versus severe HIE based on their initial background pattern of amplitude-integrated electroencephalogram. RESULTS: Twelve concomitant recordings were obtained of seven neonates. Strong correlation was found between SctO2 and CBF in asphyxiated newborns with severe HIE (r=0.88; p value=0.0085). Moreover, newborns with severe HIE had lower CBF (likely lower oxygen supply) and extracted less oxygen (likely lower oxygen demand or utilization) when comparing SctO2 and CBF to those with moderate HIE. CONCLUSIONS: NIRS is an effective bedside tool to monitor and understand brain perfusion changes in term asphyxiated newborns, which in conjunction with precise measurements of CBF obtained by MRI at particular times, may help tailor neuroprotective strategies in term newborns with HIE.

Brain perfusion in asphyxiated newborns treated with therapeutic hypothermia.

BACKGROUND AND PURPOSE: Induced hypothermia is thought to work partly by mitigating reperfusion injury in asphyxiated term neonates. The purpose of this study was to assess brain perfusion in the first week of life in these neonates. MATERIALS AND METHODS: In this prospective cohort study, MR imaging and ASL-PI were used to assess brain perfusion in these neonates. We measured regional CBF values on 1-2 MR images obtained during the first week of life and compared these with values obtained in control term neonates. The same or later MR imaging scans were obtained to define the extent of brain injury. RESULTS: Eighteen asphyxiated and 4 control term neonates were enrolled; 11 asphyxiated neonates were treated with hypothermia. Those developing brain injury despite being treated with induced hypothermia usually displayed hypoperfusion on DOL 1 and then hyperperfusion on DOL 2-3 in brain areas subsequently exhibiting injury. Asphyxiated neonates not treated with hypothermia who developed brain injury also displayed hyperperfusion on DOL 1-6 in brain areas displaying injury. CONCLUSIONS: Our data show that ASL-PI may be useful for identifying asphyxiated neonates at risk of developing brain injury, whether or not hypothermia is administered. Because hypothermia for 72 hours may not prevent brain injury when hyperperfusion is found early in the course of neonatal hypoxic-ischemic encephalopathy, such neonates may be candidates for adjustments in their hypothermia therapy or for adjunctive neuroprotective therapies.

Interobserver variability in assessment of cranial ultrasound in very preterm infants.

BACKGROUND: Cranial ultrasound (cUS) findings help doctors in the clinical management of preterm infants and in their discussion with parents regarding prediction of outcome. cUS is often used as outcome measure in clinical research studies. Accurate cUS performance and interpretation is therefore required. AIMS: The aims of this study were (i) to assess the interobserver variability in cUS interpretation, and (ii) to evaluate whether level of cUS expertise influences the interobserver variability. METHODS: Fifty-eight cUS image series of preterm infants born below 32 weeks of gestation collected within the Swiss Neonatal Network were sent to 27 observers for reviewing. Observers were grouped into radiologists, experienced neonatologists and less experienced neonatologists. Agreement between observers was calculated using Kappa statistics. RESULTS: When cystic periventricular leukomalacia, intraventricular haemorrhage and periventricular haemorrhagic infarction were combined to one outcome, agreement among all observers was moderate. When divided into subgroups, kappa for the combined outcome was 0.7 for experienced neonatologists, 0.67 for radiologists and 0.53 for inexperienced neonatologists. Marked difference in interobserver agreement between experienced neonatologists and radiologists could be found for haemorrhagic periventricular ifraction (HPI). CONCLUSIONS: Our results suggest that interobserver agreement for interpretation of cUS varies from poor to good varying with the type of abnormality and level of expertise, suggesting that widespread structured training should be made available to improve the performance and interpretation of cUS.

Perfusion abnormalities in hemimegalencephaly.

INTRODUCTION: Cerebrovascular changes are rarely discussed in patients with hemimegalencephaly. These alterations have previously been associated with epileptical activity. CASE: We report the case of a 36-week gestation neonate presenting with total right hemimegalencephaly, as demonstrated by a magnetic resonance imaging (MRI) performed in the first days of life. Perfusion-weighted imaging displayed a clear hypervascularization of the right hemisphere. Diffusion-tensor imaging showed an arrangement of white matter fibers concentrically around the ventricle on the right hemisphere. AngioMRI showed an obvious asymmetry in the size of the middle cerebral arteries, with the right middle cerebral artery being prominent. The baby was free of clinical seizures during his first week of life. An electroencephalogram at that time displayed an asymmetric background activity, but no electrical seizures. CONCLUSION: Perfusion anomalies in hemimegalencephaly may not necessarily be related to epileptical activity, but may be related to vessel alterations.

Progressive unilateral hemispheric atrophy in an infant with neurofibromatosis.

INTRODUCTION: Cerebrovascular diseases are rarely seen in neurofibromatosis type 1. These include vascular occlusive disease, moyamoya vessels, aneurysms, arteriovenous malformations and fistulae. CASE REPORT: We describe the case of an infant with genetically proven neurofibromatosis type 1 and progressive brain hemiatrophy over months, due to primary narrowing of intracranial carotid artery branches, as demonstrated by successive brain imaging. She presented with refractory seizures and a progressive hemiparesis associated with developmental delay. Surgical material from hemispherotomy done at 18 months showed severe abnormalities of the small vessels. CONCLUSION: Cerebrovascular changes seen in neurofibromatosis can be diffuse and progressive, with secondary hemiparesis, epilepsy and developmental delay.