General Supportive Management of the Term Infant with Neonatal Encephalopathy Following Intrapartum Hypoxia-Ischemia

The use of venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, for the management of depression in women of childbearing age has been on the rise, and there have been multiple case reports in the literature tying venlafaxine in-utero exposure to a form of neonatal encephalopathy presenting as neonatal abstinence syndrome. We present the case of a 5-day-old term infant whose mother was on venlafaxine throughout her pregnancy and presented with hypothermia, poor feeding, and decreased activity level. She subsequently had a negative sepsis workup and required nasogastric tube feedings for 2 weeks with spontaneous recovery and no clinical sequelae post-discharge. This case highlights the non-trivial potential risk of venlafaxine withdrawal in exposed newborns and the need for close observation. We propose a management framework for such situations in affected infants.

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HYPOXIC ISCHAEMIC ENCEPHALOPATHY IN NEWBORN INFANTS

Fetal and Maternal Medicine Review ◽

10.1017/s0965539510000069 ◽

2010 ◽

Vol 21 (3) ◽

pp. 242-262

Author(s):

NAZAKAT MERCHANT ◽

DENIS AZZOPARDI

Keyword(s):

Developing Countries ◽

Neonatal Period ◽

Newborn Infants ◽

Developed Countries ◽

Term Infant ◽

Significant Morbidity ◽

Neonatal Encephalopathy ◽

Infancy And Childhood ◽

Level Of Consciousness

Neonatal encephalopathy has been defined as “a clinically defined syndrome of disturbed neurological function in the earliest days of life in the term infant, manifested by difficulty with initiating and maintaining respiration, depression of tone and reflexes, sub normal level of consciousness and often seizures”. It occurs in about 2–3 per 1000 births in developed countries. In developing countries, neonatal encephalopathy accounts for the largest number of deaths in infancy and childhood – approximately 1 million per year worldwide. Neonatal encephalopathy is associated with significant morbidity and mortality and is an important predictor of long term neurodevelopmental disability in near- and full-term newborn infants. Fifteen to 20 percent of infants with neonatal encephalopathy die in the neonatal period, and a further 25 percent have permanent neurologic deficits.

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Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia–ischemia

Pediatric Research ◽

10.1038/s41390-021-01584-6 ◽

2021 ◽

Author(s):

Kathryn A. Martinello ◽

Christopher Meehan ◽

Adnan Avdic-Belltheus ◽

Ingran Lingam ◽

Tatenda Mutshiya ◽

...

Keyword(s):

Cell Death ◽

Microglial Activation ◽

Acute Infection ◽

Brain Cell ◽

Terminal Deoxynucleotidyl Transferase ◽

Resonance Spectroscopy ◽

List Type ◽

Neonatal Encephalopathy ◽

Perinatal Brain Injury ◽

Hypoxia Ischemia

Abstract Background Perinatal inflammation combined with hypoxia–ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown. Methods Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1–25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured. Results Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT. Conclusions We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI. Impact Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy. Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown. In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death. Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.

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Hypoxia-Ischemia Induced Age-Dependent Gene Transcription Effects at Two Development Stages in the Neonate Mouse Brain

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.587815 ◽

2020 ◽

Vol 13 ◽

Author(s):

Nicolas Dupré ◽

Céline Derambure ◽

Bérénice Le Dieu-Lugon ◽

Michelle Hauchecorne ◽

Yannick Detroussel ◽

...

Keyword(s):

Cholesterol Biosynthesis ◽

Statistical Significance ◽

Interleukin 1 ◽

Perinatal Period ◽

Term Infant ◽

Brain Lesions ◽

Term Infants ◽

Hypoxia Ischemia ◽

Age Dependent ◽

Micro Array

Human brain lesions in the perinatal period result in life-long neuro-disabilities impairing sensory-motor, cognitive, and behavior functions for years. Topographical aspects of brain lesions depend on gestational age at the time of insult in preterm or term infants and impaired subsequent steps of brain development and maturation. In mice, the Rice-Vannucci procedure of neonate hypoxia-ischemia (HI) was used at 5 days (P5) or P10, mimicking the development of 30 week-gestation fetus/preterm newborn, or full-term infant, respectively. Transcription response to HI was assessed at 3, 6, 12, and 24 h after insult, using micro-array technology. Statistical Pathway and Gene Ontology terms enrichments were investigated using DAVID®, Revigo® and Ingenuity Pathway Analysis (IPA®) to identify a core of transcription response to HI, age-specific regulations, and interactions with spontaneous development. Investigations were based on direction, amplitude, and duration of responses, basal expression, and annotation. Five major points deserve attention; (i) inductions exceeded repressions (60/40%) at both ages, (ii) only 20.3% (393/1938 records) were common to P5 and P10 mice, (iii) at P5, HI effects occurred early and decreased 24 h after insult whereas they were delayed at P10 and increased 24 h after insult, (iv) common responses at P5 and P10 involved inflammation, immunity, apoptosis, and angiogenesis. (v) age-specific effects occurred with higher statistical significance at P5 than at P10. Transient repression of 12 genes encoding cholesterol biosynthesis enzymes was transiently observed 12 h after HI at P5. Synaptogenesis appeared inhibited at P5 while induced at P10, showing reciprocal effects on glutamate receptors. Specific involvement of Il-1 (interleukin-1) implicated in the firing of inflammation was observed at P10. This study pointed out age-differences in HI responses kinetics, e.g., a long-lasting inflammatory response at P10 compared to P5. Whether the specific strong depression of cholesterol biosynthesis genes that could account for white matter-specific vulnerability at P5 or prevent delayed inflammation needs further investigation. Determination of putative involvement of Il-1 and the identification of upstream regulators involved in the delayed inflammation firing at P10 appears promising routes of research in the understandings of age-dependent vulnerabilities in the neonatal brain.

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7 Hypoglycaemia and Higher Levels of Homocysteine are Asscociated with Watershed and White Matter Injury in Neonatal Encephalopathy Following Hypoxia-Ischemia

Archives of Disease in Childhood ◽

10.1136/archdischild-2012-302724.0007 ◽

2012 ◽

Vol 97 (Suppl 2) ◽

pp. A2-A2

Author(s):

J. Harteman ◽

F. Groenendaal ◽

M. Benders ◽

A. Huisman ◽

H. Blom ◽

...

Keyword(s):

White Matter ◽

White Matter Injury ◽

Neonatal Encephalopathy ◽

Hypoxia Ischemia

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Magnesium as a Neuroprotective Agent: A Review of Its Use in the Fetus, Term Infant with Neonatal Encephalopathy, and the Adult Stroke Patient

Developmental Neuroscience ◽

10.1159/000484891 ◽

2018 ◽

Vol 40 (1) ◽

pp. 1-12 ◽

Cited By ~ 17

Author(s):

Ingran Lingam ◽

Nicola J. Robertson

Keyword(s):

Cerebral Palsy ◽

Magnesium Sulfate ◽

Low Cost ◽

Secondary Phase ◽

Term Infant ◽

Current Status ◽

Neonatal Encephalopathy ◽

Preterm Baby ◽

Neuroprotective Agent ◽

Neuroprotective Strategy

Magnesium is an intracellular cation essential for many en-zymatic processes and cellular functions. Magnesium sulfate acts as an endogenous calcium channel antagonist at neuronal synapses, thought to prevent excessive activation of N-methyl-D-aspartate receptors by excitatory amino acids, such as glutamate, and by downregulation of proinflammatory pathways. Early intervention is essential in the prevention of the secondary phase of neuronal injury. The immature brain is particularly prone to excitotoxicity, and inflammation has been strongly implicated in the pathogenesis of cerebral palsy. This article explores the current status of magnesium being used as an adjunct to hypothermia in term neonatal encephalopathy (NE) against a background of its use in other populations. There is some evidence for magnesium sulfate as a neuroprotective agent, however animal studies of NE at term equivalent age have been confounded by concomitant hypothermia induced by magnesium itself. Nevertheless, the combination of magnesium and cooling has been shown to be more effective than either treatment alone in adult rodents. In the preterm baby, magnesium sulfate given antenatally in threatened preterm labor has demonstrated a significant reduction in the risk of cerebral palsy at 2 years of age, though the benefit is not clear at school age. In adult clinical studies of ischemic and hemorrhagic stroke, there have been disappointing results for magnesium sulfate as a neuroprotective strategy. Importantly, clinical neurological scores may be affected by the increased hypotonia observed. We suggest that magnesium sulfate should be carefully re-evaluated as a neuroprotective agent given its favorable safety profile, relative low cost, and widespread availability.

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