Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study.

OBJECTIVE: To evaluate associations between neurologic outcomes and early measurements of basal ganglia (BG) and thalamic (Th) perfusion using color Doppler ultrasonography (CDUS) in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Prospective study of infants with mild (n = 18), moderate (n = 17), and severe HIE (n = 14) and controls (n = 17). Infants with moderate-severe HIE received therapeutic hypothermia (TH). CDUS was performed at 24-36 hours and brain magnetic resonance imaging (MRI) at a median of 10 days. Development was followed through 2.5-5 years. The primary outcome was the association between BG and Th perfusion and brain MRI injury. Secondary analyses focused on associations between perfusion measurements and admission neurologic examinations, MRI scores in infants treated with TH, and motor and sensory disability, or death. An exploratory analysis assessed the accuracy of BG and Th perfusion to predict brain MRI injury in infants treated with TH. RESULTS: Increased BG and Th perfusion on CDUS was observed in infants with severe MRI scores and those with significant motor and neurosensory disability or death through 2.5-5 years (P < .05). Infants with severe HIE showed increased BG and Th perfusion (P < .005) compared with infants with moderate HIE. No differences were identified between the between the control and mild HIE groups. Th perfusion ≥0.237 cm/second (Area under the curve of 0.824) correctly classified 80% of infants with severe MRI scores. CONCLUSIONS: Early dynamic CDUS of the BG and Th is a potential biomarker of severe brain injury in infants with HIE and may be a useful adjunct to currently used assessments.

Variations in medical practice of retinopathy of prematurity among 8 Asian countries from an international survey.

Advances in perinatal care have led to the increased survival of preterm infants with subsequent neonatal morbidities, such as retinopathy of prematurity (ROP). This study aims to compare the differences of neonatal healthcare systems, resources, and clinical practice concerning ROP in Asia with review of current literature. An on-line survey at the institutional level was sent to the directors of 336 neonatal intensive care units (NICU) in 8 collaborating national neonatal networks through the Asian Neonatal Network Collaboration (AsianNeo). ROP screening was performed in infants born at < 34 weeks in Indonesia and Japan. In South Korea, Malaysia, and Taiwan, most screened for ROP in infants born at < 32 weeks. In all networks, majority of NICUs conducted ROP screening to infants with birth weight < 1500 g. In most NICU's in-hospital ophthalmologists performed indirect ophthalmoscopy and some were supplemented with digital imaging. Both laser photocoagulation and anti-vascular endothelial growth factor injection are performed for treatment and, vitreous surgeries are conducted less frequently in all countries. Despite limited information collected by the survey, this first study to compare ROP practices implemented in eight Asian countries through AsianNeo will enable an understanding of the differences and facilitate quality improvement by sharing better practices.

Associations between UGT1A1 and SLCO1B1 polymorphisms and susceptibility to neonatal hyperbilirubinemia in Thai population.

Hyperbilirubinemia is the main mechanism that causes neonatal jaundice, and genetics is one of the risk factors of hyperbilirubinemia. Therefore, this study aims to explore the correlation between two genes, UGT1A1 and SLCO1B1, and hyperbilirubinemia in Thai neonates. One hundred thirty seven neonates were recruited from Division of Clinical Chemistry, Ramathibodi Hospital. UGT1A1*28 and *6 were determined by pyrosequencing whereas, SLCO1B1 388A > G and 521 T > C genetic variants were determined by TaqMan® real-time polymerase chain reaction. Neonates carrying with homozygous (AA) and heterozygous (GA) variants in UGT1A1*6 were significantly related to hyperbilirubinemia development compared with wild type (GG; P < 0.001). To the combined of UGT1A1, total bilirubin levels in homozygous variant were higher significantly than heterozygous variant and wild type (P = 0.002, P = 0.003, respectively). Moreover, SLCO1B1 combination was significant differences between the hyperbilirubinemia and the control group (P = 0.041). SLCO1B1 521 T > C variant provide protection for Thai neonatal hyperbilirubinemia (P = 0.041). There are no significant differences in UGT1A1*28 and SLCO1B1 388A > G for the different severity of hyperbilirubinemia. The combined UGT1A1*28 and *6 polymorphism is a strong risk factor for the development of severe hyperbilirubinemia in Thai neonates. Therefore, we suggest neonates with this gene should be closely observed to avoid higher severities of bilirubin.

Epidermolysis Bullosa With Congenital Absence of Skin: Congenital Corneal Cloudiness and Esophagogastric Obstruction Including Extended Genotypic Spectrum of PLEC, LAMC2, ITGB4 and COL7A1.

Epidermolysis bullosa (EB) is a rare and genetically heterogeneous disorder characterized by skin fragility and blister formation occurring spontaneously or after minor trauma. EB is accompanied by congenital absence of skin (EB with CAS) in some patients. Pathogenic variants of COL7A1 are responsible for EB with CAS in the vast majority of cases. Type and subtype diagnosis of EB with CAS generally requires specific immunohistological examinations that are not widely available plus targeted gene analysis. The present study aimed to determine the clinical features of five patients affected by EB with CAS and to identify the underlying genetic defects using whole exome sequencing (WES) followed by focused analysis of the target genes. Four patients had generalized skin involvement and one had localized defects. Two patients exhibited extremely severe skin manifestations and congenital cloudy cornea along with pyloric atresia, and one had partial esophagogastric obstruction and anuria due to vesicoureteric obstruction. In the WES analysis, the average coverage of the target exons was 99.05% (726 of 733 exons), with a range of 96.4-100% for individual genes. We identified four novel and two known pathogenic/likely pathogenic variants of five distinct genes in the examined families: PLEC:c.2536G > T (p.Glu846Ter); LAMC2:c.3385C > T (p.Arg1129Ter); KRT5:c.429G > A (p.Glu477Lys); ITGB4:c.794dupC (p.Ala266SerfsTer5); COL7A1:c.5440C > T (p.Arg1814Cys); and COL7A1:c.6103delG. All alleles were inherited from the parents, except for the KRT5 variant as a de novo finding. The findings reveal extremely rare phenotypes found in EB with CAS, namely congenital cloudy cornea, esophagogastric obstruction, and anuria, and extend the genotypic spectrum of EB-related genes. The data confirm that WES provides very high coverage of coding exons/genes and support its use as a reasonable alternative method for diagnosis of EB. The present data from an underrepresented population in Southeast Asia could further broaden the knowledge and research on EB.

Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months.

BACKGROUND: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking. OBJECTIVE: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study. STUDY DESIGN: Multicenter, prospective study of mild HIE defined as ≥1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or ≥85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5. RESULTS: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 ± 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001). CONCLUSIONS: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months.

Determination of plasma Levetiracetam level by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS-MS) and its application in pharmacokinetics studies in neonates.

BACKGROUND: Levetiracetam (LEV) is an antiepileptic drug which has good safety and efficacy in neonatal seizure (NS), a common incident in neonates with weight <1500 g. The pharmacokinetics for LEV in neonatal populations is yet to be clearly understood. In this study, we developed and validated a method for determination of LEV in plasma by liquid chromatography tandem mass spectrometry for the purpose of pharmacokinetic study. METHODS: Plasma LEV was spiked with Lamivudine as internal standard before extraction by C18 solid-phase extraction (SPE) cartridge. Chromatography was performed using isocratic elution with mobile phase A: B (10: 90) for 2.0 min with flow rate 0.4 mL/min. The mobile phase was composed of 0.1% formic acid in 10.0 mM ammonium acetate (A) and 100% methanol (B). The injection volume was 1.0 µL and the total run time was 2.0 min. Multiple reaction monitoring (MRM) with electro spray in positive mode was used. The mass transition for LEV was 171.2/126.0 and 230.0/112.0 for IS with retention time of 0.73 and 0.72 min, respectively. RESULTS: A calibration curve range from 0.50-80.0 µg/mL was obtained with a correlation coefficient >0.99 in the quadratic model. Precision and accuracy was within the acceptable range and the intra- and inter-day %CV for three concentrations of QCs were <10%. CONCLUSION: This method was reliable, accurate and applicable for LEV pharmacokinetic study in neonates with seizure.

Intestinal ultrasonography in infants with moderate or severe hypoxic-ischemic encephalopathy receiving hypothermia.

BACKGROUND: Infants with hypoxic-ischemic encephalopathy (HIE) may develop multiorgan dysfunction, but assessment of intestinal involvement is imprecise and based on nonspecific clinical signs that may occur several days later. Ultrasound imaging has been described as a helpful tool in assessing intestinal involvement in many gastrointestinal disorders. OBJECTIVE: Describe abdominal ultrasonography findings in infants receiving therapeutic hypothermia and investigate its association with the severity of the hypoxic-ischemic insult and death. MATERIALS AND METHODS: Studies were performed within the first 36 h of life to assess intestinal appearance (normal bowel, bowel wall echogenicity and thickness, and sloughed mucosa), free fluid, peristalsis and intramural perfusion. These findings were compared between infants with moderate and severe encephalopathy. Ultrasound findings were also categorized in three major groups and compared with markers of severity of the hypoxic-ischemic insult and with mortality. RESULTS: Nineteen infants with moderate and 9 with severe HIE at admission were studied (17.7 ± 9.5 h of life). Major ultrasonography findings were increased bowel wall echogenicity (78%), free fluid (75%), decreased or absent peristalsis (50%) and sloughing of the intestinal mucosa (21%). Abnormal intestinal findings such as increased bowel wall echogenicity in all quadrants and presence of sloughed mucosa were associated with more severe hypoxic-ischemic insult. All 12 patients with normal bowel appearance or increased bowel wall echogenicity restricted to only one quadrant survived, whereas 7/15 (47%) patients with increased bowel wall echogenicity in all four quadrants died during hospitalization. The presence of sloughed mucosa was associated with increased mortality (P < 0.001). CONCLUSION: In infants receiving therapeutic hypothermia, a high prevalence of intestinal involvement was noted by using ultrasonographic assessment. An association between intestinal findings and severity of hypoxic-ischemic insult was observed. The presence of sloughed mucosa is a potential ultrasonographic sign of severity.

Serum calcium concentrations and incidence of hypocalcemia in infants with moderate or severe hypoxic-ischemic encephalopathy: Effect of therapeutic hypothermia.

BACKGROUND: Hypocalcemia is a common morbidity in asphyxiated infants. Therapeutic hypothermia (TH), the standard of care for infants with moderate and severe hypoxic-ischemic encephalopathy (HIE), promotes neuroprotection by several mechanisms including a decrease in intracellular calcium (Ca(2+)) influx which may improve serum Ca(2+) levels and homeostasis. AIMS: To evaluate the impact of TH on Ca(2+) homeostasis. STUDY DESIGN: Historical, retrospective cohort analysis. SUBJECTS: Infants with moderate or severe HIE admitted to the hospital with≤24hours of age, gestational age≥36weeks, and birth weight ≥1800g, before (pre-TH) and after (post-TH) TH was implemented. OUTCOME MEASURES: Minimum and maximum serum levels of ionized Ca(2+) (iCa(2+)) and magnesium (Mg), Ca(2+) and Mg intakes, and incidence of hypo/hypercalcemia during the first week of life. RESULTS: A total of 67 infants were included: 29 pre-TH and 38 post-TH. Minimum iCa(2+)levels were significantly lower in the pre-TH group; some infants required Ca(2+) boluses infusions. In the post-TH group, a significantly lower intake of Ca(2+) was necessary to maintain normal Ca(2+) levels and no infant required boluses. The incidence of hypocalcemia was higher in the pre-TH group with a statistically significant difference on day 2 of life (18 vs 0%; p=0.01). CONCLUSIONS: After the implementation of TH, iCa(2+) levels were within normal ranges despite lower Ca(2+) intakes. A lower incidence of hypocalcemia was observed during cooling. Our findings support the hypothesis that TH improves Ca(2+) homeostasis in HIE infants.

Cow milk protein allergy presenting as feeding intolerance and eosinophilia: case reports of three preterm neonates.

Three preterm infants with cow milk protein allergy (CMPA) presented with feeding intolerance, sepsis-like episodes and persistent moderate-to-severe eosinophilia. After eliminating cow milk, the clinical symptoms improved significantly. CMPA can cause common manifestations in sick preterm infants such as feeding intolerance and eosinophilia.

Cow milk protein allergy presenting as feeding intolerance and eosinophilia: case reports of three preterm neonates.

Three preterm infants with cow milk protein allergy (CMPA) presented with feeding intolerance, sepsis-like episodes and persistent moderate-to-severe eosinophilia. After eliminating cow milk, the clinical symptoms improved significantly. CMPA can cause common manifestations in sick preterm infants such as feeding intolerance and eosinophilia.

The effect of the implementation of therapeutic hypothermia on fluid balance and incidence of hyponatremia in neonates with moderate or severe hypoxic-ischaemic encephalopathy.

AIM: To investigate the effect of the therapeutic hypothermia (TH), used in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE), on fluid balance and incidence of hyponatremia. METHODS: Retrospective cohort study of moderate and severe HIE infants before (pre) and after (post) TH implementation. Daily fluid and electrolytes intake/output were collected from the medical records of each patient from day 1 to day 4 of life. Hyponatremia was defined as sodium <130 mEq/L. RESULTS: A total of 67 infants were studied: pre-TH = 29 and post-TH = 38. Infants in the post-TH group had greater weight gain [140 g (62, 227) vs. 10 g (-100, 105) p < 0.001] and lower serum sodium (130.9 ± 4.5 mmol/L vs. 133.4 ± 5.7, p = 0.008). The incidence of hyponatremia increased from 48 to 76% (p = 0.02). CONCLUSION: In our centre, the implementation of TH was followed by an increased fluid retention and higher incidence of hyponatremia. Centres adopting TH should have clear guidelines for fluid and electrolyte management.