Understanding the current and future usage of donor human milk in hospitals: An online survey of UK neonatal units.

The use of donor human milk (DHM) where there is a shortfall of maternal milk can benefit both infant and maternal outcomes but DHM supply is not always assured. This study aimed to understand current DHM usage in UK neonatal units and potential future demand to inform service planning. An online survey was disseminated to all UK neonatal units using Smart Survey or by telephone between February and April 2022 after development alongside neonatal unit teams. Surveys were completed by 55.4% of units (108/195) from all 13 Operational Delivery Networks. Only four units reported not using DHM, and another two units only if infants are transferred on DHM feeds. There was marked diversity in DHM implementation and usage and unit protocols varied greatly. Five of six units with their own milk bank had needed to source milk from an external milk bank in the last year. Ninety units (84.9%) considered DHM was sometimes (n = 35) or always (n = 55) supportive of maternal breastfeeding, and three units (2.9%) responded that DHM was rarely supportive of breastfeeding. Usage was predicted to increase by 37 units (34.9%), and this drive was principally a result of parental preference, clinical trials and improved evidence. These findings support the assumption that UK hospital DHM demand will increase after updated recommendations from the World Health Organization (WHO) and the British Association of Perinatal Medicine. These data will assist service delivery planning, underpinned by an ongoing programme of implementation science and training development, to ensure future equity of access to DHM nationally.

Preclinical Assessment of Nebulized Surfactant Delivered through Neonatal High Flow Nasal Cannula Respiratory Support.

High-flow nasal cannula (HFNC) is a non-invasive respiratory support (NRS) modality to treat premature infants with respiratory distress syndrome (RDS). The delivery of nebulized surfactant during NRS would represent a truly non-invasive method of surfactant administration and could reduce NRS failure rates. However, the delivery efficiency of nebulized surfactant during HFNC has not been evaluated in vitro or in animal models of respiratory distress. We, therefore, performed first a benchmark study to compare the surfactant lung dose delivered by commercially available neonatal nasal cannulas (NCs) and HFNC circuits commonly used in neonatal intensive care units. Then, the pulmonary effect of nebulized surfactant delivered via HFNC was investigated in spontaneously breathing rabbits with induced respiratory distress. The benchmark study revealed the surfactant lung dose to be relatively low for both types of NCs tested (Westmed NCs 0.5 ± 0.45%; Fisher & Paykel NCs 1.8 ± 1.9% of a nominal dose of 200 mg/kg of Poractant alfa). The modest lung doses achieved in the benchmark study are compatible with the lack of the effect of nebulized surfactant in vivo (400 mg/kg), where arterial oxygenation and lung mechanics did not improve and were significantly worse than the intratracheal instillation of surfactant. The results from the present study indicate a relatively low lung surfactant dose and negligible effect on pulmonary function in terms of arterial oxygenation and lung mechanics. This negligible effect can, for the greater part, be explained by the high impaction of aerosol particles in the ventilation circuit and upper airways due to the high air flows used during HFNC.

Impact of a quality improvement intervention on neonatal mortality in a regional hospital in Burkina Faso.

BACKGROUND: The neonatal period is the most vulnerable time in terms of a child's survival, with mortality during this period accounting for approximately half of the deaths before the age of 5 years. The Neonatal Essential Survival Technology (NEST) project is a program aiming to reduce mortality by improving the quality of neonatal care in sub-Saharan Africa. This study presents the evaluation of the first phase of the NEST intervention program at Saint Camille Hospital Ouagadougou (HOSCO), Burkina Faso, in terms of the reduction in neonatal mortality. METHODS: This is a retrospective analysis, based on "pre-intervention" data collected in 2015, and "post-intervention" data collected in 2018, including all infants admitted to the neonatal unit of HOSCO. The intervention period (2016 and 2017) comprised a structured quality improvement process conducted by a multidisciplinary working group that focused on improving infrastructure, equipment, training and use of clinical protocols, team working within the neonatal unit and with other hospital departments, and communication with referring healthcare facilities. Mortality data were compared pre- vs. post-intervention using a logistic regression model. RESULTS: The analysis included 1427 infants in the pre-intervention period, and 819 post-intervention. In both time periods, more than 75% of admissions were infants with low birth weight, and nearly 50% were very low birth weight. Post-intervention, while there was a decrease in overall admission, the proportion of multiple births increased from 20% to 24% (p = .01). The overall mortality rate was 44.9% (641/1427) pre-intervention, and 42.2% (346/819) post-intervention (OR 0.90, 95% confidence interval (CI) 0.76-1.07; p = .23). Adjusting for clinically relevant factors, the intervention was not associated with a change in overall mortality (OR 1.39, 95% CI 0.91-2.12; p = .13), but was associated with a reduced likelihood of mortality in outborn infants compared to inborn infants (OR 0.57, 95% CI 0.36-0.92; p = .02). CONCLUSIONS: The first phase of the NEST quality improvement program was associated with a decrease in mortality in outborn infants admitted to the neonatal unit at HOSCO. Long-term assessment is expected to provide a more comprehensive evaluation of the program in a low-income setting.

Development of a neonatal adverse event severity scale through a Delphi consensus approach.

BACKGROUND: Assessment of the seriousness, expectedness and causality are necessary for any adverse event (AE) in a clinical trial. In addition, assessing AE severity helps determine the importance of the AE in the clinical setting. Standardisation of AE severity criteria could make safety information more reliable and comparable across trials. Although standardised AE severity scales have been developed in other research fields, they are not suitable for use in neonates. The development of an AE severity scale to facilitate the conduct and interpretation of neonatal clinical trials is therefore urgently needed. METHODS: A stepwise consensus process was undertaken within the International Neonatal Consortium (INC) with input from all relevant stakeholders. The consensus process included several rounds of surveys (based on a Delphi approach), face-to-face meetings and a pilot validation. RESULTS: Neonatal AE severity was classified by five grades (mild, moderate, severe, life threatening or death). AE severity in neonates was defined by the effect of the AE on age appropriate behaviour, basal physiological functions and care changes in response to the AE. Pilot validation of the generic criteria revealed κ=0.23 and guided further refinement. This generic scale was applied to 35 typical and common neonatal AEs resulting in the INC neonatal AE severity scale (NAESS) V.1.0, which is now publicly available. DISCUSSION: The INC NAESS is an ongoing effort that will be continuously updated. Future perspectives include further validation and the development of a training module for users.

Enrollment of Neonates in More Than One Clinical Trial.

Because the highest rates of morbidity and mortality in neonates are seen in those born at <32 weeks' gestation, this group has the most urgent need for novel therapies to improve survival and outcome. Legislative efforts in the United States and Europe have attempted to address this issue by requiring the study of drugs, biological and nutritional products, devices, and other therapies in this population through a combination of high-quality regulatory and clinical trials, quality improvement initiatives, and observational studies. Because there are relatively small numbers of very preterm neonates born each year in any 1 country or continent, and because a significant number of clinical trials are recruiting at any 1 time, a neonate may meet enrollment criteria for >1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies.

Repeated courses of antenatal corticosteroids have adverse effects on aspects of brain development in naturally delivered baboon infants.

INTRODUCTION: Repeated courses of antenatal steroids in women at risk of preterm delivery have beneficial effects on lung maturation, but concern exists about the effects on brain development. We aimed to determine whether repeated courses of corticosteroids increased the risk of neuropathology as compared with single courses or no treatment. METHODS: Single-course animals received a 6-mg dose of steroids at 123 and 124 d of gestation (dg; term, 185 dg; n = 6). Repeated-course animals received additional doses at 137 and 138 dg (n = 7). Controls received no steroids (n = 5). Baboons delivered naturally at term and necropsy was performed. Brains were assessed histologically for parameters of development and neuropathology. RESULTS: Body weights did not differ between the groups (P > 0.05); neither did brain/body weight ratio. Density of glial fibrillary acidic protein (GFAP)-immunoreactive (IR) astrocytes in white matter (WM) was increased in the single- (P < 0.05) and repeated-course (P < 0.01) groups as compared with controls. Density of myelin basic protein (MBP)-IR oligodendrocytes was reduced in the repeated-course animals as compared with both the control and single-course groups (P < 0.05); oligodendrocyte transcription factor 2 (Olig2)-IR showed no difference between groups. DISCUSSION: Repeated courses of antenatal corticosteroids have effects on myelination in the developing nonhuman primate brain, which should be taken into account when determining a dosing regimen.

Perinatal network consensus guidelines on the resuscitation of extremely preterm infants born at <27 weeks' gestation.

In spite of recent advances in perinatal care and an increase in survival of extremely preterm infants over the last few years, there remains a lack of consensus about practical aspects of resuscitation of extremely preterm infants born before 27 weeks' gestation. With this in the background, the working group of one of the Perinatal Networks in London, UK, set out to conduct a survey to explore the opinions of the doctors and nurses on resuscitation practices of infants born before 27 weeks' gestation, with the aim of developing consensus guidelines. The working group emailed a questionnaire to all neonatal units within the Perinatal Network to seek the views of paediatric medical and nursing staff on resuscitation of infants born at <27 weeks' gestation. The questionnaire was returned anonymously by post. The responses highlighted the difference of opinion that currently exists amongst the clinicians and nurses across the world around the resuscitation practices of extremely preterm infants; yet at the same time, there seemed to be some consensus on certain issues. Based on the survey (questionnaire) results and already existing literature, the working group of the North West London Perinatal Network (NWLPN) produced and implemented specific consensus guidelines on practical aspects of resuscitation for infants born before 27 weeks' gestation for the network. The network plans to audit these guidelines in future and also produce a parent information leaflet explaining the relevance of these guidelines.

Prophylactic or early selective surfactant combined with nCPAP in very preterm infants.

OBJECTIVE: Early surfactant followed by extubation to nasal continuous positive airway pressure (nCPAP) compared with later surfactant and mechanical ventilation (MV) reduce the need for MV, air leaks, and bronchopulmonary dysplasia. This randomized, controlled trial investigated whether prophylactic surfactant followed by nCPAP compared with early nCPAP application with early selective surfactant would reduce the need for MV in the first 5 days of life. METHODS: A total of 208 inborn infants who were born at 25 to 28 weeks' gestation and were not intubated at birth were randomly assigned to prophylactic surfactant or nCPAP within 30 minutes of birth. Outcomes were assessed within the first 5 days of life and until death or discharge of the infants from hospital. RESULTS: Thirty-three (31.4%) infants in the prophylactic surfactant group needed MV in the first 5 days of life compared with 34 (33.0%) in the nCPAP group (risk ratio: 0.95 [95% confidence interval: 0.64-1.41]; P = .80). Death and type of survival at 28 days of life and 36 weeks' postmenstrual age and incidence of main morbidities of prematurity (secondary outcomes) were similar in the 2 groups. A total of 78.1% of infants in the prophylactic surfactant group and 78.6% in the nCPAP group survived in room air at 36 weeks' postmenstrual age. CONCLUSIONS: Prophylactic surfactant was not superior to nCPAP and early selective surfactant in decreasing the need for MV in the first 5 days of life and the incidence of main morbidities of prematurity in spontaneously breathing very preterm infants on nCPAP.

Cerebellar development in a baboon model of preterm delivery: impact of specific ventilatory regimes.

Premature infants now have an improved chance of survival, but the impact of respiratory therapies on the brain, particularly the cerebellum, remains unclear. We examined the effects of early nasal continuous positive airway pressure (EnCPAP) ventilation and delayed (Dn) CPAP on the development of the cerebellum in prematurely delivered baboons. The baboons were delivered at 125 +/- 2days of gestation and ventilated for 28 days with either EnCPAP commencing at 24 hours (n = 5) or DnCPAP commencing at 5 days (n = 5). Gestational controls (n = 4) were delivered at 153 days. Cerebella were assessed histologically, and an ontogeny study (90 days to term) was performed to establish values for key cerebellar developmental indicators. Cerebellar weight was reduced in DnCPAP but not EnCPAP animals versus controls; cerebellar/total brain weight ratio was increased in EnCPAP (p < 0.05) versus control and DnCPAP animals. There was no overt damage in the cerebella of any animals, but a microstructural alteration index based on morphological developmental parameters and microglial immunoreactivity was increased in both prematurely delivered cohorts versus controls (p < 0.001) and was higher in DnCPAP than EnCPAP animals (p < 0.05). These results indicate that respiratory regimens can influence cerebellar development and that early compared with delayed extubation to nCPAP seems to be beneficial.

Delayed extubation to nasal continuous positive airway pressure in the immature baboon model of bronchopulmonary dysplasia: lung clinical and pathological findings.

OBJECTIVE: Using the 125-day baboon model of bronchopulmonary dysplasia treated with prenatal steroid and exogenous surfactant, we hypothesized that a delay of extubation from low tidal volume positive pressure ventilation to nasal continuous positive airway pressure at 5 days (delayed nasal continuous positive airway pressure group) would not induce more lung injury when compared with baboons aggressively weaned to nasal continuous positive airway pressure at 24 hours (early nasal continuous positive airway pressure group), because both received positive pressure ventilation. METHODS AND RESULTS: After delivery by cesarean section at 125 days (term: 185 days), infants received 2 doses of Curosurf (Chiesi Farmaceutica S.p.A., Parma, Italy) and daily caffeine citrate. The delay in extubation to 5 days resulted in baboons in the delayed nasal continuous positive airway pressure group having a lower arterial to alveolar oxygen ratio, high PaCO2, and worse respiratory function. The animals in the delayed nasal continuous positive airway pressure group exhibited a poor respiratory drive that contributed to more reintubations and time on mechanical ventilation. A few animals in both groups developed necrotizing enterocolitis and/or sepsis, but infectious pneumonias were not documented. Cellular bronchiolitis and peribronchiolar alveolar wall thickening were more frequently seen in the delayed nasal continuous positive airway pressure group. Bronchoalveolar lavage levels of interleukin-6, interleukin-8, monocyte chemotactic protein-1, macrophage inflammatory protein-1 alpha, and growth-regulated oncogene-alpha were significantly increased in the delayed nasal continuous positive airway pressure group. Standard and digital morphometric analyses showed no significant differences in internal surface area and nodal measurements between the groups. Platelet endothelial cell adhesion molecule vascular staining was not significantly different between the 2 nasal continuous positive airway pressure groups. CONCLUSIONS: Volutrauma and/or low-grade colonization of airways secondary to increased reintubations and ventilation times are speculated to play causative roles in the delayed nasal continuous positive airway pressure group findings.

Cerebral outcomes in a preterm baboon model of early versus delayed nasal continuous positive airway pressure.

BACKGROUND: The survival of prematurely born infants has greatly increased in recent decades because of advances in neonatal intensive care, which have included the advent of ventilatory therapies. However, there is limited knowledge as to the impact of these therapies on the developing brain. The purpose of this work was to evaluate the influence of randomized respiratory therapy with either early continuous positive airway pressure or delayed continuous positive airway pressure preceded by positive pressure ventilation on the extent of brain injury and altered development in a prematurely delivered primate model. METHODS: Fetal baboons were delivered at 125 days of gestation (term: approximately 185 days of gestation) by cesarean section. Animals were maintained for 28 days postdelivery with either: early continuous positive airway pressure (commencing at 24 hours; n = 6) or delayed continuous positive airway pressure (positive pressure ventilation for 5 days followed by nCPAP; n = 5). Gestational controls (n = 4) were delivered at 153 days of gestation. At the completion of the study, animals were killed, the brains were assessed histologically for growth and development, and evidence of cerebral injury and indices for both parameters were formulated. RESULTS: Brain and body weights were reduced in all of the nasal continuous positive airway pressure animals compared with controls; however, the brain/body weight ratio was increased in early continuous positive airway pressure animals. Within both nasal continuous positive airway pressure groups compared with controls, there was increased gliosis in the subcortical and deep white matter and cortex and a persistence of radial glia. Early continuous positive airway pressure was associated with less cerebral injury than delayed continuous positive airway pressure therapy. Neuropathologies were not observed in controls. CONCLUSIONS: Premature delivery, in the absence of potentiating factors, such as hypoxia or infection, is associated with a decrease in brain growth and the presence of subtle brain injury, which seems to be modified by respiratory therapies with early continuous positive airway pressure being associated with less overall cerebral injury.

Treatment of immature baboons for 28 days with early nasal continuous positive airway pressure.

Using the 125-day baboon model of long-term bronchopulmonary dysplasia, we hypothesized that early use of nasal continuous positive airway pressure (nCPAP), a noninvasive ventilatory method, combined with prophylactic surfactant therapy would permit continuation of alveolar and vascular development in the lung. Retrospective human studies have shown that infants treated with nCPAP spend less time on mechanical ventilation and thereby sustain less volutrauma. After delivery by cesarean section at 125 days (term, 185 days), the infants received two doses of surfactant (Curosurf) and daily caffeine citrate. Weaning from low-volume positive pressure ventilation to nCPAP was attempted at 24 hours of age. Serial physiological parameters were recorded. Lung histopathology and morphometric measurements of nCPAP animals were done after necropsy at 28 days and data were compared with 125- and 156-day gestational controls. Documented episodes of clinical sepsis and pneumonia at postmortem examination were absent. nCPAP lungs showed enlarged thin-walled air spaces with minimal fibroproliferation and scattered secondary crests. Internal surface area and surface-to-volume ratio dimensions were similar to those of 156-day gestational control lungs, the intrauterine developmental control. nCPAP is an effective noninvasive ventilatory technique that minimizes lung injury in baboons at risk of developing bronchopulmonary dysplasia.

Continuous positive airway pressure and surfactant; combined data from animal experiments and clinical trials.

Bronchopulmonary dysplasia (BPD) remains a cause of considerable morbidity for the preterm infant. Ventilation is a primary risk factor. This review discusses the rationale for combining surfactant and nasal continuous positive airway pressure (nCPAP) using evidence from both clinical and animal studies. The early application of nCPAP with or without surfactant is safe and reduces the need for mechanical ventilation. Combining nCPAP with surfactant results in dramatically improved lung structure in a primate model of BPD, but still does not allow for normal alveolarization. BPD is a complex condition resulting from the interaction of many factors. Experimental evaluation of nCPAP in appropriate animal models will allow new strategies for prevention and treatment of BPD to be developed.