Shin Kato

Background/Objectives: Phototherapy is an effective first-line treatment for neonatal jaundice. Previous studies have demonstrated a linear dose-dependent relationship between irradiance and bilirubin reduction during intensive phototherapy up to approximately 55 μW/cm²/nm, although others have suggested that the therapeutic effect plateaus with higher irradiance. However, the efficacy and safety of treatment at these irradiance levels remain unclear. By focusing on newborns with severe jaundice close to the exchange transfusion threshold, we aimed to examine whether the dose-dependent association between phototherapy irradiance and bilirubin reduction is maintained at irradiance levels above 55 μW/cm²/nm. Methods: Here, phototherapy delivered at estimated irradiance levels >55 μW/cm²/nm was defined as ultra-high-irradiance phototherapy. We retrospectively reviewed 92 neonates with severe jaundice admitted to a tertiary neonatal intensive care unit between 2017 and 2024. Severe jaundice was defined as total serum bilirubin levels above or within 2.5 mg/dL of the exchange transfusion threshold. We evaluated the dependence of the bilirubin reduction rate on estimated irradiance and other clinical variables. Results: Only one neonate required exchange transfusion. In multivariable analysis, the bilirubin reduction rate was associated with estimated irradiance (p < 0.001) and total serum bilirubin at phototherapy initiation (p < 0.001). Bilirubin reduction was dose-dependent on estimated irradiance up to 148 μW/cm²/nm (0.31 mg/dL/h per 100 μW/cm²/nm). Transient hyperthermia occurred in 12% of infants. Conclusions: Higher estimated irradiance was associated with greater bilirubin reduction up to 148 μW/cm²/nm. These findings support further prospective evaluation of optimized phototherapy irradiance in severe neonatal jaundice.

Introduction: Randomized controlled trials (RCTs) have not demonstrated that diuretics prevent bronchopulmonary dysplasia (BPD), but recent observational studies warrant an updated synthesis. We evaluated the preventive effects and safety of diuretics in preterm infants at risk of developing BPD. Methods: MEDLINE, Embase, Cochrane CENTRAL, and CINAHL were searched through June 2025. We included randomized and non-randomized studies of various diuretic classes with different routes, dosing regimens, and treatment durations. The risk of bias was assessed using the RoB 2 and ROBINS-I and the certainty of evidence using GRADE. Random-effects models were used to calculate the risk ratios and 95% confidence intervals. Results: Forty studies, including six RCTs, were analyzed. Furosemide was the most frequently used diuretic. The RCTs predominantly focused on short-term changes in lung mechanics and did not demonstrate any preventive effect of diuretics on BPD. The meta-analysis showed no significant effects of diuretics on death or BPD (RR, 1.10; 95% CI, 0.77–1.59) or mortality (RR, 0.44; 95% CI, 0.19–1.04). Electrolyte abnormalities were not significantly increased (RR, 1.51; 95% CI, 0.81–2.83). Non-randomized studies have reported a potential reduction in BPD occurrence. However, the overall certainty of the evidence is low to very low due to the small sample sizes and confounding. Conclusion: The current evidence does not confirm that diuretics prevent BPD. Given the uncertainty of the current evidence and the favorable safety profiles, adequately powered RCTs are needed to explore the potential role of diuretics in BPD prevention.

Background: Moderate and late preterm infants (32–36 weeks of gestation) are at significant risk of developmental impairments. Incidence of white matter lesions, which are associated with developmental impairments in very preterm infants, remains underreported in this population. This study aimed to assess the incidence and clinical risk factors associated with brain lesions, particularly white matter lesions, in moderate and late preterm infants using term-equivalent MRI. Methods: This prospective observational study included 195 preterm infants born at 32+0–36+6 weeks of gestation and admitted to a tertiary NICU between 2019 and 2020. MRI findings at term-equivalent age were evaluated. Clinical risk factors were analysed using logistic regression. Results: Among the 195 infants, 23.6% had brain lesions on MRI, with white matter lesions (73.9%), specifically punctate white matter lesions, being the most common form of lesions. Vaginal delivery (odds ratio (OR) = 3.102, 95% confidence interval (CI) = 1.250–7.696, p = 0.015), larger birth weight z-scores (OR = 1.702, 95% CI = 1.118–2.591, p = 0.013), and intubation (OR = 2.948, 95% CI = 1.269–6.850, p = 0.012) were significant risk factors for white matter lesions. Conclusions: White matter lesions, particularly punctate white matter lesions, are common in moderate and late preterm infants. These lesions are associated with perinatal factors suggestive of delayed transition and inflammation. Future research should focus on detailed clinical care measures and neurodevelopmental assessments to identify modifiable risk factors for brain injury.

Objectives Inhaled nitric oxide (iNO) is a known treatment for pulmonary hypertension (PH) associated with bronchopulmonary dysplasia in preterm infants after 7 days of age (postacute phase). However, a consensus regarding the optimal criteria for initiating iNO therapy in this population in the postacute phase is currently lacking. This study, therefore, aimed to identify the criteria for initiating iNO therapy, alongside the associated clinical and echocardiographic findings, in this population. Design We performed a scoping review using the population-concept-context framework following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Data sources PubMed, Embase and the Japanese database ‘Ichushi’ were systematically searched for relevant articles published between January 2003 and August 2023. Eligibility criteria This study included randomised controlled trials, prospective and retrospective cohort studies, case–control studies and case series on iNO therapy in the postacute phase for preterm infants born before 34 gestational weeks, written in English or Japanese. Data extraction and synthesis Data screening, extraction and charting were performed independently, with the characteristics and findings of the included studies subsequently summarised. Results We included 10 reports that analysed the data from 10 separate studies. The use of iNO therapy was categorised as prophylactic and rescue purposes. While randomised controlled trials (RCTs) and retrospective analyses indicated the safety of iNO during the postacute phase, the latter highlighted poor prognoses associated with severe cases requiring rescue iNO therapy. Additionally, although echocardiography is currently the primary diagnostic tool for identifying PH in preterm infants, standardised diagnostic criteria are lacking. Further, reports of complications and side effects associated with iNO are rare. Conclusion Our exploration of the initiation criteria for iNO revealed that definitive guidelines have not been established. Nonetheless, iNO administration during the postacute phase appeared to be safe and devoid of complications. Trial registration number UMIN000051498.

Despite advances in treatment options, such as corticosteroid administration and less invasive respiratory support, bronchopulmonary dysplasia (BPD) remains an important prognostic factor in preterm infants. We previously reported that furin regulates changes in lung smooth muscle cell phenotypes, suggesting that it plays a critical role in BPD pathogenesis. Therefore, in this study, we aimed to evaluate whether it regulates the alveolarization of immature lungs through activating alveolarization-driving proteins. We first examined furin expression levels, and its functions, using an established hyperoxia-induced BPD mouse model. Thereafter, we treated mice pups, as well as primary myofibroblast cell cultures, with furin inhibitors. Finally, we administered the hyperoxia-exposed mice pups with recombinant furin. Immunofluorescence revealed the co-expression of furin with alpha-smooth muscle actin. Hyperoxia exposure for 10 d decreased alveolar formation, as well as the expression of furin and its target, IGF-1R. Hexa-D-arginine administration also significantly inhibited alveolar formation. Another furin inhibitor, decanoyl-RVKR-chloromethylketone, accumulated pro-IGF-1R, and decreased IGF-1R phosphorylation in myofibroblast primary cultures. Finally, recombinant furin treatment significantly improved alveolarization in hyperoxia-exposed mice pups. Furin regulates alveolarization in immature lungs. Therefore, this study provides novel insights regarding the involvement of furin in BPD pathogenesis, and highlights a potential treatment target for ameliorating the impact of BPD.

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.

The lower body temperature of preterm newborns at admission to neonatal intensive care units (NICUs) is inversely associated with their morbidities and mortalities before discharge. This retrospective cohort study aimed to determine whether admission rectal temperature in very low birth weight infants (VLBWIs) is independently associated with a composite outcome of death or moderate-to-severe neurodevelopmental impairments as defined by a performance developmental quotient of < 70 at three years of age. VLBWIs admitted to the NICU between April 2010 and March 2016 were assesed. Developmental assessment was completed in 216 newborns. Nine and two infants died before and after discharge, respectively. A higher admission temperature was associated with a lower incidence of death or moderate-to-severe neurodevelopmental impairments with adjustment for gestational age, sex, antenatal steroid use, Apgar score, severe intraventricular hemorrhage, and severe bronchopulmonary dysplasia (odds ratio [OR] 0.424; 95% confidence interval [CI] 0.250–0.717; p = 0.001). The admission temperature remained as an independent variable of adverse outcome at three years of age even when the study cohort was limited to surviving infants (OR 0.448; 95% CI 0.259–0.774; p = 0.004). Further studies are needed to assess whether avoiding low body temperature at admission results in better long-term neurodevelopmental outcomes in VLBWIs.

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.

Periviable infants (PIs) born at 22–25 weeks gestational age (wGA) have a variable survival rate (49.7–86.2%) among hospitals. One factor involved in this difference may be the definition of the threshold of viability. The American Academy of Pediatrics revised the neonatal resuscitation program in late 2015 (NRP 2015) and altered the threshold of viability from 23 to 22 wGA. The impact on the survival of PIs after the guideline alteration has seldom been discussed. Since 2016, the unit of this study has implemented the renewed guideline for PIs. We retrospectively reviewed and analyzed the survival and clinical variables of PIs before and after implementation of the guideline, which included a 10-year cohort in a single center in Taiwan. There were 168 PIs enrolled between 2010 and 2019 (Epoch-I, 2010–2015; Epoch-II, 2016–2019), after excluding those with congenital anomalies and parent-decided comfort care. Compared to those in Epoch-I, the PIs in Epoch-II had significantly higher odds ratios (2.602) (95% confidence interval: 1.170–5.789; p = 0.019) for survival. Younger gestational age, small size for gestational age, cesarean delivery, low blood pH at birth, and surfactant therapeutic treatment were found to be significant risk factors associated with the survival of PIs (p < 0.05 for each). The altered threshold of viability by NRP 2015 may impact the survival of PIs. However, long-term follow-up for surviving PI is required in the future.