Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity: Two-Year Efficacy and Safety Outcomes in the Nonrandomized Controlled Trial FIREFLEYE next.

Importance: Prospective long-term data after retinopathy of prematurity (ROP) treatment with anti-vascular endothelial growth factor injections vs laser therapy are scarce. The FIREFLEYE (Aflibercept for ROP IVT Injection vs Laser Therapy) next trial is prospectively evaluating the long-term efficacy and safety outcomes following ROP treatment with intravitreal aflibercept vs laser therapy. Objective: To evaluate 2-year ophthalmic and safety outcomes after 0.4-mg aflibercept injection or laser therapy in the 24-week randomized (2:1) FIREFLEYE trial (FIREFLEYE outcomes previously reported). Design, Setting, and Participants: This prospective nonrandomized controlled trial performed in 24 countries in Asia, Europe, and South America (2020-2025) follows up participants treated in the FIREFLEYE randomized clinical trial (2019-2021) through 5 years of age. Participants included children born very or extremely preterm (gestational age ≤32 weeks) or with very or extremely low birth weight (≤1500 g) who were previously treated with a 0.4-mg injection of aflibercept compared with laser therapy for severe acute-phase ROP. Data for the present interim analysis were acquired from March 18, 2020, to July 25, 2022. Interventions: Complications of ROP treated at investigator discretion (no study treatment). Main Outcomes and Measures: Efficacy end points included ROP status, unfavorable structural outcomes, ROP recurrence, treatment for ROP complications, completion of vascularization, and visual function. Safety end points included adverse events and growth and neurodevelopmental outcomes. Results: Overall, 100 children were enrolled (median gestational age, 26 [range, 23-31] weeks; 53 boys and 47 girls). Of these, 21 were Asian, 2 were Black, 75 were White, and 2 were of more than 1 race. At 2 years of age, 61 of 63 children (96.8%) in the aflibercept group vs 30 of 32 (93.8%) in the laser group had no ROP. Through 2 years of age, 62 of 66 (93.9%) in the aflibercept group and 32 of 34 (94.1%) in the laser group had no unfavorable structural outcomes. No new retinal detachment occurred during the study. Four children in the aflibercept group (6.1%) were treated for ROP complications before 1 year of age (2 had preexisting end-stage disease and total retinal detachment; 1 had reactivated plus disease; and 1 had recurrent retinal neovascularization not further specified). Most children were able to fix and follow a 5-cm toy (aflibercept group, 118 of 122 eyes [96.7%] among 63 children; laser group, 62 of 63 eyes [98.4%] among 33 children). High myopia was present in 9 of 115 eyes (7.8%) among 5 children in the aflibercept group and 13 of 60 eyes (21.7%) among 9 children in the laser group. No relevant differences in growth and neurodevelopmental outcomes by Bayley Scales of Infant and Toddler Development, Third Edition and Vineland Adaptive Behavior Scales, Second Edition were identified. Conclusions and Relevance: In this nonrandomized follow-up of a randomized clinical trial comparing treatment of severe acute-phase ROP with 0.4-mg injection of aflibercept and laser, disease control was stable and visual function was appropriate in children through 2 years of age. No adverse effects on safety, including growth and neurodevelopment, were identified. These findings provide clinically relevant long-term information on intravitreal aflibercept injection therapy for ROP. Trial Registration: ClinicalTrials.gov Identifier: NCT04015180.

Erythropoietin and retinopathy of prematurity: a retrospective cohort study in Japan, 2008-2018.

BACKGROUND: Erythropoietin has an angiogenic effect on the retina and might increase the risk of retinopathy of prematurity (ROP). METHODS: This retrospective cohort study included infants born at 22 to 27 weeks' gestation between 2008 and 2018 who were admitted to neonatal intensive care units (NICUs). We compared mortality and morbidities between infants who received erythropoietin and those who did not. RESULTS: Among 18,955 livebirth infants, this study included 16,031 infants, among which 14,373 infants received erythropoietin. The risk of ROP requiring treatment was significantly higher in the erythropoietin group than in the control group (33% vs. 26%; aOR 1.50 [95% CI 1.28-1.76]). On the other hand, the erythropoietin group had lower risks of death and necrotizing enterocolitis. CONCLUSIONS: This study with a large sample size found that erythropoietin use was associated with increased risk of ROP requiring treatment, while being associated with reductions in deaths and NEC.

Inhaled nitric oxide therapy for preterm infants after 7 days of age: a scoping review protocol.

INTRODUCTION: Inhaled nitric oxide (iNO) use is recommended for persistent pulmonary hypertension of the newborn in term and late preterm infants. Recently, iNO therapy to prevent bronchopulmonary dysplasia (BPD) or rescue for hypoxic respiratory failure and pulmonary hypertension secondary to BPD has increasingly been used in preterm infants after 7 days of postnatal age (in the postacute phase), despite its off-label use. However, the initiation criteria of iNO therapy for preterm infants in the postacute phase are varied. The aim of this scoping review is to identify the clinical and/or echo findings at the initiation of iNO therapy in preterm infants in the postacute phase. METHODS AND ANALYSIS: We will search PubMed, Embase and the Japanese database 'Ichushi.' The following studies will be included in the review: randomised controlled trials, prospective/retrospective cohort studies, case-control studies and case series on iNO therapy for preterm infants in the postacute phase; studies published between January 2003 and August 2023; studies conducted in developed countries and studies written in English or Japanese. We will independently screen, extract and chart data using the population-concept-context framework following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We will summarise the characteristics and findings of the included studies. ETHICS AND DISSEMINATION: Obtaining an institutional review board approval is not required because of the nature of this review. A final report of review findings will be published and disseminated through a peer-reviewed journal and presentation at relevant conferences. TRIAL REGISTRATION NUMBER: UMIN000051498.

Systemic exposure to aflibercept after intravitreal injection in premature neonates with retinopathy of prematurity: results from the FIREFLEYE randomized phase 3 study.

BACKGROUND: There are no data on pharmacokinetics, pharmacodynamics, and immunogenicity of intravitreal aflibercept in preterm infants with retinopathy of prematurity (ROP). FIREFLEYE compared aflibercept 0.4 mg/eye and laser photocoagulation in infants with acute-phase ROP requiring treatment. METHODS: Infants (gestational age ≤32 weeks or birthweight ≤1500 g) with treatment-requiring ROP in ≥1 eye were randomized 2:1 to receive aflibercept 0.4 mg or laser photocoagulation at baseline in this 24-week, randomized, open-label, noninferiority, phase 3 study. Endpoints include concentrations of free and adjusted bound aflibercept in plasma, pharmacokinetic/pharmacodynamic exploration of systemic anti-vascular endothelial growth factor effects, and immunogenicity. RESULTS: Of 113 treated infants, 75 received aflibercept 0.4 mg per eye at baseline (mean chronological age: 10.4 weeks), mostly bilaterally (71 infants), and with 1 injection/eye (120/146 eyes). Concentrations of free aflibercept were highly variable, with maximum concentration at day 1, declining thereafter. Plasma concentrations of adjusted bound (pharmacologically inactive) aflibercept increased from day 1 to week 4, decreasing up to week 24. Six infants experienced treatment-emergent serious adverse events within 30 days of treatment; aflibercept concentrations were within the range observed in other infants. There was no pattern between free and adjusted bound aflibercept concentrations and blood pressure changes up to week 4. A low-titer (1:30), non-neutralizing, treatment-emergent anti-drug antibody response was reported in 1 infant, though was not clinically relevant. CONCLUSIONS: 24-week data suggest intravitreal aflibercept for treatment of acute-phase ROP is not associated with clinically relevant effects on blood pressure, further systemic adverse events, or immunogenicity. GOV IDENTIFIER: NCT04004208.

Hemodynamic evaluation of extremely low birth weight infants during the first 7 days of life.

BACKGROUND AND AIM: We aimed to investigate the hemodynamic status of extremely low birth weight (ELBW) infants during the transitional period under intensive management. METHODS: This retrospective cohort study analyzed left ventricular ejection fraction (LVEF), left ventricular end-systolic wall stress (ESWS), left ventricular internal dimension in diastole (LVIDd), and mean arterial pressure (MAP) of ELBW infants during their first week of life. Small for gestational age (SGA), histological chorioamnionitis (hCAM), severe intraventricular hemorrhage (IVH), and non-survival to discharge infants were compared to their counterparts. RESULTS: Sixty-two infants (25.7 ± 2.1 weeks, 700.7 ± 165.4 g) were analyzed. MAP gradually increased. Median LVEF was 69.8 % on day 1, decreased to 62.7 % on day 2, then increased throughout the week. ESWS was lowest at birth, rose to 28.2 g/cm2 on day 2, and decreased on day 6. There were no significant changes in LVIDd. SGA infants had higher MAP throughout, higher LVEF on day 2 and 3, but lower LVEF on day 5 to 7. LVIDd was lower in hCAM group. Severe IVH group had a more significant drop in LVEF on day 2, higher ESWS, and a higher incidence of hemodynamic significant patent ductus arteriosus (hsPDA). Non-survival had lower LVIDd. CONCLUSIONS: MAP increased gradually. Hemodynamic instability was observed in the first two days, with decreased LVEF and increased ESWS before stabilization. We observed an alteration in hemodynamic adaptation in SGA and hCAM infants. Severe IVH group experienced early hemodynamic instability and a higher incidence of hsPDA.

Postnatal longitudinal analysis of serum Nitric oxide and eosinophil counts in extremely preterm infants.

BACKGROUND: Nitric oxide (NO) may be related to the pathogenesis of several morbidities in extremely preterm infants, including late-onset adrenal insufficiency. However, eosinophilia is observed under pathological conditions with adrenal insufficiency. Therefore, this study explored postnatal changes in NO levels and eosinophil counts in extremely preterm infants with and without morbidities. METHODS: Nineteen extremely preterm infants with a median gestational age of 27.0 weeks and median birth weight of 888 g were enrolled in this study. Serum levels of nitrogen oxides (NOx) and peripheral blood eosinophil counts were measured at birth and every 2 weeks thereafter. Morbidities of the study group were diagnosed using a single criterion. RESULTS: Serum NOx levels (mean ± standard deviation) were 22.5 ± 14.9 µmol/L, 51.2 ± 23.7 µmol/L, 42.4 ± 15.2 µmol/L, and 33.8 ± 9.4 µmol/L at birth and 2, 4, and 6 weeks of age, respectively. The serum NOx level at 2 weeks of age was significantly higher than that at birth and 6 weeks of age. Eosinophil counts, which increase with adrenal insufficiency, were measured simultaneously and were 145 ± 199/µL, 613 ± 625/µL, 466 ± 375/µL, and 292 ± 228/µL at birth and 2, 4, and 6 weeks of age, respectively. These values showed that the eosinophil count was significantly higher at 2 weeks of age than at birth and 6 weeks of age. The serum NOx level of infants without chorioamnionitis was significantly increased at 4 weeks of age, and the eosinophil count of infants with necrotizing enterocolitis was significantly increased at 2 weeks of age. No correlation with the NOx level or eosinophil count was observed in infants with late-onset circulatory collapse. CONCLUSION: The postnatal serum NOx level and eosinophil count were significantly correlated with each other and peaked at 2 weeks of age.

Evaluation of Postnatal Complications in Clinical and Histological Chorioamnionitis in Extremely Preterm Infants: A Japanese Cohort Study.

OBJECTIVE: Terminating pregnancy appropriately before the intrauterine infection has progressed may have an improved prognosis for preterm infants. We evaluate how the combination of histological chorioamnionitis (hCAM) and clinical chorioamnionitis (cCAM) affects the short-term prognosis of infants. STUDY DESIGN: This retrospective multicenter cohort study based on the Neonatal Research Network of Japan included extremely preterm infants born weighing <1,500 g between 2008 and 2018. Demographic characteristics, morbidity, and mortality were compared between the cCAM(-)hCAM(+) and cCAM(+)hCAM(+) groups. RESULTS: We included 16,304 infants. The progression to cCAM in infants with hCAM was correlated with the increase in home oxygen therapy (HOT) (adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], 1.11-1.44) and persistent pulmonary hypertension of the newborn (PPHN) (1.20, 1.04-1.38). Furthermore, increased progression of the hCAM stage in infants with cCAM correlated with an increase in bronchopulmonary dysplasia (BPD; 1.05, 1.01-1.11), HOT (1.10, 1.02-1.18), and PPHN (1.09, 1.01-1.18). However, it had a negative impact on hemodynamically significant patent ductus arteriosus (hsPDA; 0.87, 0.83-0.92) and death before discharge from the neonatal intensive care unit (NICU; 0.88, 0.81-0.96). CONCLUSION: Progression to cCAM in infants with hCAM positively correlated with HOT and PPHN. Progression of hCAM staging in infants with cCAM further increases the prevalence of BPD and the need for HOT and PPHN while reducing the prevalence of hsPDA and death before discharge from the NICU. The effects of the progressive hCAM stage in infants with cCAM vary from positive to negative by disease. KEY POINTS: · Retrospective multicenter cohort study based on the Neonatal Research Network of Japan.. · Clinical and histological chorioamnionitis increases the prevalence of BPD, HOT, and PPHN.. · Progression of histological chorioamnionitis in infants reduces the prevalence of hsPDA and death..

Evaluation of newborns with Down syndrome with weight less than 1500 g in the neonatal intensive care unit: A Japanese multicentre study.

AIM: This study aimed to clarify the characteristics and their mortality-related factors in very low birthweight infants with Down syndrome (DS) in Japan. METHODS: This retrospective case-control study enrolled newborns with DS weighing <1500 g admitted to neonatal intensive care unit (NICU) of the perinatal centre registered with the Neonatal Research Network of Japan (NRNJ) database from 2008 to 2019. The clinical characteristics and their mortality-related factors were compared among the Dead group (newborns with DS who died in the NICU), the Survival group (newborns with DS who were alive from the NICU) and the Control group (newborns without congenital or chromosomal condition). RESULTS: A total of 53 656 newborns weighing <1500 g were registered in the NRNJ database for 12 years. Of these, 310 (0.6%) were diagnosed with DS: 62 newborns in the Dead group, 248 in the Survival group and 49 786 in the Control group without chromosomal condition. Logistic analysis revealed that there was a significant difference in the mortality-related factors in congenital anomalies, pulmonary haemorrhage and persistent pulmonary hypertension of the newborn; the adjusted odds ratios were 8.6, 121 and 9.5, respectively. Newborns with DS weighing <1000 g showed the earliest death in the NICU on the Kaplan-Meier survival curve (P < 0.01). CONCLUSION: The mortality rate for newborns with DS weighing <1500 g was 20% (5% in the Control group). The mortality-related factors were complications of congenital anomalies, pulmonary haemorrhage and persistent pulmonary hypertension of the newborn.

Bronchopulmonary Dysplasia in Extremely Premature Infants: A Scoping Review for Identifying Risk Factors.

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.

Validation of eligibility criteria for the Japan Obstetric Compensation System for Cerebral Palsy in preterm infants: A case-control cohort study.

AIM: To verify validity of the criteria used for the Japan Obstetric Compensation System for Cerebral Palsy (JOCS-CP) in preterm infants, the association between the criteria and the development of CP was studied using a neonatal database. Our hypothesis was that the criteria would not be sufficient due to the recent advances made in perinatal care. METHODS: Preterm infants born between 2003 and 2019 and registered in the Neonatal Research Network of Japan database with a birth weight of 1500 g or less or a gestational age of less than 32 weeks were analyzed. The database included the clinical information of registered infants during their stay in NICUs and outcomes at 3 years of age. RESULTS: The database included 73 615 infants. After excluding those with an unknown outcome at discharge, 73 464 infants were analyzed for short-term outcomes, including mortality and morbidities. The incidence of CP at 3 years of age was analyzed in 36 151 infants. Furthermore, 16 467 infants born between 28 and 31 weeks of gestation were examined in terms of the validity of the current eligibility criteria. The mortality and incidences of severe intraventricular hemorrhage and periventricular leukomalacia significantly decreased during the study period (Cochrane-Armitage test, p < 0.01). Furthermore, the eligibility criteria were not sufficiently nor strongly associated with indicators for detecting perinatal hypoxia-ischemia resulting in CP. CONCLUSION: The existing eligibility criteria of the JOCS-CP used for preterm infants born between 28 and 31 weeks were no longer suitable because of the advances in perinatal care in Japan.

Inhaled Nitric Oxide Therapy in the Post-Acute Phase in Extremely Preterm Infants: A Japanese Cohort Study.

OBJECTIVE: To determine the trends in inhaled nitric oxide (iNO) utilization in the late phase of hospitalization in a large Japanese cohort of extremely preterm infants and evaluate its benefit on long-term outcomes. STUDY DESIGN: This was a retrospective multicenter cohort study of 15 977 extremely preterm infants born at <28 weeks of gestational age between 2003 and 2016, in the Neonatal Research Network, Japan. Demographic characteristics, morbidity, and mortality were compared between extremely preterm infants with and without post-acute iNO therapy. Multivariable logistic analysis was performed to determine factors associated with post-acute iNO and its impact on neurodevelopmental outcomes at 3 years of age. RESULTS: Post-acute iNO utilization rates increased from 0.3% in 2009 to 1.9% in 2016, even under strict insurance coverage rules starting in 2009. Gestational age (1-week increment; aOR 0.82, 95% CI 0.76-0.88), small for gestational age (1.47, 1.08-1.99), histologic chorioamnionitis (1.50, 1.21-1.86), 5-minute Apgar score <4 (1.51, 1.10-2.07), air leak (1.92, 1.30-2.83), and bubbly/cystic appearance on chest X-Ray (1.68, 1.37-2.06) were associated with post-acute iNO. Post-acute iNO was not associated with neurodevelopmental outcomes at 3 years of age. CONCLUSIONS: The increasing post-acute iNO utilization rate among extremely preterm infants has been concurrent with improved survival rates of extremely preterm infants in Japan. Infants treated with post-acute iNO had more severe disease and complications than the comparison group, but there were no differences in neurodevelopmental outcome at 3 years. This suggests post-acute iNO may benefit extremely preterm infants.

Rapidly growing thrombus from a ductus arteriosus aneurysm in a neonate.

Ductus arteriosus aneurysm (DAA) is a rare cardiovascular anomaly, and thrombosis of DAA is even less common. The management of asymptomatic DAA with a thrombus is controversial. We here report a neonate with a thrombus from a DAA that grew rapidly into the pulmonary artery. The thrombus was detected incidentally in the main pulmonary artery by routine screening echocardiography. There was no clinical evidence of its presence until a few days after birth. The thrombus grew rapidly, despite administration of heparin. Six days after birth, the patient became cyanotic and had developed right ventricular pressure overload as a result of obstruction of the left pulmonary artery. The thrombus was immediately removed and the DAA resected. The patient was discharged home without any complications. Complications related to thrombus of a DAA can be critical and therefore require careful monitoring. Learning objective: A thrombus extending from a ductus arteriosus aneurysm into the pulmonary artery can have serious consequences; thus, careful monitoring is required. Any signs of such complications should prompt immediate consideration of removal of the aneurysm and thrombus.

Small for Gestational Age Affects Outcomes on Singletons and Inborn Births in Extremely Preterm Infants: A Japanese Cohort Study.

OBJECTIVE: This study aimed to compare the short- and long-term outcomes of extremely preterm small for gestational age (SGA) infants and appropriate for gestational age (AGA) infants in Japan. STUDY DESIGN: We retrospectively assessed 434 SGA and 1,716 AGA infants born at 22 to 27 weeks of gestational age (GA) and examined their outcomes on singletons and inborn births between 2003 and 2012. Infants were followed-up for 3 years, and the clinical characteristics and outcomes were compared. Fisher's exact and Student's t-tests were used for independent sample comparison. Logistic regression was used to identify associated factors. RESULTS: The prevalence of intraventricular hemorrhage ≥ grade 3 was significantly lower (adjusted odds ratio [aOR]: 0.28; 95% confidence interval [CI]: 0.11 - 0.72), and the prevalence of bronchopulmonary dysplasia at 36 weeks of GA and the need for home oxygen therapy were significantly higher (aOR: 2.20; 95% CI: 1.66 - 2.91 and aOR: 2.46; 95% CI: 1.75-3.47, respectively) in SGA infants than in AGA infants. SGA infants born at 24 to 25 weeks of GA had a significantly higher prevalence of developmental quotient (DQ) < 70 (aOR: 1.73; 95% CI: 1.08 - 2.77). Those born at 26 to 27 weeks of GA showed a significantly higher prevalence of cerebral palsy (CP) and visual impairment (aOR: 2.31; 95% CI: 1.22 - 4.40 and aOR: 2.61; 95% CI: 1.21 - 5.61, respectively). CONCLUSION: In SGA infants, birth at 24 to 25 weeks of GA is an independent risk factor for DQ < 70, and birth at 26 to 27 weeks of GA is an independent risk factor for CP and visual impairment. However, we did not consider nutritional and developmental factors, and a longer follow-up would help assess neurodevelopmental outcomes. KEY POINTS: · SGA is a risk factor for poor outcomes.. · In SGA infants, birth at 25 to 26 weeks is a risk factor for low a DQ.. · In SGA infants, birth at 26 to 27 weeks is a risk factor for CP..

Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial.

Importance: Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments. Objective: To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment. Design, Setting, and Participants: This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021). Interventions: Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified. Main Outcomes and Measures: The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%. Results: Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators. Conclusions and Relevance: Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT04004208.

Practical procedures for the delivery room resuscitation of micropreemies.

There are no standardized procedures for the resuscitation of micropreemies but respiratory and circulatory stabilization immediately after birth should be prioritized. Without aggressive support by positive pressure ventilation, establishing effective respiration among micropreemies is not possible. The first step in postnatal stabilization is initiated by positive airway pressure with a bag and mask. Once the heart rate increases above 100 beats/m, intratracheal intubation should be achieved because it is unusual for a micropreemie to breathe spontaneously or by non-invasive respiratory support for a protracted duration. Until further information is available, initial FiO2 should be between 0.3 and 0.6, and titrated to achieve SpO2 obtained from healthy term infants for the first 10 min of life. Temperature control of infants is also critical for successful resuscitation and heat-loss minimizing procedures should be used e.g. with insulating bags. After securing the intratracheal tube, the infants should be transferred to the NICU for further procedures, including pulmonary surfactant installation and umbilical cord catheterization. Procedures in a delivery room under a radiant warmer should be limited to the initial resuscitation. In NICUs, the infants should be placed into a closed incubator to maintain high environmental temperature and humidity as well as decrease exposure to intervention and noise. Increased number of staff will also be needed to stabilize the infants further in the NICU. Finally, appropriate equipment (e.g. appropriate sized laryngoscopes) should be made readily available, along with regular practical training and education, whether in person or through SIM courses which are essential for all staff to achieve competence in successful resuscitation of the newborn micropreemie.

Severe bronchopulmonary dysplasia in extremely premature infants: a scoping review protocol for identifying risk factors.

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.

Evaluation of postoperative complications for patent ductus arteriosus in extremely-low-birthweight infants.

BACKGROUND: Patent ductus arteriosus (PDA), which disrupts the hemodynamics early after birth, causes intraventricular hemorrhage and neonatal necrotizing. Unlike medical treatment for hemodynamically significant PDA, there are institutional disparities in the criteria for surgical treatment METHODS: We aimed to clarify the postoperative indications of surgery for hemodynamically significant PDA and the postoperative complications associated with surgery. RESULTS: Thirty-six extremely-low-birthweight infants (median gestational age 25.2 weeks, median birthweight 699 g) required video-assisted thoracoscopic surgery for PDA (VATS-PDA). The treatment indication of VATS-PDA was resistance to medical treatment in 17 cases, relapsed PDA in 15 cases, and no additional administration of indomethacin because of severe side effects in four cases. Complications with VATS-PDA occurred in eight of 36 cases. There were three cases of pneumothorax, two of thoracotomy transition, two of pulmonary hemorrhage, and four of post-ligation cardiac syndrome (PLCS). VATS-PDA-related death occurred in two cases due to PLCS. The frequency of four or more administrations of indomethacin, with or without postoperative complications, was 88% vs. 39%, respectively (P = 0.04). CONCLUSIONS: All postoperative deaths were caused by PLCS, which had the highest risk of poor prognosis. VATS-PDA should be considered for unclosed PDA after one course of indomethacin administration.

A Retrospective Cohort Study on Mortality and Neurodevelopmental Outcomes of Preterm Very Low Birth Weight Infants Born to Mothers with Hypertensive Disorders of Pregnancy.

OBJECTIVE: We examined the effects of maternal hypertensive disorders of pregnancy (HDP) on the mortality and neurodevelopmental outcomes in preterm very low birth weight (VLBW) infants (BW ≤1,500 g) based on their intrauterine growth status and gestational age (GA). STUDY DESIGN: We included singleton VLBW infants born at <32 weeks' gestation registered in the Neonatal Research Network Japan database. The composite outcomes including death, cerebral palsy (CP), and developmental delay (DD) at 3 years of age were retrospectively compared among three groups: appropriate for GA (AGA) infants of mothers with and without HDP (H-AGA and N-AGA) and small for GA (SGA) infants of mothers with HDP (H-SGA). The adjusted odds ratios (AOR) and 95% confidence intervals (CI) stratified by the groups of every two gestational weeks were calculated after adjusting for the center, year of birth, sex, maternal age, maternal diabetes, antenatal steroid use, clinical chorioamnionitis, premature rupture of membranes, non-life-threatening congenital anomalies, and GA. RESULTS: Of 19,323 eligible infants, outcomes were evaluated in 10,192 infants: 683 were H-AGA, 1,719 were H-SGA, and 7,790 were N-AGA. Between H-AGA and N-AGA, no significant difference was observed in the risk for death, CP, or DD in any GA groups. H-AGA had a lower risk for death, CP, or DD than H-SGA in the 24 to 25 weeks group (AOR: 0.434, 95% CI: 0.202-0.930). The odds for death, CP, or DD of H-SGA against N-AGA were found to be higher in the 24 to 25 weeks (AOR: 2.558, 95% CI: 1.558-3.272) and 26 to 27 weeks (AOR: 1.898, 95% CI: 1.427-2.526) groups, but lower in the 30 to 31 weeks group (AOR: 0.518, 95% CI: 0.335-0.800). CONCLUSION: There was a lack of follow-up data; however, the outcomes of liveborn preterm VLBW infants of mothers with HDP depended on their intrauterine growth status and GA at birth. KEY POINTS: · The effects of HDP on preterm low birth weight infants need to be further examined.. · The outcomes were not different between AGA infants with and without maternal HDP.. · The outcomes of SGA infants with maternal HDP were dependent on their GA..

Respiratory management for extremely premature infants born at 22 to 23 weeks of gestation in proactive centers in Sweden, Japan, and USA.

Survival of preterm newborn infants have increased steadily since the introduction of surfactant treatment and antenatal steroids. In the absence of randomized controlled trials on ventilatory strategies in extremely preterm infants, we present ventilatory strategies applied during the initial phase and the continued ventilatory care as applied in three centers with proactive prenatal and postnatal management and well documented good outcomes in terms of mortality and morbidity in this cohort of infants.