Noninvasive neurally-adjusted ventilatory assist in preterm infants: a systematic review and meta-analysis.

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.

Prolonged oligohydramnios and the adverse composite outcome of death or severe neurodevelopmental impairment at 3 years of age in infants born at 22-29 gestational weeks.

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.

High oxygen exposure's impact on newborn mice: Temporal changes observed via micro-computed tomography.

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.

Survival and unique clinical practices of extremely preterm infants born at 22-23 weeks' gestation in Japan: a national survey.

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.

Predictability of the neurodevelopmental assessment based on the Kyoto Scale of Psychological Development 2001 at 18-24 months of corrected age and 3 years of age in identifying cognitive impairment at 6 years of age in very preterm infants: A retrospective study at a Japanese tertiary center.

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.

Genetic Ablation of Pyruvate Dehydrogenase Kinase Isoform 4 Gene Enhances Recovery from Hyperoxic Lung Injury: Insights into Antioxidant and Inflammatory Mechanisms.

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.

Handling of human milk to prevent acquired cytomegalovirus infection in Japanese neonatal intensive care units: The first nationwide survey.

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.

Association of hyaluronan and proteoglycan link protein 1 gene with the need of home oxygen therapy in premature Japanese infants with bronchopulmonary dysplasia.

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.

The serum thioredoxin-1 levels are not associated with bronchopulmonary dysplasia and retinopathy of prematurity.

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.

Management of bronchopulmonary dysplasia in Japan: A nationwide survey.

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.

Interventions for treating umbilical granuloma: a protocol for a systematic review and meta-analysis of randomised controlled trials.

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.

Antenatal corticosteroids in specific groups at risk of preterm birth: a systematic review.

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.

School-Age Outcomes of Antenatal Magnesium Sulphate in Preterm Infants.

BACKGROUND: Antenatal magnesium sulphate (MgSO4) 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 MgSO4 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 MgSO4 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 MgSO4 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 MgSO4 therapy on school-age outcomes. Further accumulation of long-term data is required.

Heterogeneity and Gaps in Reporting Primary Outcomes From Neonatal Trials.

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.

Strengthening Reporting of Neonatal Trials.

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.

Management and outcomes of periviable neonates born at 22 weeks of gestation: a single-center experience in Japan.

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.

Burden of Treatments for Respiratory Complications in Extremely Premature Infants: Interviews with Caregivers.

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.

Effect of Fentanyl for Preterm Infants on Mechanical Ventilation: A Systematic Review and Meta-Analysis.

INTRODUCTION: Because excessive physical stress is harmful, reducing pain and discomfort in premature neonates during mechanical ventilation is a major challenge for physicians. There are no consensus and systematic review on the use of fentanyl, the most commonly used pain reliever in preterm neonates during mechanical ventilation. We aim to compare the benefits and harms of fentanyl versus placebo or no drug for preterm neonates receiving mechanical ventilation. METHODS: A systematic review of randomized controlled trials (RCTs) was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The systematic review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Scientific databases such as MEDLINE, Embase, CENTRAL, and CINAHL were searched. All preterm infants on mechanical ventilation and enrolled in an RCT of fentanyl versus control were included. RESULTS: Of 256 reports initially retrieved, 4 reports met the eligibility criteria. Fentanyl was not associated with mortality risk compared to the control (risk ratio: 0.72, 95% confidence intervals [CIs]: 0.36-1.44). No increase in ventilation duration (mean difference [MD]: 0.04, 95% CIs: -0.63-0.71) and no effect on hospital stay length (MD: 4.00, 95% CIs: -7.12-15.12) were found. Fentanyl intervention does not affect any other morbidities, including bronchopulmonary dysplasia, periventricular leukomalacia, patent ductus arteriosus, intraventricular hemorrhage (IVH), severe IVH, sepsis, and necrotizing enterocolitis. CONCLUSION: The present systematic review and meta-analysis failed to demonstrate the benefit of administering fentanyl to preterm infants on mechanical ventilation in mortality and morbidities. Follow-up studies are required to investigate the long-term neurodevelopment of the children.

iPAPP: study protocol for a multicentre randomised controlled trial comparing safety and efficacy of intravenous paracetamol and indomethacin for the treatment of patent ductus arteriosus in preterm infants.

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.