Retinopathy of Prematurity

Purpose: Over the last 10 years, recommendations regarding the ideal level of oxygen for resuscitation in preterm infants have changed from 100 percent, down to low levels of oxygen (\<30 percent), up to moderate concentration (30-65 percent). In addition, in 2010, oxygen saturation targeting was recommended as standard of care and this contributed to a change in clinical practice as clinicians were more likely and comfortable to start resuscitation at either 21percent (room air) or titrated levels of oxygen such as 30-40 percent. When the guidelines were again revised in 2015, the International Liaison Committee on Resuscitation (ILCOR) acknowledged that a critical knowledge gap continued to exist for the resuscitation of the preterm infants \<37 weeks, highlighting the need to provide more concrete guidelines. This leaves clinicians in a challenging position. Despite the advances that have been achieved in perinatal and neonatal care, neonates are still vulnerable to the consequences of the oxidative effects from hyperoxia as well as the deleterious effects from hypoxia. A large, multi-centre international trial of sufficient sample size that is powered to look at safety outcomes such as mortality and adverse neurodevelopmental outcomes is required to provide the necessary evidenced to guide clinical practice with confidence. Hypothesis: the null hypothesis for this study is that the incidence of mortality or abnormal neurodevelopmental outcomes at 24+/- 6 months corrected age will be no different by using either higher initial oxygen concentration of 60 percent compared to using lower initial oxygen concentration of 30 percent for resuscitation of preterm infants of 23 0/7- 28 6/7 weeks gestation. Justification: The use of supplementary oxygen may be crucial, but also potentially detrimental to premature infants at birth. High oxygen levels may lead to organ damage through oxidative stress, while low oxygen levels may lead to increased mortality. Excess oxygen exposure during the early post-birth period is associated with many complications and morbidities of preterm birth. Preterm infants have lower levels of anti-oxidant pathways consistent with their expected fetal environment of low oxygen exposure. Excess of oxygen free-radicals in infants intrinsically deficient in enzymatic antioxidants and non-enzymatic antioxidants may contribute to these morbidities. Pulmonary oxygen toxicity, through the generation of reactive oxygen and nitrogen species in excess of antioxidant defenses, is believed to be a major contributor to the development of bronchopulmonary dysplasia (BPD). Using lower oxygen concentrations at birth results in decreased oxidative stress markers and a decrease risk of developing BPD compared to higher oxygen concentrations. Other organs that may be damaged by such oxidative stress include kidneys, myocardium and the retina. There is equally growing evidence that using lower oxygen concentrations will lead to lower oxygen saturation levels and bradycardia, which may lead to increased rates of mortality in this vulnerable group of infants. An individual patient analysis of clinical trials reported that 46% of preterm infants resuscitated with initial low oxygen concentration did not reach SpO2 of 80% at 5 min. This was associated with increased risk of major intraventricular hemorrhage (IVH), and an almost five times higher risk of death in this vulnerable group of infants. These data provide a warning note for the use of higher vs. lower initial oxygen concentration during delivery room resuscitation. As the investigator proceed in determining a safe range for resuscitation of ELBW/ELGA infants, it is highly likely that the optimum level of oxygen concentration is between the two extremes of 21 percent and 100 percent. Objectives: To determine whether initial resuscitation of preterm neonates with 60 percent versus 30 percent oxygen results in better neurodevelopmental outcomes at 24+/- 6 months. Research Method/Procedures: This will be a cluster crossover design, unmasked randomized controlled trial (RCT) comparing two oxygen concentrations at initiation of resuscitation. Infants will be placed on the resuscitation table with the initial steps of resuscitation carried out as per standard of care at each centre which usually follows current resuscitation guidelines. All centres will make every effort to establish adequate lung expansion using CPAP or positive pressure ventilation as needed. Enrolled infants will have a pulse oximeter sensor placed on the right arm in the first minute of life. Their resuscitation will be initiated with an oxygen concentration of 30 or 60 percent depending on the randomization sequence at the centre at the given time. Infants in the 30 percent group will remain in 30 percent oxygen until 5 min of age unless the infant's heart rate (HR) remains 100/min or less and does not show a tendency towards progressive increase before reaching 5 min of age or infant needs chest compression and/or epinephrine. No alteration in oxygen concentration will be made for an infant who is responding to resuscitation efforts with HR progressively increasing as minutes go by. At 5 min of age, the clinical team will assess oxygen saturation. If the saturation is less than 85 percent, oxygen should be increased by 10-20 percent every 60 sec to achieve saturations of 85 percent or greater or a saturation of 90-95 percent at 10 min of age. If saturations are greater than 95 percent at or before 5 min of age, oxygen should be decreased stepwise (every 60 sec) with an aim to maintain saturations of 85 percent or greater during 5-10 min of age or 90-95 percent at and beyond 10 min of age. The procedure for infants in the 60 percent group will be identical. The intervention duration for the trial will be the first 5 min after birth followed by initial monitoring/action for the next 5 min where titration in oxygen concentration will be made to achieve stability making a total of 10 min for study intervention. Titration of oxygen before 5 min after birth will only be made if the infant remains bradycardic (HR less than 100) and does not show a tendency towards a sustained increase in HR or if the oxygen saturation exceeds 95 percent. If the infant does not respond to ventilation with increasing HR in the first 5 min after birth, steps to ensure effective ventilation should be done before oxygen is titrated. Plan for Data Analysis: Generalized linear mixed model with binary outcome and maximum likelihood estimate will be used to evaluate the effect of an oxygen concentration on the primary outcome (as a composite at 24+/- 6 months corrected age of all-cause mortality or the presence of a major neurodevelopmental outcome). To account for cluster crossover design of the study, effects of centers (clusters) and a period (oxygen concentration) within center will be considered random, and effects of a period (oxygen concentration) will be entered as a fixed effect. This hierarchical model allows for the correlation of patients within periods and within clusters. The model will be adjusted for gestational age and whether or not infant required mask ventilation as potential confounding variables. Similar generalized linear mixed models will be performed to evaluate the effect of group on secondary outcomes. In addition, three subgroup analysis will be performed: i) Gestational age will be categorized into 2 categories: 23+0- 25+6 vs. 26+0-28+6 weeks; ii) Breathing support will be categorized by infants supported only with CPAP vs. received mask ventilation; iii) Sex/Gender will be categorized into 2 categories: female vs. male. For subgroup analysis baseline characteristics will be compared using linear and generalized linear mixed models. Sensitivity analysis will be performed to analyze the missing data; however, a very low number of missing values are expected due to the design of the study.

The purpose of this study is to determine if an investigational drug can prevent Bronchopulmonary Dysplasia, reducing the burden of chronic lung disease in extremely premature infants, as compared to extremely premature infants receiving standard neonatal care alone.

The goal of this nationwide multicenter observational study is to comprehensively investigate the severity of Small Vulnerable Newborns (SVN) issues across China and to propose further preventive and intervention measures. The primary aim is to provide a thorough description of SVN problems using a unified definition and framework, and to develop targeted prevention strategies. Participating centers across the country will collect clinical data on vulnerable newborns under their care and complete detailed questionnaires to support this research.

This is an observational study to collect data from Japanese babies with retinopathy of prematurity (ROP) who will be treated with Eylea. In observational studies, only observations are made without specified advice or interventions. ROP is a condition that affects the eye and occurs only in babies who are born too early. Most cases of ROP are mild and get better without treatment, but more serious cases need to be treated in time. ROP happens when the blood vessels in the "retina" grow abnormally. The retina is the layer of tissue at the back of the eye that picks up light and sends messages to the brain. In babies with ROP, these abnormal blood vessels can leak. This causes damage to the retina and can sometimes move it out of place causing medical problems such as blindness. Eylea is received as an injection into the eye. It works by blocking a certain protein (VEGF) that can cause blood vessels in the retina to grow abnormally. Eylea is already available in Japan and is approved for doctors to prescribe to babies with ROP. The participants in this study are Japanese babies with ROP that their doctors decided to treat with Eylea before the start of this study. Babies with ROP that were already prescribed Eylea by their doctors may also be included. The main purpose of this study is to collect more data on how safe the treatment with Eylea is in babies with ROP under a real-world setting. Another purpose of this study is to collect more data on how well Eylea works in these participants. To see how safe Eylea is, the study doctors will collect all medical problems that the participants treated with Eylea have. These medical problems are called adverse events. Doctors keep track of all the adverse events that happen, even if they do not think that they might be related to the treatment. To see how well Eylea works, the study doctors will check the number of participants: * with no active ROP after starting treatment * where ROP came back up to 6 months after start of treatment In this study, the study doctor will: * collect past data of the participants from medical records * interview the participants * collect treatment-related data during routine visits. The study duration is 6 months with 3 planned visits. One visit will be at start of treatment, one at one month and one at 6 months after start of treatment. All data required for this study will be collected during routine visits. Besides this data collection, no further tests or examinations are planned in this study.

Continuous positive airway pressure (CPAP) is an essential, non-invasive therapy for treating various respiratory conditions in the Neonatal Intensive Care Units (NICU). CPAP is an effective treatment for respiratory distress syndrome, apneas, or after extubation, exerting its physiological benefits by maintaining upper airway patency and functional residual capacity. Bubble CPAP (bCPAP) is the most widely used CPAP due to its low cost and ease of use. It consists of an inspiratory tube carrying heated and humidified air, a nasal interface, and an expiratory tube immersed in a water chamber. The generation of bubbles in the water chamber by exhaled gas creates low amplitude and high-frequency pressure oscillations that are transmitted back to the chest. Successful CPAP requires constant transmission of the pressure via an unobstructed circuit. However, this is difficult to achieve in practice due to inadequate interface, leaks from an open mouth, and obstructed airway. As a result, bCPAP requires frequent manual checks by nurses and respiratory therapists to ensure that the circuit is secure and unobstructed. As a proposed solution, bCPAP sounds heard in the patient room or upon auscultation are routinely used to assess the effectiveness of CPAP therapy. This sound can be heard both from the water tank creating the vibrations and during auscultation with a stethoscope, as the sound vibration is transmitted to the neonatal lungs. In the current era of digital technology, acoustic sounds can be converted to electronic signals for further processing and analysis. We hypothesize that continuous recording and analysis of bCPAP sounds could be used as a proxy for real-time objective monitoring of the pressure transmitted to infants' lungs.

When the transition from intrauterine to extrauterine life necessitates Neonatal Resuscitation, specialized monitoring of vital signs is required. Sudden Unexpected Postnatal Collapse (SUPC) is an apnea or cardiorespiratory failure occurring in otherwise healthy near-term or term neonates, usually in the first 48 hours of age, during the initial Kangaroo Mother Care (KMC) in the obstetrical center. SUPC carries a high morbidity and mortality rate. Approximately 10 million babies do not breathe immediately after birth, and 60% require basic resuscitation interventions. Sudden Unexpected Postnatal Collapse has been estimated to occur in 2.6-133 cases per 100.000 newborns and over 50% of the cases occur following accidental suffocation, which frequently goes unrecognised by parents in the obstetrical center during unsupervised KMC. Current guidelines recommend monitoring of heart rate (HR), oxygen saturation (SpO2), and skin temperature (Tskin) during neonatal resuscitation. This is usually achieved by using wired electrodes and sensors that require expensive and large base units attached to a power supply. SUPC is a rare but largely preventable cause of neonatal mortality that deserves particular attention. Better resuscitation and prevention of SUPC might be achieved by continuous non-intrusive monitoring of vital signs immediately after delivery and while in the obstetrical center. This research will address a very important gap in care; the need for safe and accurate advanced, non-invasive, and non-intrusive wireless technologies for monitoring of vital signs immediately after birth and during the immediate postnatal care, potentially preventing cases of SUPC while in the obstetrical center. Reliable and low-cost wireless monitoring that could be used immediately after delivery would promote widespread adoption of neonatal resuscitation recommendations in low and middle income countries, improve detection of vital signs quickly after delivery and during early unsupervised KMC, and optimize neonatal care in the obstetrical centers or during hospital stay, to prevent cases of SUPC and its associated high mortality.

Previous studies have shown that mortality and morbidity in preterm neonates are correlated with the fall in body temperature on admission. Hypothermia can be decreased by reducing body heat losses to the environment. The investigator research hypothesis is that a new calculation of the air temperature in the incubator would promote the newborn infant weight growth from the period between birth and day 10 of life compared to cutaneous mode. The secondary hypotheses assumes a decrease in the side effects usually observed in both morbidity and mortality. A software is used to calculate the body heat loss (BHL) of each individual preterm infant, and to propose a specific air temperature setting inside the incubator to reduce BHL to zero. This software has been validated in a previous pilot study (Degorre et al. 2015). This study aims to compare the energy costs of providing incubated preterm infants born between 25 and 32 weeks of gestation with homeothermia using either specific individualized air temperature control (ATC) or skin servocontrol (SSC).

Title: Arginine Supplementation and the Postoperative Immune REsponse (ASPIRE) in neonates Population: Preterm infants \<30 weeks gestation requiring a laparotomy/major bowel surgery or diagnosed with necrotising enterocolitis (Modified Bell's Stage II or higher) before discharge before discharge ; Term and near term infants (born \>35 weeks gestation) requiring a laparotomy/major bowel surgery in the first 3 days of life (gastroschisis; major bowel atresias expected to require at least 7 days PN). Number of infants: 48 infants (completing the study) will be recruited over approximately 24-36 months: 24 in the preterm group and 24 in the term group. Number of sites: Two sites - Alder Hey Children's Hospital (AHCH) and Liverpool Women's Hospital (LWH) under the umbrella of the Neonatal Partnership. Eligible infants will undergo surgery at AHCH and will receive early postoperative care at either AHCH or LWH Study duration: Informed consent will take place preoperatively where possible, or within 5 days of surgery or NEC diagnosis. In the term group, antenatal recruitment will be attempted. The first study related blood sample will be taken as soon as possible postoperatively following consent with the last sample taken on day 30 post-operatively. Other study assessments reflect those routinely performed in preterm infants receiving parenteral nutrition (PN). Study intervention: All infants will receive standard clinical treatment. 8 preterm and 8 term infants will receive PN as determined by local clinical guidelines (6.3 or 8.4% arginine content). 8 term infants and 8 preterm infants will receive PN as determined by local clinical guidelines (6.3 or 8.4% arginine content) and enteral arginine supplementation. Enteral L-arginine will start with the first enteral feedings: starting 0.75mmol/kg/day, doubled to 1.5mmol/kg (261mg/kg/day) when reaching 40% of enteral feeds. 8 preterm and 8 term infants will receive PN with an additional arginine supplement and oral supplementation. PN supplementation will aim to achieve up to 18% arginine intake (allocated according to intervention PN stock availability) and will be titrated against oral supplementation during the transition to enteral feeds. Primary objective: To examine the changes in gene expression present in arginine supplemented infants between day 3 and day 10 post-operatively. Thus will be done via illumina RNA sequencing and statistical pathway analysis. The changes in gene expression will be compared with those seen between day 3 and day 10 in unsupplemented preterm and term infants. The genes of interest are those involved in immune function and inflammatory pathways. Secondary objectives: 1. To explore other biological pathways i) known to be involved in the pathogenesis of necrotising enterocolitis ii) involved in arginine metabolism iii) that are related to the insulin-IGF-I axis 2. To determine the changes in metabolomic profiles of these infants during the first 30 days postoperatively. 3. Growth and body composition data during study period.

BACKGROUNDS Nowadays, phacoemulsification for cataract treatment is the most common surgical procedure performed and anesthetics procedure has been shifted from retrobulbar or peribulbar anesthesia to topical anesthesia (TA). Phacoemulsification under TA proved to be a safe and low risk procedure with the incidence of adverse events requiring medical emergency team interventions to be 0.04%. However, it is not uncommon that patients can suffer from pain, anxiety and unpleasant visual sensation during this procedure. Complementary sedation has long been thought to alleviate the anxiety and pain of the patient during surgery with local anesthesia. Studies revealed that approximately one fourth of the patients underwent phacoemulsification under TA or retrobulbar anesthesia requested additional intravenous sedation of midazolam. \[8\] However, the intravenous sedation, such as midazolam, propofol, or etomidate, increase the risk of additional anesthetic complications of heart rate, blood pressure, body temperature, and nausea, \[9,10\] and therefore, anesthesia monitoring was mandatory during the surgery. Compared with intravenous sedation, oral sedation is less costly and less invasive. Studies with different oral sedation agents revealed different effects. In the study of 41 patients serving themselves as control, patients reported more pain and photophobia in the surgery with TA alone than the other with midazolam syrup and oral transmucosal fentanyl citrate. However, two studies comparing oral diazepam or triazolam with intravenous midazolam showed similar rates of anxiety and pain or noninferior satisfaction. Moreover, the randomized control trial containing 50 procedures in each groups revealed that patients received TA alone during phacoemulsification reported similar pain or anxiety level to those received complementary intravenous midazolam. Despite the abundant results from above, nearly 40% patients reported moderate to extremely anxiety during phacoemulsification under TA, and approximate 7% of patients rated themselves extreme anxiety or were diagnosed as anxiety. A simple comparison between with or without complementary sedation for general patients underwent phacoemulsification with TA is merely not enough. Further investigations to reduce the anxiety experienced during phacoemulsification with TA according to patients' characteristics is therefore mandatory. Previous studies had showed that patients with higher level of trait anxiety reported higher anxiety response for a stressful situation. Preoperative anxiety levels were also reported to be a significant predictor of pain experience during phacoemulsification with TA. The need for complementary sedation could be different in patients with different trait anxiety. Furthermore, different severity levels of anxiety and pain were experienced during the first and second eye surgery. Therefore, in this study, the investigators will investigate the trait anxiety of patients planned for phacoemulsification under TA and its effect on their anesthetic satisfaction with complementary oral sedation. The investigators will also analysis the anxiety and pain experienced in the first and second eye phacoemulsification in patients with different levels of trait anxiety. The investigators choose alprazolam as the oral sedative. It was reported to have a shorter half-life and less side effects of drowsiness and lightheadedness than diazepam used in previous studies.

This is an observational study in which only data from babies with retinopathy of prematurity (ROP) who are being treated with aflibercept (Eylea) in prefilled syringe (PFS) using a paediatric dosing device (PDD) are collected and studied. ROP is a condition that affects the eyes of preterm babies. It occurs when the baby's retina, the part of the eye that senses light, does not develop normally. This may result in vision problems, including blindness, if left untreated. Preterm babies are born before 37 weeks of pregnancy. ROP is more likely to develop in babies who are born before 32 weeks of pregnancy or weigh less than 1.5 kilograms at birth. Aflibercept is a drug that is injected into the eye. It works by blocking a protein called vascular endothelial growth factor (VEGF) which causes abnormal growth of blood vessels in the retina. Aflibercept in PFS given using a PDD is approved for the treatment of babies with ROP. The prefilled syringe will be fitted with an injection needle to give aflibercept. And a PDD is a tool used to give the right amount of aflibercept to children in a safe manner. Since there are other treatments which are commonly used for babies with ROP, the extent of use of aflibercept given using a PDD is unknown. The main purpose of this study is to: * find the number of preterm babies who are treated with aflibercept using a PDD in the UK * inform whether this number is enough to perform a study to learn about the long-term safety of aflibercept given using a PDD in babies with ROP An additional purpose of this study is to describe characteristics including age, sex, and race, and signs and symptoms of ROP observed in babies being treated with aflibercept using a PDD. The data will come from a database called the National Neonatal Research Database. The study will cover the period from March 2024 to March 2025, if the number of babies found is enough to perform the safety study. If not, data will be collected till April 2027. In this study only available data from preterm babies born during the study period are collected. No visits or tests are required as part of this study.