Stage III Chorioamnionitis is Associated with Reduced Risk of Severe Retinopathy of Prematurity.

OBJECTIVE: To identify whether histologically confirmed chorioamnionitis (hCAM) is associated with development of retinopathy of prematurity (ROP). STUDY DESIGN: We retrospectively analyzed 2 different cohorts. Cohort 1 was the national database of newborns in Japan born at ≤1500g or <32 weeks' gestation (January 2003 through April 2021, n = 38 013). Cohort 2 was babies born at <1500g from a single institution in Tsuchiura, Japan, (April 2015 through March 2018, n = 118). RESULTS: For Cohort1, after adjusting for potential confounders, stage III CAM (n = 5554) was associated with lower odds of severe ROP (stage ≥3 or required peripheral retinal ablation) by 14% (OR: 0.86; 95% CI: 0.78-0.94]. CAM of stage I (n = 3277) and II (n = 4319) was not associated with the risk of ROP. For Cohort 2, the odds of severe ROP were significantly reduced in moderate to severe hCAM groups (stage II, OR: 0.06, 95% CI: 0.05-0.82; stage III, OR: 0.10, 95% CI: 0.01-0.84). Neonates with funisitis, comorbidity of hCAM, and a finding of fetal inflammatory response had lower odds of severe ROP (OR: 0.11; 95% CI: 0.01-0.93). CONCLUSIONS: After adjusting for confounders, severe hCAM with fetal inflammatory response was associated with reduced risk of ROP.

Effects of ultra-pure soft water on the hands of nurses in a neonatal intensive care unit: A randomized crossover study.

BACKGROUND: Healthcare workers (HCWs) wash their hands with tap water (TW) and soap. However, hard TW causes dermatitis. OBJECTIVES: The present study aimed to compare the effects of ultra-pure soft water (UPSW) with those of TW on the hands of HWCs. METHODS: The present study was a prospective randomized trial with a crossover design. All the nurses in the neonatal intensive care unit (NICU) at the study centre were divided into Sequence 1 (UPSW to TW) or 2 (TW to UPSW) and washed their hands with TW or UPSW in alternating 4-week periods with a 4-week washout period. Trans-epidermal water loss (TEWL) and stratum corneum hydration (SCH) were evaluated. Skin condition was self-assessed. RESULTS: Twenty-one and 22 nurses were assigned to Sequence 1 and Sequence 2, respectively. USPW increased SCH to a significantly greater degree than TW (mean: 26.3 µS ± 12.3 SD; 95% confidence interval: 1.12-51.54; p = 0.041) although it did not affect TEWL. UPSW use significantly improved the subjects' skin condition, as reflected in an overall increase in the assessment scores. CONCLUSIONS: UPSW improved SCH and the condition of hand skin. Prolonged USPW use may increase nurses' comfort during work and hand hygiene compliance.

Furosemide clearance in very preterm neonates early in life: A pilot study using scavenged samples.

BACKGROUND: Furosemide is an off-label drug, frequently used as a diuretic in neonates with oliguria and/or edema. Its clearance in preterm neonates is lower than in term neonates or children. We aimed, herein, to clarify furosemide clearance (CL) in very preterm (VP) neonates (<28 weeks' gestation) within the first 2 weeks of life and identify the factors predictive of the pharmacokinetics (PK) parameters, such as CL. METHODS: Furosemide was administered at 0.5 or 1 mg/kg in a 0.5-h infusion via a syringe pump; blood samples were drawn from an artery or vein after the intravenous injection. The serum furosemide concentration was measured using high-performance liquid chromatography. The PK parameters were then analyzed using Bayesian estimation. RESULTS: Thirteen blood samples were obtained from 10 VP neonates after intravenous injection. The mean postconceptional age and mean postnatal days at exposure to furosemide were 26.9 weeks and 7.1 days, respectively. The estimated mean CL was 16.5 mL/kg/h. The mean distribution volume (Vd) and elimination half-life (t1/2) were 0.37 L/kg and 15.3 h, respectively. Furosemide CL was negatively associated with serum creatinine (SCr) [CL = 84.2 - 67.1 × SCr (mg/dL)]. CONCLUSIONS: Very preterm neonates within the first 2 weeks of life had a higher CL than subjects in other preterm neonatal studies. The SCr level was the sole parameter influencing furosemide CL and might serve as a good index for furosemide dosing in VP neonates.

Cytomegalovirus-related sepsis-like syndrome in very premature infants in Japan.

BACKGROUND: Very premature infants are at high risk of developing a symptomatic postnatal cytomegalovirus (CMV) disease, such as CMV-related sepsis-like syndrome (CMV-SLS). To address the limited data regarding its clinical features, a nationwide survey of CMV-SLS was conducted. METHODS: A questionnaire regarding CMV status and the clinical outcomes of CMV-SLS was sent to centers with reported cases of CMV-SLS. RESULTS: Twelve CMV-SLS cases, nine confirmed and three probable cases, were reported during the 3-year survey period. The median gestational age and birthweight were 25 weeks and 547 g, respectively. At disease onset, the median age was 49 days, and the corrected age was 31 weeks. Untreated breast milk was given in four cases (33%), whereas frozen breast milk was given in nine (75%). No specific symptoms and laboratory data regarding CMV-SLS were found. CONCLUSIONS: Very premature infants developed CMV-SLS after 1 month of age. There are no symptoms and signs specific for the diagnosis of CMV-SLS, so CMV-SLS should be considered as a differential diagnosis for premature infants who have unexplained sepsis-like symptoms during the convalescent phase.

Short-term outcomes in infants with mild neonatal encephalopathy: a retrospective, observational study.

BACKGROUND: Neonatal encephalopathy due to acute perinatal asphyxia is a major cause of perinatal brain damage. Moderate to severe neonatal encephalopathy is associated with high mortality and morbidity rates. However, the neurodevelopmental outcomes in neonates with mild neonatal encephalopathy are unclear. The primary aim of this single-center observational study was to assess the short-term outcomes in term neonates with mild neonatal encephalopathy due to perinatal asphyxia. A secondary aim was to identify predictors of poor prognosis by identifying the characteristics of these infants according to their short-term outcomes. METHODS: We retrospectively investigated all infants with perinatal asphyxia at Tokyo Metropolitan Children's Medical Center from January 2014 to December 2019. An abnormal short-term outcome was defined as any one of the following: seizures or abnormal electroencephalography, abnormal brain magnetic resonance imaging obtained within the first 4 weeks of life, and abnormal neurological examination findings at discharge. RESULTS: In total, 110 term infants with perinatal asphyxia during the study period were screened and 61 were diagnosed with mild neonatal encephalopathy. Eleven (18 %) of these infants had an abnormal short-term outcome. The median Thompson score at admission was significantly higher in infants with abnormal short-term outcomes than in those with normal short-term outcomes (5 [interquartile range, 4-5.5] vs. 2 [interquartile range, 1-3], p < 0.01). Receiver operating characteristic curve analysis showed that a cutoff value of 4 had high sensitivity and specificity (90.9 and 83.0 %, respectively) for prediction of an abnormal short-term outcome. CONCLUSIONS: 18 % of infants with mild encephalopathy had an abnormal short-term outcome, such as abnormal brain magnetic resonance imaging findings. The Thompson score at admission may be a useful predictor of an abnormal short-term outcome in infants with mild neonatal encephalopathy.

A Pilot Study of Soluble Form of LOX-1 as a Novel Biomarker for Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To evaluate the soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) as a biomarker of severity staging and prognosis in neonatal hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: We performed an observational study enrolling 27 infants with HIE and 45 control infants of gestational age ≥36 weeks and birth weight ≥1800 g. The HIE criteria were pH ≤7.0 or a base deficit ≥16 mmol/L within 60 minutes after birth, and a 10-minute Apgar score ≤5 or resuscitation time ≥10 minutes. HIE severity was evaluated using modified Sarnat staging. We measured plasma sLOX-1 level and assessed general and neurologic signs at discharge, and classified infants with no neurosensory impairments as intact survival. RESULTS: sLOX-1 level within 6 hours after birth was correlated with the severity of HIE. sLOX-1 differentiated moderate-severe HIE (median, 1017 pg/mL; IQR, 553-1890 pg/mL) from mild HIE (median, 339 pg/mL; IQR, 288-595 pg/mL; P = .007). The sensitivity and specificity of the differentiation with a cutoff value of ≥550 pg/mL were 80.0% and 83.3%, respectively. In 19 infants with therapeutic hypothermia, a sLOX-1 cutoff value of <1000 pg/mL differentiated intact survival (median, 761 pg/mL; IQR, 533-1610 pg/mL) from death or neurosensory impairment (median, 1947 pg/mL; IQR, 1325-2506 pg/mL; P = .019) with 100% specificity and a positive predictive value. CONCLUSION: sLOX-1 may be a useful biomarker of neonatal HIE for severity staging and outcome prediction. Further investigations will facilitate its clinical use.

First report on USA300 outbreak in a neonatal intensive care unit detected by polymerase chain reaction-based open reading frame typing in Japan.

Outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) in the neonatal intensive care unit (NICU) have been reported worldwide. Some outbreaks were caused by USA300, which is a community-associated MRSA clone. In 2011, polymerase chain reaction-based open reading frame typing (POT) for the initial MRSA isolates from all inpatients was started at the Tokyo Metropolitan Children's Medical Center. From March 2014 to April 2015, a total of 131 MRSA strains were isolated, 104 of which were analyzed as healthcare-associated MRSA. Thirteen stains (12.5%) had a POT number of 106-9-93, which strongly suggested USA300; these included 6 from nasal swabs, 6 from blood cultures and 1 from subcutaneous pus. All the MRSA strains were isolated from patients in the NICU; were typed as sequence type 8, spa type t008, and staphylococcal cassette chromosome type mec IVa; and possessed the lukS-lukF and arginine catabolic mobile element-arcA gene. Pulsed-field gel electrophoresis of all the strains, with USA300-0114 as a reference, showed indistinguishable banding pattern. Based on these results, POT was useful in recognizing this first MRSA outbreak of USA300 in a Japanese NICU and was advantageous in terms of swiftness, less cost and monitoring change of the epidemic MRSA lineage.

Sibling visits and viral infection in the neonatal intensive care unit.

BACKGROUND: Sibling visits to the neonatal intensive care unit (NICU) are a part of family-centered care, which is now being increasingly endorsed as a positive development in patient care. Sibling visits, however, pose a risk of viral infection, and hence many NICU in Japan impose strict limits on the practice. The aim of this study was therefore to assess whether sibling visits to the NICU are related to an increase in the nosocomial viral infection rate. METHODS: This retrospective study was conducted between April 2012 and March 2017 at Tokyo Metropolitan Children's Medical Center in Japan. Sibling visits were implemented after screening for symptoms of viral illness. Symptomatic patients in the NICU were tested for common viruses on rapid antigen test and polymerase chain reaction. The number of sibling visits and the rate of nosocomial viral infections were examined on Spearman's correlation test. RESULTS: The total number of sibling visits and rate of nosocomial viral infection in the NICU was 102 and 0.068 per 1,000 patient-days during the study period, respectively. The number of enterovirus, respiratory syncytial virus, human metapneumovirus, influenza virus A, and Herpes simplex virus infections was 3, 2, 1, 1, 1, and 1, respectively. No infections were identified after sibling visits. The number of sibling visits and the rate of nosocomial viral infections were not correlated (correlation coefficient, -0.1; P = 0.873). CONCLUSION: Sibling visits to the NICU did not result in an increase in the nosocomial viral infection rate.

A case of cutaneous Paecilomyces formosus infection in an extremely premature infant.

BACKGROUND: Many types of weak pathogenic microorganisms often cause opportunistic infections in extremely preterm infants. Paecilomyces formosus is one such opportunistic fungus that can lead to a serious infection. Here, we report the clinical course of P. formosus infection in an extremely preterm infant. CASE PRESENTATION: An extremely preterm male infant was born at 23 weeks of gestation. Six days after birth, he developed yellowish-brown nodules on the skin of the back extending to the buttocks. P. formosus was identified by culture of samples from the cutaneous lesions. We treated the infection with intravenous micafungin and lanoconazole ointment application. The skin lesions improved dramatically and healed without scar tissue formation. CONCLUSION: Neonatologists should consider opportunistic P. formosus infections. This is the first report to describe that micafungin is effective for P. formosus cutaneous infection in extremely premature infants.

Congenital dacryocystoceles controlled by nCPAP via nasal mask in a neonate.

Congenital dacryocystocele is a relatively rare type of nasolacrimal duct obstruction that may induce respiratory distress during the early neonatal period. We encountered a case of bilateral congenital dacryocystoceles with intranasal cysts in a premature infant delivered at 34 weeks of gestation. The patient developed symptoms of respiratory failure immediately after birth, but no ophthalmologic symptoms. Treatment with nasal continuous positive airway pressure via a nasal mask, instead of a nasal prong, effectively relieved the symptoms. Early diagnosis and appropriate treatment are critical for infants with nasal obstruction.

Comparison of High-Frequency Oscillatory Ventilators.

BACKGROUND: The performance of high-frequency oscillatory ventilators (HFOV) differs by the waveform generation mode and circuit characteristics. Few studies have described the performance of piston-type HFOV. The present study aimed to compare the amplitude required to reach the target high-frequency tidal volume ([Formula: see text]); determine the relationship between the settings and actual pressure in amplitude or mean airway pressure ([Formula: see text]); and describe the interaction among compliance, frequency, and endotracheal tube (ETT) inner diameter in 4 HFOV models, including Humming X, Vue (a piston type ventilator commonly used in Japan), VN500 (a diaphragm type), and SLE5000 (a reverse jet type). METHODS: The oscillatory ventilators were evaluated by using a 50-mL test lung with 0.5 and 1.0 mL/cm H2O compliance, [Formula: see text] of 10 cm H2O, frequency of 12 and 15 Hz, and ETT inner diameters 2.0, 2.5, and 3.5 mm. At each permutation of compliance, frequency, and ETT, the target high-frequency [Formula: see text] was increased from 0.5 to 3.0 mL. The change in [Formula: see text] from the ventilator (ventilator [Formula: see text]) to Y-piece (Y [Formula: see text]) and alveolar pressure (alveolar [Formula: see text]) and the change in amplitude from the ventilator (ventilator amplitude) to Y-piece (Y amplitude) and alveolar pressure (alveolar amplitude) were determined at high-frequency [Formula: see text] of 1.0 and 3.0 mL. RESULTS: To achieve the target high-frequency [Formula: see text], the Humming X and Vue required a higher amplitude than did the SLE5000, but the maximum amplitude in the VN500 was unable to attain a larger high-frequency [Formula: see text]. Ventilator [Formula: see text] and alveolar pressure decreased at the Y-piece with the Humming X and Vue but increased with the SLE5000. The ventilator [Formula: see text] in the VN500 decreased remarkably at a frequency of 15 Hz. The ventilator amplitude in all 4 ventilators decreased while temporarily increasing at the Y-piece in the VN500. CONCLUSIONS: The actual measured value, such as alveolar [Formula: see text] and high-frequency [Formula: see text], varied according to the type of HFOV system and the inner diameter of the ETT, even with identical settings. Clinicians should therefore determine the setting appropriate to each HFOV model.

Subcutaneous fat necrosis after selective head cooling in an infant.

Hypoxic-ischemic encephalopathy in neonates causes irreversible damage to tissue and organs and results in multiple organ failure and poor outcome. Therapeutic hypothermia is the most effective therapy in neonates with hypoxic-ischemic encephalopathy. We report here a case of subcutaneous fat necrosis (SCFN) after therapeutic hypothermia by selective head cooling. Selective head cooling was provided for 72 h after birth. SCFN developed on the patient's cheeks and back at the age of 21 days. Thus, SCFN may be caused by selective head cooling, similarly to whole-body cooling.

Neonatal asphyxia as an inflammatory disease: Reactive oxygen species and cytokines.

Neonatologists resuscitate asphyxiated neonates by every available means, including positive ventilation, oxygen therapy, and drugs. Asphyxiated neonates sometimes present symptoms that mimic those of inflammation, such as fever and edema. The main pathophysiology of the asphyxia is inflammation caused by hypoxic-ischemic reperfusion. At birth or in the perinatal period, neonates may suffer several, hypoxic insults, which can activate inflammatory cells and inflammatory mediator production leading to the release of larger quantities of reactive oxygen species (ROS). This in turn triggers the production of oxygen stress-induced high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular patterns (DAMPs) protein bound to toll-like receptor (TLR) -4, which activates nuclear factor-kappa B (NF-κB), resulting in the production of excess inflammatory mediators. ROS and inflammatory mediators are produced not only in activated inflammatory cells but also in non-immune cells, such as endothelial cells. Hypothermia inhibits pro-inflammatory mediators. A combination therapy of hypothermia and medications, such as erythropoietin and melatonin, is attracting attention now. These medications have both anti-oxidant and anti-inflammatory effects. As the inflammatory response and oxidative stress play a critical role in the pathophysiology of neonatal asphyxia, these drugs may contribute to improving patient outcomes.

Temporal alteration of serum G-CSF and VEGF levels in perinatal asphyxia treated with head cooling.

OBJECTIVE: Granulocyte-colony stimulating factor (G-CSF) and vascular endothelial growth factor (VEGF) are thought to be associated with the pathophysiology of perinatal asphyxia. To clarify any such association, we analyzed the serum levels in neonates with perinatal asphyxia treated with head cooling. STUDY DESIGN: Temporal alterations of serum G-CSF and VEGF levels were measured within 24h of birth in five neonatal cases of severe asphyxia treated with head cooling, five neonatal cases without head cooling, and four healthy neonatal cases. RESULTS: G-CSF in sera markedly increased and sustained in severely asphyxiated neonates treated with head cooling, while VEGF decreased and remained low. CONCLUSION: G-CSF and VEGF levels in sera might be associated with an early phase of brain protection after birth in severe asphyxia treated with head cooling.

Evaluation of the accuracy of a non-invasive hemoglobin-monitoring device in schoolchildren.

BACKGROUND: Iron deficiency anemia (IDA) is a public health problem in children and adolescents that is characterized by reduced hemoglobin (Hb) levels. Non-invasive monitoring devices can measure Hb levels continuously without pain or discomfort; however, little is known about their accuracy in children and adolescents. This study estimated the accuracy of a non-invasive Hb monitor in this age group. METHODS: Participants were outpatients visiting the Tokyo Metropolitan Children's Medical Center for blood tests between January and March 2019. Hb levels were measured using both non-invasive Astrim Fit monitoring devices and invasive blood collection followed by automated analysis. Bland-Altman analysis assessed the agreement between the two measurements. RESULTS: Overall, 120 schoolchildren (9-15 years old, 51 % female) were enrolled. The non-invasive measuring device recorded Hb levels of 13.5 ± 1.6 g/dL (mean ± standard deviation [SD]), while the mean Hb level obtained from the collected blood was 13.7 ± 1.7 g/dL. Therefore, the mean difference of bias and SD of precision was 0.17 ± 1.95 g/dL. Values of lower and upper limits of agreement were -3.65 and 3.99, respectively. There was no systematic fixed or proportion bias. Fifty-nine participants (49 %) had a relative error of ± 0.10. CONCLUSION: The Astrim Fit non-invasive Hb monitor can be used to evaluate Hb levels among schoolchildren for health promotion or research purposes because of its extremely low bias (or precision), no systematic biases (including fixed or proportion biases), and positive correlation between non-invasive monitoring and blood drawing. However, it is difficult to assess Hb levels in children and adolescents using the Astrim Fit device for diagnostic purposes.

Transcriptome analysis of umbilical cord mesenchymal stem cells revealed fetal programming due to chorioamnionitis.

Although chorioamnionitis (CAM) has been demonstrated to be associated with numerous short- and long-term morbidities, the precise mechanisms remain unclear. One of the reasons for this is the lack of appropriate models for analyzing the relationship between the fetal environment and chorioamnionitis and fetal programming in humans. In this study, we aimed to clarify the fetal programming caused by CAM using the gene expression profiles of UCMSCs. From nine preterm neonates with CAM (n = 4) or without CAM (n = 5), we established UCMSCs. The gene expression profiles obtained by RNA-seq analysis revealed distinctive changes in the CAM group USMSCs. The UCMSCs in the CAM group had a myofibroblast-like phenotype with significantly increased expression levels of myofibroblast-related genes, including α-smooth muscle actin (p < 0.05). In the pathway analysis, the genes involved in DNA replication and G1 to S cell cycle control were remarkably decreased, suggesting that cellular proliferation was impaired, as confirmed by the cellular proliferation assay (p < 0.01-0.05). Pathway analysis revealed that genes related to white fat cell differentiation were significantly increased. Our results could explain the long-term outcomes of patients who were exposed to CAM and revealed that UCMSCs could be an in vitro model of fetal programming affected by CAM.

Maternal mesalazine-induced neonatal gastrointestinal bleeding.

Ulcerative colitis often develops in the reproductive age women and can cause exacerbation by pregnancy. Mesalazine (5-aminosalicylic acid) is recommended as a safe anti-inflammatory drug during pregnancy. However, maternal mesalazine is transferred to the fetus through the placenta and may cause allergic events. A pregnant woman with severe ulcerative colitis was treated with a dose of mesalazine 4,000 mg/day from early gestation to delivery. Immediately after birth, the preterm neonate vomited bloody contents and discharged massive gross haematochezia. Serum concentrations of mesalazine and its main metabolite were high in the mother and the umbilical cord. Faecal eosinophils and drug-induced lymphocyte stimulation test suggested possibility that sensitisation with mesalazine in utero caused allergic enterocolitis like food protein-induced allergic proctocolitis. Maternal mesalazine has a potential of fetal sensitisation and cause allergic disease.