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Objective: To investigate the association between prolonged oligohydramnios and a composite outcome of death or severe neurodevelopmental impairment (NDI) at 3 years of age., Methods: This single-center retrospective cohort study enrolled infants born at 22-29 weeks of gestational age without major congenital anomalies. The patients were classified into three groups depending on the existence and duration of oligohydramnios: no/non-prolonged oligohydramnios (no or 0-7 days of oligohydramnios), prolonged oligohydramnios (8-14 days), and very prolonged oligohydramnios (> 14 days). The primary outcome was a composite of death or severe NDI, which was defined as severe cerebral palsy, developmental delay, severe visual impairment, or deafness at age 3., Results: Out of the 843 patients, 784 (93 %), 30 (3.6 %), and 29 (3.4 %) were classified into the no/non-prolonged, prolonged, and very prolonged oligohydramnios groups, respectively. After excluding patients lost to follow-up, the adverse composite outcome at 3 years of age was observed in 194/662 (29 %), 7/26 (27 %), and 8/23 (35 %) in the corresponding groups. The composite outcome showed no significant trend with the duration of oligohydramnios (P = 0.70). In a logistic regression model controlling the known predictors of gestational age, birth weight, small-for-gestational-age, male sex, multiple pregnancy, hypertensive disorders of pregnancy, antenatal corticosteroids, and the number of family-social risk factors, the duration of oligohydramnios was not independently associated with the composite outcome; odds ratio 1.3 (95 % confidence interval, 0.78-2.0)., Conclusion: Prolonged oligohydramnios was not associated with the composite outcome of death or severe NDI at 3 years of age., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Noninvasive neurally-adjusted ventilatory assist (NIV-NAVA) improves patient-ventilator synchrony and may reduce treatment failure in preterm infants compared with nasal continuous positive airway pressure (NCPAP) and noninvasive positive-pressure ventilation (NIPPV). We conducted a systematic review and meta-analysis to assess the effects of NIV-NAVA in preterm infants with respiratory distress., Methods: Four investigators independently assessed the eligibility of studies in CENTRAL, CINAHL, ClinicalTrials.gov, Embase, MEDLINE, PubMed, and WHO ICTRP databases, and extracted data. The included studies were randomized controlled trials (RCTs) comparing NIV-NAVA with other noninvasive ventilation modalities in preterm infants. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The objective of the meta-analysis was to compare NIV-NAVA vs CPAP/NIPPV as a primary mode post extubation., Results: Five RCTs which examined 279 preterm infants were included. In the subgroup of post-extubation respiratory support, NIV-NAVA decreased treatment failure compared with NCPAP/NIPPV (risk ratio 0.29; 95% confidence interval [0.10, 0.81], 2 RCTs, 96 infants, low certainty of the evidence). NIV-NAVA did not significantly reduce the risk of treatment failure in the subgroup of primary respiratory support (very low certainty of the evidence). There were no significant differences in secondary outcomes with low to very low certainty of evidence., Conclusions: In a small cohort with low certainty of evidence, NIV-NAVA may prevent reintubation in preterm infants. Further large-scale RCTs are needed to determine the effects and safety of NIV-NAVA in preterm infants.

Background: Bronchopulmonary dysplasia (BPD) has a lasting effect on the respiratory function of infants, imposing chronic health burdens. BPD is influenced by various prenatal, postnatal, and genetic factors. This study explored the connection between BPD and home oxygen therapy (HOT), and then we examined the association between HOT and a specific single-nucleotide polymorphism (SNP) in the hyaluronan and proteoglycan link protein 1 ( HAPLN1 ) gene among premature Japanese infants., Materials and Methods: Prenatal and postnatal data from 212 premature infants were collected and analyzed by four SNPs (rs975563, rs10942332, rs179851, and rs4703570) around HAPLN1 using the TaqMan polymerase chain reaction method. The clinical characteristics and genotype frequencies of HAPLN1 were assessed and compared between HOT and non-HOT groups., Results: Individuals with AA/AC genotypes in the rs4703570 SNP exhibited significantly higher HOT rates at discharge than those with CC homozygotes (odds ratio, 1.20, 95% confidence interval, 1.07-1.35, p  = .038). A logistic regression analysis determined that CC homozygotes in the rs4703570 SNP did not show a statistically significant independent association with HOT at discharge., Conclusions: Although our study did not reveal a correlation between HAPLN1 and the onset of BPD, we observed that individuals with CC homozygosity at the rs4703570 SNP exhibit a reduced risk of HOT.

Background: It is unknown how accurately the current Japanese classification system for neurodevelopmental delay based on the assessment with the Kyoto Scale of Psychological Development (KSPD) at toddlerhood and pre-school periods predicts cognitive impairment at school age., Methods: This single-center retrospective cohort study enrolled infants born at 22-29 weeks of gestational age. At 18-24 months of corrected age and 3 years of age, the patients were categorized according to the current Japanese criteria for neurodevelopmental delay based on their overall developmental quotient calculated using the KSPD-2001. Cognitive impairment at 6 years of age was classified according to the calculated or estimated full-scale intelligence quotient. The predictability of the current Japanese classification of neurodevelopmental delay for cognitive impairment at 6 years of age was investigated., Results: Of 566 eligible patients, 364 (64 %) completed the protocol. The current classification for the neurodevelopmental delay showed significant agreement with the severity of cognitive impairment at 6 years of age. The sensitivity and specificity of the KSPD-2001-based assessment for any cognitive impairment at 6 years of age were 0.64 and 0.74 at 18-24 months of corrected age and 0.83 and 0.70 at 3 years of age. The corresponding sensitivity and specificity for moderate/severe cognitive impairment were 0.51 and 0.96 at 18-24 months of corrected age and 0.68 and 0.95 at 3 years of age., Conclusion: The KSPD-2001 is a useful tool to predict the severity of cognitive impairment at school age., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: To investigate prognosis and clinical practices of infants born at 22-23 weeks' gestational age (wkGA) in Japan., Design: A national institutional-level electronic questionnaire surveys performed in September 2021., Setting: All perinatal centres across Japan., Patients: Infants born at 22-23 wkGA in 2018-2020., Main Outcome Measures: Proportion of active resuscitation and survival at neonatal intensive care unit (NICU) discharge, and various clinical practices., Results: In total, 255 of 295 NICUs (86%) responded. Among them, 145 took care of infants born at 22-23 wkGA and answered the questions regarding their outcomes and care. In most NICUs (129 of 145 (89%)), infants born at 22 +0 wkGA can be actively resuscitated. In almost half of the NICUs (79 of 145 (54%)), infants born at ≥22 +0 wkGA were always actively resuscitated. Among 341 and 757 infants born alive at 22 and 23 wkGA, respectively, 85% (291 of 341) and 98% (745 of 757) received active resuscitation after birth. Among infants actively resuscitated at birth, 63% (183 of 291) and 80% (594 of 745) of infants born at 22 and 23 wkGA survived, respectively. The survey revealed unique clinical management for these infants in Japan, including delivery with caul in caesarean section, cut-cord milking after clamping cord, immediate intubation at birth, hydrocortisone use for chronic lung disease, analgesia/sedation use for infants on mechanical ventilation, routine echocardiography and brain ultrasound, probiotics administration, routine glycerin enema and skin dressing to prevent pressure ulcers., Conclusions: Many 22-23 wkGA infants were actively resuscitated in Japan and had a high survival rate. Various unique clinical practices were highlighted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pyruvate dehydrogenase kinase isoform 4 (PDK4) plays a pivotal role in the regulation of cellular proliferation and apoptosis. The objective of this study was to examine whether the genetic depletion of the PDK4 gene attenuates hyperoxia-induced lung injury in neonatal mice., Methods: Neonatal PDK4-/- mice and wild-type (WT) mice were exposed to oxygen concentrations of 21% (normoxia) and 95% (hyperoxia) for the first 4 days of life. Pulmonary histological assessments were performed, and the mRNA levels of lung PDK4, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were assessed. The levels of inflammatory cytokines in lung tissue were quantified., Results: Following convalescence from neonatal hyperoxia, PDK4-/- mice exhibited improved lung alveolarization. Notably, PDK4-/- mice displayed significantly elevated MCP-1 protein levels in pulmonary tissues following 4 days of hyperoxic exposure, whereas WT mice showed increased IL-6 protein levels under similar conditions. Furthermore, neonatal PDK4-/- mice subjected to hyperoxia demonstrated markedly higher MCP-1 mRNA expression at 4 days of age compared to WT mice, while IL-6 mRNA expression remained unaffected in PDK4-/- mice., Conclusions: Newborn PDK4-/- mice exhibited notable recovery from hyperoxia-induced lung injury, suggesting the potential protective role of PDK4 depletion in mitigating lung damage.

Accurate clinical staging is important in diffuse large B-cell lymphoma (DLBCL) to adapt to optimal therapy. Splenic involvement of DLBCL has been recently more detectable with the advancement of a diagnostic scan by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). Our clinical question is whether splenic involvement was adequately diagnosed by FDG-PET/CT imaging. This retrospective study aimed to determine the optimal index for evaluating splenic involvement in patients with DLBCL. Patients with newly diagnosed DLBCL who were examined with FDG-PET/CT at diagnosis and the end of induction chemotherapy (EOI) was enrolled. The splenic involvement with the splenic FDG uptake value higher than that of the liver at diagnosis or with the decrease of splenic uptake at EOI by visual evaluation was evaluated as positive. The calculative evaluation of splenic involvement, based on the data of standardized uptake value (SUV) of the spleen, used maximum SUV (SUVmax), mean SUV (SUVmean), spleen total lesion glycolysis (spleen TLG), and spleen length. A change in each index following induction chemotherapy was expressed as an index. Receiver operating characteristic analysis was used to set the cutoff value for each index. This study included 52 patients. Spleen TLG (0.904) showed the best accuracy, followed by SUVmax (0.885) and SUVmean (0.885), among the 5 indexes for splenic involvement at diagnosis. Splenic involvement was predicted with a higher accuracy level (0.923) when selecting the cases with values higher than the cutoff level on both spleen TLG and SUVmax. The decision at EOI was more suitable by selecting both positive cases of ∆ TLG and ∆ SUVmax. Obtaining both the positive spleen TLG and SUVmax is recommended at diagnosis to predict splenic involvement. The assessment by ∆ spleen TLG and ∆ SUVmax seems to be optimal., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: We hypothesized that the serum TRX-1 in extremely preterm infants (EPIs) after birth was associated with the development of severe bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP)., Methods: This single-centered retrospective study enrolled EPIs treated at our institution. Serum TRX-1 concentrations of the residual samples taken on admission, day 10-20 of life, and 36-40 weeks of postmenstrual age (PMA) were measured with an enzyme-linked immunosorbent assay., Results: The serum TRX-1 levels on admission were not different between the severe BPD (n = 46) and non-severe BPD groups (n = 67): [median (interquartile range) 147 (73.0-231) vs. 164 (80.5-248) ng/mL] (P = 0.57). These had no significant difference between the severe ROP (n = 47) and non-severe ROP groups (n = 66): [164 (71.3-237) vs. 150 (80.9-250) ng/mL] (P = 0.93). The TRX-1 levels at 10-20 days of life and 36-40 weeks of PMA also had no association with the development of severe BPD and ROP., Conclusion: The serum TRX-1 levels after birth are not predictive of severe BPD and ROP., Impact: Serum thioredoxin-1 levels in extremely preterm infants on the day of birth are lower than those in term or near-term infants hospitalized for transient tachypnea of the newborn. In extremely preterm infants, the serum thioredoxin-1 levels on the day of birth, at 10-20 days of life, and at postmenstrual age of 36-40 weeks were not associated with severe bronchopulmonary dysplasia and retinopathy of prematurity. The thioredoxin system is under development in extremely preterm infants; however, the serum thioredoxin-1 level is not predictive for severe bronchopulmonary dysplasia and retinopathy of prematurity., (© 2024. The Author(s).)

Background: Human milk (HM) has been proven to provide immunological and nutritional advantages to neonates; however, acquired cytomegalovirus (CMV) infection can be associated with raw HM. In Japan, there are no standardized guidelines concerning HM handling. This cross-sectional survey was performed to reveal specific trends in HM handling in neonatal intensive care units (NICUs) in Japan., Methods: A questionnaire was sent to 255 NICUs participating in the Japanese Neonatologist Association in May 2020. It involved HM handling practices, such as maternal screening, pasteurization, storage, and the workforce., Results: Of 255 NICUs, 174 (67.8%) responded to the survey. Maternal CMV screening was carried out in 37 units (22.2%), and CMV inactivation in HM was performed in 44 units (26.5%). For CMV inactivation, a freeze-thawing method was employed in about 90% of units. In 70% of units providing CMV inactivation, CMV inactivation was conducted regardless of bodyweight and corrected gestational age of infants until the infants' discharge. Acquired CMV infection in preterm neonates was observed in 43 units (25.7%) in the survey period., Conclusion: A wide range of HM handling practices are used in Japanese NICUs. A national guideline for handling HM in NICUs should be created to promote the infection control of CMV., (© 2024 Japan Pediatric Society.)

Introduction: Bronchopulmonary dysplasia (BPD) impacts life expectancy and long-term quality of life. Currently, BPD mouse models exposed to high oxygen are frequently used, but to reevaluate their relevance to human BPD, we attempted an assessment using micro-computed tomography (µCT)., Methods: Newborn wildtype male mice underwent either 21% or 95% oxygen exposure for 4 days, followed until 8 wk. Weekly µCT scans and lung histological evaluations were performed independently., Results: Neonatal hyperoxia for 4 days hindered lung development, causing alveolar expansion and simplification. Histologically, during the first postnatal week, the exposed group showed a longer mean linear intercept, enlarged alveolar area, and a decrease in alveolar number, diminishing by week 4. Weekly µCT scans supported these findings, revealing initially lower lung density in newborn mice, increasing with age. However, the high-oxygen group displayed higher lung density initially. This difference diminished over time, with no significant contrast to controls at 3 wk. Although no significant difference in total lung volume was observed at week 1, the high-oxygen group exhibited a decrease by week 2, persisting until 8 wk., Conclusion: This study highlights µCT-detected changes in mice exposed to high oxygen. BPD mouse models might follow a different recovery trajectory than humans, suggesting the need for further optimization.

Objective: We aimed to present the active management and outcomes of infants born at 22 weeks of gestation., Study Design: This retrospective observational study presented the resuscitation methods, management during hospitalization, and outcomes of 29 infants born at 22 weeks of gestation who were actively resuscitated and admitted to our center during 2013-2020., Results: The survival rate was 82.8% (24/29). Tracheal intubation was performed in all patients, and surfactant was administered for 27 (93.1%). Conventional mechanical ventilation was introduced in 27 (93.1%), and this was changed to high-frequency oscillatory ventilation in more than half by day 4. Surgical treatments of patent ductus arteriosus, necrotizing enterocolitis, and retinopathy of prematurity were required in 4 (13.7%), 3 (10.3%), and 15 (51.7%) patients, respectively. No patient required a tracheostomy or ventriculoperitoneal shunt., Conclusions: The overall survival rate and survival rate without morbidities were high among infants born at 22 weeks of gestation., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The incidence of bronchopulmonary dysplasia (BPD) and respiratory management practices for extremely low birth weight infants (ELBWIs) widely vary among institutions and countries., Aims: To clarify the variation and characteristics of the current practices of Japanese neonatologists managing patients with BPD., Study Design: Questionnaire-based survey., Participants: Level II and III perinatal centers certified by the Japan Society of Perinatal and Neonatal Medicine., Outcome Measures: Policies of the neonatal intensive care units (NICUs) regarding respiratory care and medications for BPD prevention and treatment., Results: A total of 76 % of facilities (207/274) responded to our survey. The response rates of level III and II facilities were 91 % (102/112) and 35 % (105/296), respectively. INtubation-SURfactant-Extubation and Less Invasive Surfactant Administration methods were performed in 23 % (47/206) and 1 % (3/206) of facilities, respectively. For the prophylactic purpose, systemic and inhaled steroids were administered "frequently" or "occasionally" in 14 % (28/205) and 42 % (86/204) of NICUs, respectively. For the therapeutic purpose, systemic and inhaled steroids were administered "frequently" or "occasionally" in 84 % (171/204) and 29 % (59/204) of NICUs, respectively. Approximately half of the NICUs (99/202) used volume-targeted ventilation (VTV) "frequently" or "occasionally" in progressing BPD. High-frequency oscillation ventilation (HFOV) was used for progressing BPD "frequently" and "occasionally" in 89 % (180/202) of the facilities., Conclusions: Our study provided an overview and characteristics of BPD management in Japan in recent years. Noninvasive approaches with surfactant administration remain not widely used in Japan. HFOV is a widely accepted management for progressing BPD., Competing Interests: Declaration of competing interest None of the authors have financial or non-financial competing interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The most frequent umbilical abnormality in infancy period is umbilical granuloma. Although umbilical granuloma treatment with silver nitrate is practised worldwide, silver nitrate cauterisation is high in cost and if silver nitrate comes into contact with healthy tissues, it might cause injury. This systematic review aims to look for evidence concerning the safety and efficacy of all interventions for treating umbilical granuloma in neonates., Methods and Analysis: Individual and cluster randomised controlled trials will be included in our study. The direct comparisons between two of any interventions for treating umbilical granuloma, including silver nitrate cauterisation, dry care, common salt, alcoholic wipes, topical doxycycline, topical steroid ointment, ligatures, cryosurgery, electrocautery, surgical excision and no intervention will be investigated. Primary outcomes will be the healing rate after 2 weeks of treatment and the incidence of cord-related adverse events. We will search CENTRAL, Embase and MEDLINE., Ethics and Dissemination: Ethical approval is not applicable in this study since we will retrieve and analyse data from previous published studies. The results of this systematic review are expected to be published in a scientific journal and presented at medical conferences., Prospero Registration Number: CRD42022369915., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study aimed to synthesise available evidence on the efficacy of antenatal corticosteroid (ACS) therapy among women at risk of imminent preterm birth with pregestational/gestational diabetes, chorioamnionitis or fetal growth restriction (FGR), or planned caesarean section (CS) in the late preterm period., Methods: A systematic search of MEDLINE, EMBASE, CINAHL, Cochrane Library, Web of Science and Global Index Medicus was conducted for all comparative randomised or non-randomised interventional studies in the four subpopulations on 6 June 2021. Risk of Bias Assessment tool for Non-randomised Studies and the Cochrane Risk of Bias tool were used to assess the risk of bias. Grading of Recommendations Assessment, Development and Evaluations tool assessed the certainty of evidence., Results: Thirty-two studies involving 5018 pregnant women and 10 819 neonates were included. Data on women with diabetes were limited, and evidence on women undergoing planned CS was inconclusive. ACS use was associated with possibly reduced odds of neonatal death (pooled OR: 0.51; 95% CI: 0.31 to 0.85, low certainty), intraventricular haemorrhage (pooled OR: 0.41; 95% CI: 0.23 to 0.72, low certainty) and respiratory distress syndrome (pooled OR: 0.59; 95% CI: 0.45 to 0.77, low certainty) in women with chorioamnionitis. Among women with FGR, the rates of surfactant use (pooled OR: 0.38; 95% CI: 0.23 to 0.62, moderate certainty), mechanical ventilation (pooled OR: 0.42; 95% CI: 0.26 to 0.66, moderate certainty) and oxygen therapy (pooled OR: 0.48; 95% CI: 0.30 to 0.77, moderate certainty) were probably reduced; however, the rate of hypoglycaemia probably increased (pooled OR: 2.06; 95% CI: 1.27 to 3.32, moderate certainty)., Conclusions: There is a paucity of evidence on ACS for women who have diabetes. ACS therapy may have benefits in women with chorioamnionitis and is probably beneficial in FGR. There is limited direct trial evidence on ACS efficacy in women undergoing planned CS in the late preterm period, though the totality of evidence suggests it is probably beneficial., Prospero Registration Number: CRD42021267816., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Clear outcome reporting in clinical trials facilitates accurate interpretation and application of findings and improves evidence-informed decision-making. Standardized core outcomes for reporting neonatal trials have been developed, but little is known about how primary outcomes are reported in neonatal trials. Our aim was to identify strengths and weaknesses of primary outcome reporting in recent neonatal trials., Methods: Neonatal trials including ≥100 participants/arm published between 2015 and 2020 with at least 1 primary outcome from a neonatal core outcome set were eligible. Raters recruited from Cochrane Neonatal were trained to evaluate the trials' primary outcome reporting completeness using relevant items from Consolidated Standards of Reporting Trials 2010 and Consolidated Standards of Reporting Trials-Outcomes 2022 pertaining to the reporting of the definition, selection, measurement, analysis, and interpretation of primary trial outcomes. All trial reports were assessed by 3 raters. Assessments and discrepancies between raters were analyzed., Results: Outcome-reporting evaluations were completed for 36 included neonatal trials by 39 raters. Levels of outcome reporting completeness were highly variable. All trials fully reported the primary outcome measurement domain, statistical methods used to compare treatment groups, and participant flow. Yet, only 28% of trials fully reported on minimal important difference, 24% on outcome data missingness, 66% on blinding of the outcome assessor, and 42% on handling of outcome multiplicity., Conclusions: Primary outcome reporting in neonatal trials often lacks key information needed for interpretability of results, knowledge synthesis, and evidence-informed decision-making in neonatology. Use of existing outcome-reporting guidelines by trialists, journals, and peer reviewers will enhance transparent reporting of neonatal trials., (Copyright © 2023 by the American Academy of Pediatrics.)

Background and Objectives: There is variability in the selection and reporting of outcomes in neonatal trials with key information frequently omitted. This can impact applicability of trial findings to clinicians, families, and caregivers, and impair evidence synthesis. The Neonatal Core Outcomes Set describes outcomes agreed as clinically important that should be assessed in all neonatal trials, and Consolidated Standards of Reporting Trials (CONSORT)-Outcomes 2022 is a new, harmonized, evidence-based reporting guideline for trial outcomes. We reviewed published trials using CONSORT-Outcomes 2022 guidance to identify exemplars of neonatal core outcome reporting to strengthen description of outcomes in future trial publications., Methods: Neonatal trials including >100 participants per arm published between 2015 to 2020 with a primary outcome included in the Neonatal Core Outcome Set were identified. Primary outcome reporting was reviewed using CONSORT 2010 and CONSORT-Outcomes 2022 guidelines by assessors recruited from Cochrane Neonatal. Examples of clear and complete outcome reporting were identified with verbatim text extracted from trial reports., Results: Thirty-six trials were reviewed by 39 assessors. Examples of good reporting for CONSORT 2010 and CONSORT-Outcomes 2022 criteria were identified and subdivided into 3 outcome categories: "survival," "short-term neonatal complications," and "long-term developmental outcomes" depending on the core outcomes to which they relate. These examples are presented to strengthen future research reporting., Conclusions: We have identified examples of good trial outcome reporting. These illustrate how important neonatal outcomes should be reported to meet the CONSORT 2010 and CONSORT-Outcomes 2022 guidelines. Emulating these examples will improve the transmission of information relating to outcomes and reduce associated research waste., (Copyright © 2023 by the American Academy of Pediatrics.)

Background: Antenatal magnesium sulphate (MgSO 4 ) therapy given to women at risk of preterm birth reduced the risk of cerebral palsy in early childhood. However, its effect on longer-term neurological outcomes remains uncertain. This study aimed to assess the effects of antenatal MgSO 4 therapy on school-age outcomes of preterm infants., Methods: We conducted a systematic review and meta-analysis. We searched MEDLINE, EMBASE, CENTRAL, and CINAHL for randomized controlled trials (RCTs). Two reviewers independently evaluated the eligibility for inclusion and extracted data., Results: Ten RCTs were included. Only two of them were on school-age outcomes. Antenatal MgSO 4 therapy had no impact on cerebral palsy, hearing impairment, neurosensory disability, and death at school-age. Meta-analysis on mental retardation and visual impairment was not able to be performed due to different methods of evaluation. In the analysis of short-term outcomes conducted as secondary outcomes, antenatal MgSO 4 therapy increased the risk of maternal adverse events with any symptom (3 RCTs; risk ratio 2.79; 95% confidence interval 1.10 to 7.05, low certainty of evidence) but was not associated with any neonatal symptoms., Conclusions: The number of cases was insufficient to determine the impact of antenatal MgSO 4 therapy on school-age outcomes. Further accumulation of long-term data is required.

Objectives: The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation., Study Design: This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models., Results: Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively., Conclusion: Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Patent ductus arteriosus (PDA) causes severe morbidity in premature infants. Although the use of indomethacin is the standard therapy for PDA, it is sometimes not applicable because of its adverse effects, such as renal and platelet dysfunctions. Paracetamol has emerged as an alternative to indomethacin owing to its excellent safety profile in infants. Of the recently reported case series and clinical trials on the use of paracetamol for PDA, there are few reports in Japan on paracetamol use in preterm infants. Furthermore, indications for the use of paracetamol for PDA have not been approved for use in PDA. While the safety of intravenous paracetamol therapy in case series of preterm infants treated for haemodynamically significant PDA (hsPDA) has been reported, studies which were conducted to compare paracetamol to indomethacin are limited. We, therefore, intend to investigate the hypothesis that intravenous administration of paracetamol has superior safety over indomethacin., Methods and Analysis: Multicentre open-label randomised controlled trial for intravenous administration of paracetamol for PDA in preterm infants. The inclusion criteria are (1) hsPDA, (2) gestational age from 24 to 34 weeks and birth weight (BW) from 500 to 2000 g, (3) enrolment between 24 hours and 7 days from birth and (4) obtaining parental consent. The primary outcome is renal dysfunction within 48 hours from the last dose of the study drug. Enrolled patients fulfilling all the inclusion criteria are randomly allocated to either intravenous paracetamol or intravenous indomethacin. This trial requires 110 patients., Ethics and Dissemination: The clinical trial would follow Japan's Clinical Trials Act. The trial protocol was approved by the Clinical Research Review Board of Saitama Medical University (approval number: 222001). A written informed consent would be obtained from one of the parents. The results are expected to be published in a scientific journal., Trial Registration Number: jRCTs031220386., Protocol Version: 31 March 2022, version 1.0., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This systematic review aimed to identify the benefits and possible harms of tocolytic therapy for preterm labour management in the context of pregnant women with extremely preterm birth, multiple gestations, or growth-restricted foetuses. A comprehensive search using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, CINAHL, and the WHO Global Index Medicus databases was conducted from 10 to 15 July 2021. We included randomized controlled trials and non-randomized studies that assessed the effects of tocolysis compared with placebo or no treatment. We found 744 reports and, finally, nine studies (three randomized controlled trials and six cohort studies) pertaining to women with <28 weeks of gestation were included. No eligible studies were identified among women with a multiple pregnancy or a growth-restricted foetus. A meta-analysis of the trial data showed that there were no clear differences in perinatal death nor for a delay in birth. Non-randomized evidence showed that tocolysis delayed birth by 7 days, though there was no clear difference for preterm birth. In summary, it remains unclear whether tocolytic therapy for inhibiting preterm labour is beneficial for these subgroups of women and their newborns. Further well-designed randomized controlled trials and observational studies are needed to address the lack of evidence regarding tocolytic agents in these populations.

Background: Over the years, bronchopulmonary dysplasia (BPD) affects the pulmonary function of infants, resulting in chronic health burdens for infants and their families. The aim of this scoping review was to screen available evidence regarding perinatal risk factors associated with the development and severity of BPD., Methods: The eligibility criteria of the studies were year of publication between 2016 and 2021; setting of a developed country; English or Japanese as the study language; and randomized controlled, cohort, or case-control design. The titles and abstracts of the studies were screened by independent reviewers., Results: Of 8189 eligible studies, 3 were included for severe BPD and 26 were included for moderate BPD. The risk factors for severe BPD were male sex, iatrogenic preterm birth, maternal hypertensive disorders of pregnancy (HDP), low gestational age, small-for-gestational-age (SGA) birth weight, mechanical ventilation on day 1, and need for patent ductus arteriosus (PDA) management. The risk factors for moderate or severe BPD included male sex, premature rupture of membranes, clinical chorioamnionitis, maternal HDP, SGA birth weight, bubbly/cystic appearance on X-ray, and PDA management., Conclusions: We identified several risk factors for BPD. We plan to confirm the validity of the new classification using the existing dataset.

Introduction: Extremely premature (EP) infants (<28 weeks gestational age) with respiratory conditions after discharge from the neonatal intensive care unit (NICU) impose a significant burden on caregivers. This study explored caregiver burden post-NICU discharge and perceptions of meaningful change in infant chronic respiratory morbidity., Methods: Adult primary caregivers of EP infants 3-14 months corrected age were recruited through patient advocacy organizations or hospital centers in the USA, Northern Ireland, Germany, and Japan and interviewed by phone. Interviews explored caregiver experiences with infants with respiratory conditions, associated treatment burden, and meaningful change in infant respiratory morbidity as measured by treatment use. Qualitative analysis of interview data was performed using MAXQDA software. Sociodemographic data were summarized using descriptive statistics., Results: Forty-five caregivers (95.6% female) of EP infants were interviewed. Respiratory morbidities post-NICU discharge included coughing (78%), breathing difficulties (76%), wheezing (58%), and bronchopulmonary dysplasia/chronic lung disease of prematurity (56%). Respiratory medications were required by 87% of infants, 80% used home respiratory technology support (e.g., supplemental oxygen), 38% were re-hospitalized, and 33% had emergency department visits. Caregivers considered visits to the emergency department to be the most burdensome treatment requirement they experienced, and reduction in the number of emergency department visits was considered the most meaningful change in treatment use., Conclusion: These findings underscore the significant burden faced by caregivers of EP infants with respiratory morbidities. Development of treatments for respiratory complications should take into consideration the concerns and preferences of caregivers in order to provide a meaningful benefit., Competing Interests: S. Sarda, L. Han, and A. Mangili were employees of Takeda when the study took place. M. Vanya was an employee of ICON at the time of the study and is currently an employee of Takeda. E. Schwartz is an employee of ICON and has no other disclosures to declare. K. Sorrells is an employee of NICU Parent Network and has no other disclosures to declare. F. Namba and S. Hirano are involved in clinical trials sponsored by Takeda. A. McNulty is an employee of TinyLife and has no other disclosures to declare., (© 2023 The Author(s) Published by S. Karger AG, Basel.)

Background: Inhaled nitric oxide (iNO) has been used as a rescue treatment for preterm infants with hypoxemic respiratory failure (HRF). However, its effectiveness remains debatable. Thus, in this study, we aimed to examine the impact of iNO therapy on HRF in extremely preterm infants., Methods: A retrospective observational study was performed. Extremely preterm infants admitted to our neonatal intensive care unit who received iNO therapy later in their postnatal life were included. The oxygen saturation index (OSI) was used as an index of the severity of respiratory failure., Results: In total, 30 extremely preterm infants were included in this study. Oxygenation was enhanced after the administration of iNO in infants with HRF. The OSI decreased by more than 20% in 12 patients (40%, positive responder) and did not decrease in 17 patients (57%, negative responder) within the first 6 h of treatment. The iNO initiation day was the significant independent factor associated with a positive response to iNO therapy in extremely preterm infants with HRF., Conclusions: iNO therapy was effective in enhancing oxygenation in extremely preterm infants with HRF. Earlier use of iNO was the significant factor associated with a positive therapeutic response to iNO, implying that iNO may be more effective in pulmonary vessels which are less damaged by shorter-term mechanical ventilation., (© 2022 Japan Pediatric Society.)

Introduction: The remarkable improvement in the long-term prognosis of extremely premature infants has led to an increase in the number of cases of bronchopulmonary dysplasia (BPD). BPD affects pulmonary function and developmental outcomes, resulting in high chronic health burdens for infants and their families over the years. Therefore, identifying its risk factors in the early period of life and exploring better prophylactics and treatment strategies are important.The objectives of our scoping review are to screen available evidence, identify perinatal risk factors involved in the development and severity of BPD and devise a novel disease classification system that can predict long-term prognosis., Methods and Analysis: Eligibility criteria are as follows: articles published from 2002 to 2021; studies conducted in developed countries; articles written in English (PubMed) or Japanese (Ichushi); randomised controlled trials, prospective/retrospective cohort studies or case-control studies; extremely premature infants born before 28 weeks of gestational age; and articles in which endpoint was severe BPD as classified by the National Institute of Child Health and Human Development.We will screen the titles and abstracts of studies identified by independent reviewers using the population-concept-context framework. After a full-text review and data charting, we will provide the perinatal risk factors for severe BPD along with the risk ratio or odds ratio, 95% confidence interval and p values., Ethics and Dissemination: Institutional review board approval is not required due to the nature of the study. The results of this review will be disseminated through peer-reviewed publications and presentations at relevant conferences.Protocol V.1, 22 September 2021 TRIAL REGISTRATION NUMBER: UMIN000045529., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this study was to assess whether oxidative and inflammatory mediators in the cord blood of newborns with funisitis and chorioamnionitis can serve as indicators of their inflammatory status, and whether there is a positive association between higher mediator levels and an increased risk of admission to the neonatal intensive care unit (NICU). This study was conducted prospectively in a neonatology department of a university hospital. In total, 52 full-term newborns were evaluated, including 17 funisitis cases, 13 chorioamnionitis cases, and 22 control newborns without funisitis or chorioamnionitis. Cord blood samples were measured for oxidative stress and inflammatory status markers. The oxidative stress markers included the total nitric oxide (NO), total hydroperoxide (TH), biological antioxidant potential (BAP), and TH/BAP ratio, comprising the oxidative stress index (OSI). Inflammatory markers included interleukin (IL)-1b, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNFα), interferon γ (IFNγ), and complement component C5a. TH, OSI, IL-1b, IL-6, and IL-8 concentrations were higher in the funisitis group than in the chorioamnionitis and control groups. C5a was higher in the funisitis and chorioamnionitis groups than in the control group. Among all enrolled newborns, 14 were admitted to the NICU. Multiple logistic regression analysis showed that elevated umbilical cord blood levels of OSI and TH were associated with a higher risk of admission to the NICU (OSI: R = 2.3, 95% CI 1.26-4.29, p = 0.007 and TH: R = 1.02, 95%CI = 1.004-1.040, p = 0.015). In conclusion, OSI and TH in cord blood from full-term newborns can provide an index of inflammatory status, and higher levels are associated with the risk of admission to the NICU and, therefore, could serve as an early indicator of inflammatory conditions in newborns.

Background: Bronchopulmonary dysplasia (BPD) is a common and serious complication of extremely preterm birth. Given the anti-inflammatory properties, docosahexaenoic acid (DHA) supplementation has been proposed as a strategy for the management of BPD. This study aimed to investigate the effects of DHA supplementation on BPD based on a systematic review., Methods: A comprehensive literature search was conducted using ClinicalTrials.Gov, CINAHL, Cochrane Library, EMBASE, MEDLINE, PubMed, and the WHO ICTRP from their respective dates of inception to June 2017. The studies included were randomized controlled trials (RCTs) that enrolled preterm infants <33 weeks of gestational age. Trials were included if DHA supplementation was compared with a control., Results: Four RCTs from five reports (1,966 neonates) met our inclusion criteria. The meta-analysis of these studies showed that DHA supplementation did not decrease the risk of BPD at 36 weeks of postmenstrual age among preterm infants ( low certainty of evidence ). DHA supplementation did not significantly reduce the risk of other neonatal morbidities including death ( low certainty of evidence ), BPD at 28 days of life ( moderate certainty of evidence ), necrotizing enterocolitis ( low certainty of evidence ), intraventricular hemorrhage, severe retinopathy of prematurity, or sepsis., Conclusion: DHA supplementation may not exert significant clinical benefits in the treatment of BPD and other neonatal morbidities.

Oxygen-induced retinopathy (OIR) is an animal model for retinopathy of prematurity, which is a leading cause of blindness in children. Thioredoxin-1 (TRX) is a small redox protein that has cytoprotective and anti-inflammatory properties in response to oxidative stress. The purpose of this study was to determine the effect of TRX on OIR in newborn mice. From postnatal day 7, C57BL/6 wild type (WT) and TRX transgenic (TRX-Tg) mice were exposed to either 21% or 75% oxygen for 5 days. Avascular and neovascular regions of the retinas were investigated using fluorescence immunostaining. Fluorescein isothiocyanate-dextran and Hoechst staining were used to measure retinal vascular leakage. mRNA expression levels of proinflammatory and angiogenic factors were analyzed using quantitative polymerase chain reaction. Retinal histological changes were detected using immunohistochemistry. In room air, the WT mice developed well-organized retinas. In contrast, exposing WT newborn mice to hyperoxia hampered retinal development, increasing the retinal avascular and neovascular areas. After hyperoxia exposure, TRX-Tg mice had enhanced retinal avascularization compared with WT mice. TRX-Tg mice had lower retinal neovascularization and retinal permeability during recovery from hyperoxia compared with WT mice. In the early stages after hyperoxia exposure, VEGF-A and CXCL-2 expression levels decreased, while IL-6 expression levels increased in WT newborn mice. Conversely, no differences in gene expressions were observed in the TRX-Tg mouse retina. IGF-1 and Angpt1 levels did not decrease during recovery from hyperoxia in TRX-Tg newborn mice. As a result, overexpression of TRX improves OIR in newborn mice by modulating proinflammatory and angiogenic factors.

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., (© 2021 Japan Pediatric Society.)

Background: Small for gestational age (SGA) infants have an increased risk for neonatal mortality and morbidities. However, few studies have examined the risk of large for gestational age (LGA) on these factors. We compared the risk of mortality and morbidities in LGA premature infants with those of appropriate for gestational age (AGA) infants., Methods: Premature infants who were born between 2003 and 2012 at <26 weeks of gestational age were included. Relative risks of mortality and morbidities were evaluated between LGA and AGA infants., Results: From 6898 extremely premature infants, 357 (5.2%), 5530 (80.2%), and 1011 (14.7%) were LGA, AGA, and SGA, respectively. A total of 5887 infants (5530 AGA and 357 LGA) were examined after excluding infants with congenital anomalies, unknown sex, and deficient data. The risk of mortality in LGA and AGA infants did not differ (relative risk (95% confidence interval) 1.04 (0.83-1.32)). Compared to AGA infants, LGA infants did not increase the risk of morbidities, including intraventricular hemorrhage, cystic periventricular leukomalacia, treated retinopathy of prematurity, necrotizing enterocolitis, and bronchopulmonary dysplasia., Conclusions: This study demonstrates that being born LGA does not correlate with an increased risk of mortality and morbidities in extremely premature infants., Impact: It is currently unknown if being large for gestational age is a risk for neonatal morbidity. A total of 6898 preterm infants born <26 weeks gestational age were included in the study. It was found that being large for gestational age was not related to increased risk of mortality and morbidities., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Many clinical trials have indicated that ibuprofen (IBU) has similar effects to indomethacin (IND) on the closure of patent ductus arteriosus (PDA) with fewer adverse effects. Owing to the scarce evidence on IBU use in Japan because of its recent approval we performed this observational study to compare the efficacy and safety of IBU with the efficiency and safety of IND., Methods: We included infants (gestational age < 30 weeks) with hemodynamically significant PDA under a prophylactic IND protocol for intraventricular hemorrhage who were treated with either IND (n = 30) or IBU (n = 30). We compared a PDA closing effect, changes in ultrasonography findings, and adverse effects between the groups., Results: There was no significant difference in the rates of PDA closure in the first treatment course (IND vs IBU: 46.7% vs 50.0%, P = 0.796) and surgical closure (IND vs IBU: 20.0% vs 20.0%, P = 1.000) between the groups. Both groups showed significant oliguria (IND vs IBU: 30.0% vs 23.3%, P = 0.559) and increased serum creatinine levels after treatment. However, an increase in serum creatinine level by >0.3 mg/dL, a criterion for acute kidney injury, was less frequent in the IBU group (35.7%) compared with that in the IND group (84.2%, P = 0.004). There were no significant differences in echocardiographic changes and jaundice and hypoglycemia incidence rates between the groups., Conclusions: Except for an increase in serum creatinine levels by >0.3 mg/dL, which was less frequent with IBU, IBU had similar efficacy and safety as IND for preterm PDA. Ibuprofen and IND should be cautiously administered., (© 2020 Japan Pediatric Society.)

Objective: Delayed cord clamping (DCC) is recommended for healthy term infants. However, the effectiveness of umbilical cord milking (UCM) in term infants remains unknown. The study aimed to compare the effects of UCM versus DCC on term infants., Study Design: A systematic review and meta-analysis were conducted which included individual and clustered RCTs comparing UCM with DCC for infants born at ≥37 weeks of gestation., Results: Three trials (650 term infants) were included. Compared with DCC, UCM was associated with higher hemoglobin levels at 6 weeks after birth [infants, 621; mean difference, 0.17; 95% confidence interval, 0.05-0.29] and had no statistical differences in hemoglobin levels at birth, serum bilirubin levels at 48 h after birth, or hematocrit levels at 48 h after birth., Conclusion: This study suggested that UCM might be as beneficial as DCC in term infants, however, further RCTs are required to accurately assess the outcomes., (© 2020. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Bronchopulmonary dysplasia (BPD) is a serious complication of preterm delivery and low birthweight infants. The incidence of BPD has not decreased, and there is no effective treatment for the disease. Since the survival rate of premature infants has increased, it has become difficult to obtain pathological tissue samples from BPD death cases. There is also no in vitro experimental system for complex three-dimensional structures, such as alveolarization and pulmonary angiogenesis; thus, the use of animal models is necessary to elucidate the pathology of BPD and develop new treatments. To date, BPD animal models were being developed by exposing immature animal lungs to various stimuli. In the present review, I summarize BPD animal models that use (i) highly concentrated oxygen, (ii) mechanical ventilation, and (iii) infection/inflammation. In addition, with mesenchymal stromal cell (MSC) therapy for BPD as an example, I will discuss the expectations for new treatments that would be applied from animal models to humans., (© 2021 Japan Pediatric Society.)

Background: Bronchopulmonary dysplasia (BPD) remains one of the most serious morbidities associated with preterm birth. Previous study reported that bubbly/cystic appearance on chest X-rays in the neonatal period is the strongest determinant of impaired lung function at school age in BPD patients., Aims: To determine perinatal risk factors for bubbly/cystic appearance on chest X-rays in extremely premature infants with BPD exposed to histological chorioamnionitis histological chorioamnionitis (hCAM)., Study Design: Multicenter retrospective cohort study., Subjects: We analyzed 1369 extremely premature infants with severe hCAM who were admitted to the neonatal intensive care units participating in the Neonatal Research Network, Japan (NRNJ) Neonatal research network Japan., Outcome Measures: Perinatal characteristics were compared and logistic regression analysis was performed for multivariate risk factor assessment., Result: Infants with bubbly/cystic appearance on chest X-rays underwent longer duration of invasive mechanical ventilation and required inhaled nitric oxide and home oxygen therapy more frequently. Low gestational age (odds ratio 1.244; 95% confidence interval 1.139-1.359) and preterm premature rupture of membranes (odds ratio 1.507; 95% confidence interval 1.200-1.893) were significant risk factors., Conclusion: Low gestational age and preterm premature rupture of membranes were independent risk factors for bubbly/cystic appearance in extremely premature infants with BPD following exposure to severe hCAM.

Background: Because of the improvements in survival rates for preterm infants, not only the rates of bronchopulmonary dysplasia (BPD) but also those of long-term respiratory complications of premature birth are increasing, resulting in financial and health burdens in developed countries. Thus far, the risk factors of respiratory morbidities in extremely preterm infants remain unknown. Furthermore, the definition and the predictive ability of BPD for long-term respiratory outcomes are yet to be determined., Objective: The objective of our study, Extreme Prematurity and Pulmonary Outcomes Program in Saitama, is to develop the diagnostic criteria for BPD and to determine the prognostic factors contributing to the long-term pulmonary outcomes manifesting in extremely preterm infants., Methods: The Extreme Prematurity and Pulmonary Outcomes Program in Saitama is an observational prospective cohort study performed by a consortium of six neonatal intensive care units (NICUs) in Saitama, Japan. The subjects included in this study are infants (from each clinical center) with gestational ages 22 to 27 weeks. The target is 400 subjects. This study aims to determine the definition of BPD and other perinatal factors that accurately predict the long-term pulmonary outcomes in survivors of extreme prematurity. Moreover, the association between BPD and postprematurity respiratory disease will be investigated using generalized linear models., Results: The protocol and consent forms were evaluated and approved on September 5, 2019, by the Ethics Committee of Saitama Medical Center, Saitama Medical University. Enrollment began on April 1, 2020. It is expected to end on March 31, 2023. The follow-up for 1 year corrected age is expected to continue through the middle of 2024., Conclusions: The Extreme Prematurity and Pulmonary Outcomes Program in Saitama incorporates aspects of neonatal care in secondary- and tertiary-level NICUs to develop existing research studies on the definition of BPD, objective biomarkers, and outcome measures of respiratory morbidity in extremely preterm infants beyond NICU hospitalization, thereby leading to a novel understanding of the nature and natural history of BPD and potential mechanistic and therapeutic targets in at-risk subjects., International Registered Report Identifier (irrid): DERR1-10.2196/22948., (©Fumihiko Namba, Kosuke Tanaka, Sayu Omori, Kazushige Ikeda, Ken Kawabata, Hiroaki Sato, Masakazu Honda, Tomonori Ichikawa, Yoshihiro Minosaki, Takehiro Michikawa, Shuntaro Oka, Kazuhiko Kabe. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 05.03.2021.)

We herein report a unique case of aortic rupture due to co-localization of aortic intimal myofibroblastic sarcoma (IMFS) and urothelial carcinoma (UC). A 76-year-old man who was being followed up after surgery for UC 5 years earlier developed aortic rupture and underwent emergency surgery. Intraoperatively, a tumorous mass on the luminal side of the aortic arch was found near the rupture. A histopathological analysis of the mass revealed aortic IMFS. Furthermore, co-localization of IMFS and UC cells was found near the rupture. The fragility of the aortic wall due to co-localization of IMFS and UC was believed to contribute to the aortic rupture.

Objective: Hypoglycemia increases the risk of adverse neurological outcomes in neonates. Adequate glucose monitoring requires repetitive and painful blood sampling. We aimed to evaluate the feasibility and accuracy of a continuous glucose monitoring system (CGMS) using factory-calibrated sensors to improve glucose monitoring and decrease the frequency of blood samples in neonates., Material and Methods: A methodological study was conducted to investigate a correlation of CGMS values with blood glucose measurements., Results: Factory-calibrated CGMS sensors were placed on 21 infants at risk of hypoglycemia after delivery. CGMS values were compared with blood glucose concentrations. Thirty-seven pairs of CGMS and blood glucose values were obtained. There was a good correlation between CGMS and blood glucose values (R=0.67, p<0.01) with a mean difference (2 standard deviations) of 9.78 (-24.68 to 44.25) mg/dL. The mean differences at <3 hours and ≥3 hours after sensor placement were 17.35 (-4.54 to 39.21) mg/dL and 0.88 (-37.62 to 39.38) mg/dL, respectively. CGMS values were significantly higher than blood glucose concentration at <3 hours after sensor placement (p<0.01), whereas no significant differences in glucose values were observed between the CGMS and blood glucose values at ≥3 hours after sensor placement (p=0.852)., Conclusion: The factory-calibrated CGMS was a safe and feasible modality for glucose monitoring. However, it has a tendency to overestimate the blood glucose concentrations. Therefore, this system should be used cautiously for neonates at risk of hypoglycemia, especially within 3 hours after sensor placement., Competing Interests: Conflict of Interest: FreeStyle Libre System was leased from Abbott Japan Co., Ltd. (Tokyo, Japan)., (Copyright © 2021 Turkish Pediatric Association.)

Objectives: Our aim is to compare the efficacy and safety of high-flow nasal cannula (HFNC) against those of nasal continuous positive airway pressure (NCPAP) or nasal intermittent positive-pressure ventilation (NIPPV) after extubation in preterm infants., Methods: This prospective, randomized, noninferiority trial was conducted in 6 tertiary NICUs. Infants born at <34 weeks who needed noninvasive ventilation after extubation were enrolled. We randomly assigned infants to an HFNC group when HFNC was used or to an NCPAP/NIPPV group when NCPAP or NIPPV was used. The primary outcome was treatment failure within 7 days after extubation. We then examined clinical aspects of treatment failure with HFNC use., Results: In total, 176 and 196 infants were assigned to the HFNC and NCPAP/NIPPV groups, respectively. The HFNC group showed a significantly higher rate of treatment failure than that of the NCPAP/NIPPV group, with treatment failure occurring in 54 infants (31%) compared with 31 infants (16%) in the NCPAP/NIPPV group (risk difference, 14.9 percentage points; 95% confidence interval, 6.2-23.2). Histologic chorioamnionitis ( P = .02), treated patent ductus arteriosus ( P = .001), and corrected gestational age at the start of treatment ( P = .007) were factors independently related to treatment failure with HFNC use., Conclusions: We found HFNC revealed a significantly higher rate of treatment failure than NCPAP or NIPPV after extubation in preterm infants. The independent factors associated with treatment failure with HFNC use were histologic chorioamnionitis, treated patent ductus arteriosus, and a younger corrected gestational age at the start of treatment., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Branched-chain amino acids (BCAAs) play a vital role in neonatal nutrition. Optimal BCAA supplementation might improve neonatal nutrient storage, leading to better physical and neurological development and other outcomes., Objectives: To determine the effect of BCAA supplementation on physical growth and neurological development in term and preterm neonates. We planned to make the following comparisons: parenteral nutrition with and without BCAA supplementation; enteral BCAA supplementation versus no supplementation; and any type of supplementation including enteral, parenteral and both ways versus no supplementation. To investigate the supplementation effectiveness for different dosages assessed in the eligible trials., Search Methods: We conducted comprehensive searches using Cochrane Neonatal's standard search strategies: Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 6), MEDLINE, Embase and CINAHL (up to July 2016). We updated the search with CENTRAL (2019, Issue 8), MEDLINE, Embase and CINAHL (up to August 2019). We also searched clinical trials registries and reference lists of retrieved articles., Selection Criteria: We planned to include individual and cluster-randomised and quasi-randomised controlled trials comparing BCAA supplementation versus placebo or no supplementation in term and preterm neonates. We excluded trials presented only as abstracts and cross-over trials., Data Collection and Analysis: Two review authors independently assessed the eligibility of all potential studies identified from the search strategy. We planned to extract data using a pilot-tested standard data extraction form and assess risk of bias of the included studies following the methods described in the Cochrane Handbook for Systematic Reviews of Interventions. We planned to analyse treatment effects and report their effect estimates as per dichotomous or continuous data with 95% confidence intervals. We planned to conduct subgroup analysis to investigate heterogeneity, and perform sensitivity analysis where possible. We planned to use fixed-effect meta-analysis to combine data wherever appropriate. We planned to assess evidence quality using the GRADE approach., Main Results: We did not identify any potentially eligible studies that met the inclusion criteria in this review., Authors' Conclusions: We found no trial data to support or refute the idea that BCAA supplementation affects physical and neurological development and other outcomes in term and preterm neonates., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: Neonatal lungs are more tolerant to hyperoxic injury than are adult lungs. This study investigated differences in the response to hyperoxic exposure between neonatal and adult mouse lungs using metabolomics analysis with capillary electrophoresis time-of-flight mass spectrometry (CE- TOFMS)., Methods: Neonatal and adult mice were exposed to 21% or 95% O2 for four days. Subsequently, lung tissue samples were collected and analyzed by CE-TOFMS. Pyruvate dehydrogenase (PDH) enzyme activity was determined using a microplate assay kit. PDH kinase (Pdk) 1, Pdk2, Pdk3, and Pdk4 mRNA expression levels were determined using quantitative reverse transcription-polymerase chain reaction. Pdk4 protein expression was quantified by Western blotting and Pdk4 protein localization was evaluated by immunohistochemistry., Results: Levels of 3-phosphoglyceric acid, 2-phosphoglyceric acid, phosphoenolpyruvic acid, and lactic acid were significantly elevated in the lungs of hyperoxia-exposed versus normoxia-exposed adult mice, whereas no significant differences were observed with hyperoxia exposure in neonatal mice. PDH activity was reduced in the lungs of adult mice only. Pdk4 mRNA expression levels after hyperoxic exposure were significantly elevated in adult mice compared with that in neonatal mice. Conversely, gene expression levels of Pdk1, Pdk2, and Pdk3 did not differ after hyperoxic exposure in either neonatal or adult mice. Pdk4 protein levels were also significantly increased in adult mouse lungs exposed to hyperoxia and were localized mainly to the epithelium of terminal bronchiole., Conclusions: Specific metabolites associated with glycolysis and gluconeogenesis were altered after hyperoxia exposure in the lungs of adult mice, but not in neonates, which was likely a result of reduced PDH activity due to Pdk4 mRNA upregulation under hyperoxia., Competing Interests: The authors have declared that no competing interests exist.

Background: Bronchopulmonary dysplasia (BPD) is a common complication in very preterm infants. Despite advances in perinatal medicine, the number of BPD patients is increasing in Japan. The aim of this study was to conduct a nationwide survey of the strategies used for the prevention or treatment of BPD., Methods: Questionnaires assessing the current strategies used to prevent or treat BPD, including neonatal resuscitation, drug therapy, and respiratory supportive care, were sent to secondary or tertiary perinatal units in 2015; responses were compared with those obtained from similar surveys in 2005 and 2010. The annual trend in incidence of BPD among the very low birth weight infants (VLBWIs) was determined using the Neonatal Research Network of Japan database., Results: The response rates in 2005, 2010, and 2015 were 86.8% (230/265), 64.5% (185/287), and 82.8% (236/285) of units, respectively. The use of patient-triggered ventilation for initial management significantly increased from 50% of units in 2005 to 91% in 2015. By contrast, decreased use of high-frequency oscillatory ventilation (HFOV) from 72% to 65% and that of nasal continuous positive airway pressure from 79% to 68% were reported. The proportion of units where the upper limit of targeted blood oxygen saturation before a diagnosis of BPD was set to ≥95% decreased substantially from 92% to 56% over the 10-year period. Despite these changes in management of BPD, the incidence of BPD among VLBWIs in Japan was increasing over a decade., Conclusion: This survey demonstrated that there were various changes in practice regarding the prevention or treatment of BPD in Japan. Continuous surveys are required to understand the current clinical situation, and research is needed to develop and evaluate a novel treatment for BPD in premature infants., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2019. Published by Elsevier B.V.)

Premature infants are often exposed to positive pressure ventilation and supplemental oxygen, which leads to the development of chronic lung disease (CLD). There are currently no standard serum biomarkers used for prediction or early detection of patients who go on to develop CLD. MicroRNAs (miRNAs) are a novel class of naturally occurring, short, noncoding substances that regulate gene expression at the posttranscriptional level and cause translational inhibition and/or mRNA degradation and present in body fluids packaged in extracellular vesicles (EVs), rendering them remarkably stable. Our aim was to evaluate miRNAs identified in serum EVs of premature infants as potential biomarkers for CLD. Serum EVs were extracted from premature infants at birth and on the 28th day of life (DOL). Using a human miRNA array, we identified 62 miRNAs that were universally expressed in CLD patients and non-CLD patients. Of the 62 miRNAs, 59 miRNAs and 44 miRNAs were differentially expressed on DOL0 and DOL28 in CLD and non-CLD patients, respectively. Of these miRNAs, serum EV miR-21 was upregulated in CLD patients on DOL28 compared with levels at birth and downregulated in non-CLD patients on DOL28 compared with levels at birth. In neonatal mice exposed to hyperoxia for 7days, as a model of CLD, five miRNAs (miR-34a, miR-21, miR-712, miR-682, and miR-221) were upregulated, and 7 miRNAs (miR-542-5p, miR-449a, miR-322, miR-190b, miR-153, miR-335-3p, miR-377) were downregulated. MiR-21 was detected as a common miRNA that changed in CLD patients and in the hyperoxia exposed mice. We conclude that EV miR-21 may be a biomarker of CLD.

The role of thioredoxin-1 (TRX), a small redox-active protein with antioxidant effects, during hyperoxic lung injury in newborns remains undetermined. We investigated TRX impact on hyperoxic lung injury in newborn TRX transgenic (TRX-Tg) and wildtype (WT) mice exposed to 21% or 95% O 2 for four days, after which some mice were allowed to recover in room air for up to 14 days. Lung morphology was assessed by hematoxylin/eosin and elastin staining, as well as immunostaining for macrophages. The gene expression levels of proinflammatory cytokines were evaluated using quantitative real-time polymerase chain reaction. During recovery from hyperoxia, TRX-Tg mice exhibited an improved mean linear intercept length and increased number of secondary septa in lungs compared with the WT mice. Neonatal hyperoxia enhanced the mRNA expression levels of proinflammatory cytokines in the lungs of both TRX-Tg and WT mice. However, interleukin-6, monocyte chemoattractant protein-1, and chemokine (C-X-C motif) ligand 2 mRNA expression levels were reduced in the lungs of TRX-Tg mice compared with the WT mice during recovery from hyperoxia. Furthermore, TRX-Tg mice exhibited reduced macrophage infiltration in lungs during recovery. These results suggest that in newborn mice TRX ameliorates hyperoxic lung injury during recovery likely through the suppression of proinflammatory cytokines.

Background: Intrauterine inflammation affects fetal lung development. BTB and CNC homology 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1) and interleukin-6 (IL-6) genes. We investigated the role of Bach1 in the development of fetal mouse lungs exposed to lipopolysaccharide (LPS) using a whole fetal lung tissue culture system., Methods: We isolated and cultured embryonic day 12.5 fetal mouse lungs from pregnant Bach1 knockout ( -/- ) and wild-type (WT) mice. Airway branching morphogenesis was assessed by microscopically counting peripheral lung buds after incubation with/without LPS. Expression levels of genes related to inflammation and oxidative stress were evaluated using quantitative PCR. Zinc protoporphyrin, HO-1-specific inhibitor, was used., Results: Branching morphogenesis was observed in Bach1 -/- and WT fetal mice lungs without LPS exposure; after exposure to LPS, the number of peripheral lung buds was suppressed in Bach1 -/- group only. Basal messenger RNA (mRNA) and protein expression of HO-1 was significantly higher in Bach1 -/- group than in WT group; IL-6 and monocyte chemoattractant protein-1 mRNA expression was significantly increased after LPS exposure in both groups. Zinc protoporphyrin mitigated the LPS-induced suppression of branching morphogenesis in Bach1 -/- mice., Conclusion: The ablation of Bach1 suppresses airway branching morphogenesis after LPS exposure by increased basal expression levels of HO-1.

Background: The arterial oxygen saturation of infants requiring resuscitation can be monitored using a pulse oximeter. However, the device cannot provide information about cerebral oxygenation. Thus, we used a new portable near-infrared spectroscopy (NIRS) device that can monitor regional cerebral tissue oxygen saturation (crSO 2 ) with a probe attached to the examiner's finger., Aim: To identify the reference ranges for crSO 2 within the first 10 min after birth in term infants who did not receive any medical intervention in the delivery room., Results: crSO 2 in the left frontoparietal area of the forebrain was measured within the first 10 min of life in 127 healthy term infants. The median gestational age and birth weight were 37.6 weeks and 2742 g, respectively, and 85% of the infants were delivered via a scheduled cesarean section. The 3rd-97th percentile values for crSO 2 ranged from 33.1% to 56.7% at 1 min, from 33.2% to 59.5% at 2 min, and from 38.7% to 66.6% at 5 min after birth. A median of 3.5 min was required to achieve a crSO 2  > 50%., Conclusions: This study showed the reference ranges for crSO 2 measured with the new portable NIRS device within the first 10 min after birth in term infants., Competing Interests: Declaration of competing interest A KN-15 NIRS device was leased from ASTEM Co., Ltd. (Kawasaki, Japan)., (Copyright © 2019 Elsevier B.V. All rights reserved.)