Neonatal Encephalopathy: Need for Recognition of Multiple Etiologies for Optimal Management

Neonatal encephalopathy (NE) is associated with high mortality and morbidity. Factors predisposing to NE can be antenatal, perinatal, or a combination of both. Antenatal maternal factors, familial factors, genetic predisposition, hypoxic ischemic encephalopathy, infections, placental abnormalities, thrombophilia, coagulation defects, and metabolic disorders all have been implicated in the pathogenesis of NE. At present, therapeutic hypothermia is the only treatment available, regardless of etiology. Recognizing the etiology of NE involved can also guide investigations such as metabolic and sepsis workups to ensure optimal management. Understanding the etiology of NE may allow the development of targeted adjunctive therapies related to the underlying mechanism and develop preventative strategies

Is antenatal screening for syphilis still necessary?

Congenital syphilis continues to present a significant public health problem worldwide. The cornerstone of prevention of congenital syphilis is antenatal screening and treatment of affected mothers with penicillin. If untreated, symptoms develop within weeks or months. Early congenital syphilis occurs in children between 0 and 2 years old, however newborns may be asymptomatic and are only identified on routine screening. If such infants are missed and untreated, they can develop late congenital syphilis after 2 years. Syphilis is known as the “Great Imitator” and congenital syphilis can present as neurosyphilis, juvenile paresis, optic atrophy, blindness, progressive sensorineural deafness, dental and skeletal abnormalities

Fluidity of Equipoise in a Multi-Centred Pilot RCT:Influences on Clinician Decision-Making in Offering Trial Entry

Objectives: The embedded Qualitative Process Evaluation (QPE) within the CSTICH- Pilot RCT explored facilitators and barriers to recruitment within the Pilot. This study reports a secondary analysis of the overarching theme of Fluidity of Equipoise and the influences on individual and community clinical equipoise around the use of Emergency Cervical Cerclage (ECC). Study design: RCT recruitment assumes clinical equipoise and is defined as genuine uncertainty about an intervention. The ability of trial recruiters to convey this equipoise is also key to participant recruitment and fully informed consent. This exploratory qualitative process evaluation used semi-structured interviews with healthcare professionals (HCPs) involved in trial recruitment. Interviews were audio-recorded, transcribed, and analysed using codebook thematic analysis. Results: 23 HCPs were interviewed. Clinical equipoise around the use of ECC was variable and influenced by a multitude of factors including: (1) obstetric history; (2) gestation; (3) standard site practice, and (4) HCPs previous experiences of ECC. We have interpreted this variability as ‘fluidity of equipoise’. Conclusions: Clinical equipoise around complex pregnancy related conditions was fluid and influenced by the complexities of obstetric histories and gestation at presentation. Equipoise of HCPs involved in trial recruitment should be considered carefully as it can impact the nuances of recruitment, particularly in more challenging trials such as CSTICH-2. Study-specific documents and training can be used to increase staff and patient awareness of uncertainty in the evidence base for interventions under investigation. Further research is needed around the potential consequences of equipoise fluidity

Management of Multi Organ Dysfunction in Neonatal Encephalopathy.

Neonatal Encephalopathy (NE) describes neonates with disturbed neurological function in the first post-natal days of life. NE is an overall term that does not specify the etiology of the encephalopathy although it often involves hypoxia-ischaemia. In NE, although neurological dysfunction is part of the injury and is most predictive of long-term outcome, these infants may also have multiorgan injury and compromise, which further contribute to neurological impairment and long-term morbidities. Therapeutic hypothermia (TH) is the standard of care for moderate to severe NE. Infants with NE may have co-existing immune, respiratory, endocrine, renal, hepatic, and cardiac dysfunction that require individualized management and can be impacted by TH. Non-neurological organ dysfunction not only has a negative effect on long term outcome but may also influence the efficacy of treatments in the acute phase. Post resuscitative care involves stabilization and decisions regarding TH and management of multi-organ dysfunction. This management includes detailed neurological assessment, cardio-respiratory stabilization, glycaemic and fluid control, sepsis evaluation and antibiotics, seizure identification, and monitoring and responding to biochemical and coagulation derangements. The emergence of new biomarkers of specific organ injury may have predictive value and improve the definition of organ injury and prognosis. Further evidence-based research is needed to optimize management of NE, prevent further organ dysfunction and reduce neurodevelopmental impairment

Coagulation profiles are associated with early clinical outcomes in neonatal encephalopathy

Introduction: Neonatal encephalopathy (NE) is associated with coagulation abnormalities. We aimed to investigate the serial alterations in coagulation profiles in term infants with NE and correlate with their clinical outcomes. This was a prospective cohort study in a tertiary referral, university-affiliated maternity hospital. Neonates exposed to perinatal asphyxia were recruited (n = 82) and 39 received therapeutic hypothermia. Infants had serial coagulation tests including platelets, prothrombin time (PT), activated partial thromboplastin time (aPTT) and fibrinogen in the first week of life. The main outcome measures included MRI brain and EEG seizures. Our results show that mortality was predicted on day 1 by decreased Fibrinogen (AUC = 0.95, p = 0.009) and by PT on day 2 with a cutoff of 22 s. An abnormal MRI was predicted by Fibrinogen on day 3 with a cut-off value of 2 g/L. For prediction of grade II/III NE, PT on day 2 of life was strongest with a cut-off value of 14 s. Only elevated APTT levels on day 1 of life were predictive of seizures (AUC = 0.65, p = 0.04). Conclusion: Coagulation parameters are strong predictors of outcomes such as abnormal NE grade, seizures, and mortality

Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans

BACKGROUND: Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, while supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome and congenital anomalies. Inositol status may be influenced by diet, synthesis, transport, utilisation and catabolism. OBJECTIVES: We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites. METHODS: Gas chromatography mass spectrometry was used to determine plasma MI concentration of more than 2,000 healthy, young adults (aged 18-28 years) from the Trinity Student Study. Genotyping data was used to test association of plasma MI with SNPs in candidate genes, encoding inositol transporters and synthesising enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with D-chiro inositol, glucose and other metabolites by Spearman's rank correlation. RESULTS: Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 µM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11, encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (p < 5 × 10-8). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (p < 1 × 10-5), 3 of which were located within or close to genes: MTDH, LAPTM4B and ZP2. We found significant positive correlation of plasma MI concentration with concentration of D-chiro-inositol and several other biochemicals including glucose, methionine, betaine, sarcosine and tryptophan. CONCLUSION: Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11 which is worthy of further investigation

Complex spectrum of phenobarbital effects in a mouse model of neonatal hypoxia-induced seizures

Seizures in neonates, mainly caused by hypoxic-ischemic encephalopathy, are thought to be harmful to the brain. Phenobarbital remains the first line drug therapy for the treatment of suspected neonatal seizures but concerns remain with efficacy and safety. Here we explored the short- and long-term outcomes of phenobarbital treatment in a mouse model of hypoxia-induced neonatal seizures. Seizures were induced in P7 mice by exposure to 5% O-2 for 15 minutes. Immediately after hypoxia, pups received a single dose of phenobarbital (25 mg.kg(-1)) or saline. We observed that after administration of phenobarbital seizure burden and number of seizures were reduced compared to the hypoxic period; however, PhB did not suppress acute histopathology. Behavioural analysis of mice at 5 weeks of age previously subjected to hypoxia-seizures revealed an increase in anxiety-like behaviour and impaired memory function compared to control littermates, and these effects were not normalized by phenobarbital. In a seizure susceptibility test, pups previously exposed to hypoxia, with or without phenobarbital, developed longer and more severe seizures in response to kainic acid injection compared to control mice. Unexpectedly, mice treated with phenobarbital developed less hippocampal damage after kainic acid than untreated counterparts. The present study suggests phenobarbital treatment in immature mice does not improve the long lasting functional deficits induces by hypoxia-induced seizures but, unexpectedly, may reduce neuronal death caused by exposure to a second seizure event in later life