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Prevention of Inflammatory Disorders in the Preterm Neonate: An Update with a Special Focus on Bronchopulmonary Dysplasia
Abstract
Background: The rates of major neonatal morbidities, such as bronchopulmonary dysplasia, necrotizing enterocolitis, preterm white matter disease, and retinopathy of prematurity, remain high among surviving preterm infants. Exposure to inflammatory stimuli and the subsequent host innate immune response contribute to the risk of developing these complications of prematurity. Notably, the burden of inflammation and associated neonatal morbidity is inversely related to gestational age – leaving primarily but not exclusively the tiniest babies at highest risk. Summary: Avoidance, prevention, and treatment of inflammation to reduce this burden remain a major goal for neonatologists worldwide. In this review, we discuss the link between the host response to inflammatory stimuli and the disease state. We argue that inflammatory exposures play a key role in the pathobiology of preterm birth and that preterm neonates hereafter are highly susceptible to immune stimulation not only from their surrounding environment but also from therapeutic interventions employed in clinical care. Using bronchopulmonary dysplasia as an example, we report clinical studies demonstrating the potential utility of targeting inflammation to prevent this neonatal morbidity. On the contrary, we highlight limitations in our current understanding of how inflammation contributes to disease prevention and treatment. Key Message: To be successful in preventing and treating inflammation-driven morbidity in neonatal intensive care, it may be necessary to better identify at-risk patients and pair therapeutic interventions to key pathways and mediators of inflammation-associated neonatal morbidity identified in pre-clinical and translational studies.
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Background/Objectives: Lumbar lordotic curvature (LLC), closely associated with low back pain (LBP) when decreased, is infrequently assessed in clinical settings due to the spatiotemporal limitations of radiographic methods. To overcome these constraints, this study used an inertial measurement system to compare the magnitude and maintenance of LLC across various sitting conditions, categorized into three aspects: verbal instructions, chair type, and desk task types. Methods: Twenty-nine healthy participants were instructed to sit for 3 min with two wireless sensors placed on the 12th thoracic vertebra and the 2nd sacral vertebra. The lumbar lordotic angle (LLA) was measured using relative angles for the mediolateral axis and comparisons were made within each sitting category. Results: The maintenance of LLA (LLAdev) was significantly smaller when participants were instructed to sit upright (−3.7 ± 3.9°) compared to that of their habitual sitting posture (−1.2 ± 2.4°) (p = 0.001), while the magnitude of LLA (LLAavg) was significantly larger with an upright sitting posture (p = 0.001). LLAdev was significantly larger when using an office chair (−0.4 ± 1.1°) than when using a stool (−3.2 ± 7.1°) (p = 0.033), and LLAavg was also significantly larger with the office chair (p < 0.001). Among the desk tasks, LLAavg was largest during keyboard tasks (p < 0.001), followed by mouse and writing tasks; LLAdev showed a similar trend without statistical significance (keyboard, −1.2 ± 3.0°; mouse, −1.8 ± 2.2°; writing, −2.9 ± 3.1°) (p = 0.067). Conclusions: Our findings suggest that strategies including the use of an office chair and preference for computer work may help preserve LLC, whereas in the case of cueing, repetition may be necessary.
Innate immunity is present in all animals. In this review, we explore the main conserved mechanisms of recognition and innate immune responses among animals. In this sense, we discuss the receptors, critical for binding to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs); the downstream signaling proteins; and transcription factors that govern immune responses. We also highlight conserved inflammatory mediators that are induced after the recognition of DAMPs and PAMPs. At last, we discuss the mechanisms that are involved in the regulation and/or generation of reactive oxygen species (ROS), influencing immune responses, like heme-oxygenases (HOs).
Mitochondria are not only the power plant for intracellular oxidative phosphorylation and ATP synthesis, but also involved in cell proliferation, differentiation, signaling and apoptosis. Recent studies have shown that mitochondria play an important role in other pathophysiological functions in addition to cellular energy metabolism. Mitochondria release mitochondrial DNA (mtDNA) as a damage-associated molecular pattern (DAMP) to activate Toll-like receptor 9 (TLR9), NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune signaling pathways against foreign pathogenic microorganisms. The innate immune response not only promotes antimicrobial immune defense and regulates antiviral signaling, but their overactivation also induces the onset and progression of inflammatory diseases. In this paper, we review the role of mtDNA in the activation of innate immune signaling pathways and the crosstalk among innate immune signaling pathways activated by mtDNA, providing clues for the study of inflammatory diseases caused by mtDNA cytoplasmic translocation.
Introduction:
Intrauterine infection with Ureaplasma species (U.spp.) is mostly a result of vaginal colonization with subsequent ascending infection and is associated with adverse pregnancy outcome. Little is known about rates and risk factors for ascending infection. Aim of the current study was to analyse the frequency of ascending U.spp. infection in vaginally colonized pregnant women delivering preterm and subsequent short- and long-term outcome of infants.
Methods:
Women delivering ≤32 weeks of gestation with available data on vaginal U.spp. colonization in early pregnancy as well as amniotic and placental colonization screening during caesarean section were included. Neonatal short- and long-term outcome was analysed depending on vaginal and intrauterine colonization.
Results:
Seventy-two women giving birth to 104 preterm infants were included. Intrauterine microbial invasion was found in 23/72 (31.9%) pregnancies. The most commonly detected organisms were U.spp. (52.2%), followed by E. coli (21.7%) and Enterococcus faecalis (17.4%). Intrauterine growth of U.spp. occurred exclusively after previous vaginal colonization in early pregnancy (42/72; 58.3%) and was found in 12/42 (28.6%) cases. Ascending U.spp. infection mainly occurred in pregnancies delivering <28 weeks after preterm rupture of membranes or preterm labour (9/17, 52.3%). Intrauterine detection of U.spp., but not vaginal colonization, was associated with a significantly higher rate of severe intraventricular haemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, and unfavourable psychomotor outcome.
Conclusion:
Ascending U.spp. infection after previous vaginal colonization occurred in almost one-third of pregnancies delivering ≤32 weeks, with particularly high rates in those <28 weeks, and was associated with adverse outcome of preterm infants.
Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants, leading to chronic respiratory disease. There has been an improvement in perinatal care, but many infants still suffer from impaired branching morphogenesis, alveolarization, and pulmonary capillary formation, causing lung function impairments and BPD. There is an increased risk of respiratory infections, pulmonary hypertension, and neurodevelopmental delays in infants with BPD, all of which can lead to long-term morbidity and mortality. Unfortunately, treatment options for Bronchopulmonary dysplasia are limited. A growing body of evidence indicates that mesenchymal stromal/stem cells (MSCs) can treat various lung diseases in regenerative medicine. MSCs are multipotent cells that can differentiate into multiple cell types, including lung cells, and possess immunomodulatory, anti-inflammatory, antioxidative stress, and regenerative properties. MSCs are regulated by mitochondrial function, as well as oxidant stress responses. Maintaining mitochondrial homeostasis will likely be key for MSCs to stimulate proper lung development and regeneration in Bronchopulmonary dysplasia. In recent years, MSCs have demonstrated promising results in treating and preventing bronchopulmonary dysplasia. Studies have shown that MSC therapy can reduce inflammation, mitochondrial impairment, lung injury, and fibrosis. In light of this, MSCs have emerged as a potential therapeutic option for treating Bronchopulmonary dysplasia. The article explores the role of MSCs in lung development and disease, summarizes MSC therapy’s effectiveness in treating Bronchopulmonary dysplasia, and delves into the mechanisms behind this treatment.
Introduction
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the premature retina with the potential to progress to extraretinal neovascularisation. This review serves as an introduction to retinopathy of prematurity (ROP), outlining key parts of ROP pathophysiology, diagnosis and treatment. ROP is traditionally diagnosed by indirect ophthalmoscopy and classified using anatomical zones, stages of disease, and the presence or absence of “plus disease” (dilation and tortuosity of the major retinal arterioles and venules). ROP has a bi-phasic pathophysiology: initial hyperoxia causes reduced retinal vascularisation, followed by pathological vaso-proliferation resulting from subsequent hypoxia and driven by vascular endothelial growth factor (VEGF).
Advancements in management
This review summarises previous trials to establish optimum oxygen exposure levels in newborns and more recently the development of anti-VEGF agents locally delivered to block pathological neovascularisation, which is technically easier to administer and less destructive than laser treatment.
Future directions
There remains an ongoing concern regarding the potential unwanted systemic effects of intravitreally administered anti-VEGF on the overall development of the premature baby. Ongoing dosing studies may lessen these fears by identifying the minimally effective dose required to block extraretinal neovascularisation.
Background
Prophylactic low-dose hydrocortisone (HC) was found to improve survival without bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, appropriately adjusting for baseline risks of BPD or death might substantially increase the precision of the HC effect size.
Methods
We conducted a secondary analysis of the PREMILOC trial. The treatment effect was evaluated on the primary endpoint through a covariance analysis ANCOVA, adjusting for the baseline covariates using a mixed linear model. Several sensitivity analyses were conducted to assess the potential heterogeneity of the treatment effect across centers and subpopulations.
Results
The interaction between treatment group and baseline risk for BPD or death was not statistically significant ( p = 0.498). After adjusting for the patient’s probability of BPD-free survival using baseline predictors alone, the HC treatment exhibited a highly significant effect (OR [95% CI] = 2.053 [1.602–2.501], p = 0.002), with a number needed to treat NNT [95% CI] = 5.8 [4.1–23.0]. Despite a weak interaction with sex, we found a lack of heterogeneity in the treatment effect across specific subpopulations.
Conclusions
In the PREMILOC trial, the beneficial effect of prophylactic HC versus placebo on BPD-free survival in extremely preterm neonates was found to be greater when adjusted to baseline risks of BPD or death.
Registration numbers
EudraCT number 2007-002041-20, ClinicalTrial.gov number NCT00623740.
Impact
Prophylactic low-dose hydrocortisone (HC) provided past evidence of a beneficial effect in improving survival without BPD in infants born extremely preterm.
Adjustment for baseline risks of BPD or death might substantially increase the precision of the HC effect size.
The beneficial effect of prophylactic HC vs placebo on BPD-free survival in extremely preterm neonates was found to be greater when adjusted to baseline risks of BPD or death.
We evidenced a lack of heterogeneity in the treatment effect in specific subpopulations despite some weak interaction with sex.
As the leading cause of neonatal morbidity and mortality, preterm birth is recognized as a major public health concern around the world. The purpose of this review is to analyze the connection between infections and premature birth. Spontaneous preterm birth is commonly associated with intrauterine infection/inflammation. The overproduction of prostaglandins caused by the inflammation associated with an infection could lead to uterine contractions, contributing to preterm delivery. Many pathogens, particularly Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Gardnerella vaginalis, Ureaplasma urealyticum, Mycoplasma hominis, Actinomyces, Candida spp., and Streptococcus spp. have been related with premature delivery, chorioamnionitis, and sepsis of the neonate. Further research regarding the prevention of preterm delivery is required in order to develop effective preventive methods with the aim of reducing neonatal morbidity.
Importance:
Meta-analyses suggest that corticosteroids may be associated with increased survival without cerebral palsy in infants at high risk of bronchopulmonary dysplasia (BPD) but are associated with adverse neurologic outcomes in low-risk infants. Whether this association exists in contemporary practice is uncertain because most randomized clinical trials administered corticosteroids earlier and at higher doses than currently recommended.
Objective:
To evaluate whether the pretreatment risk of death or grade 2 or 3 BPD at 36 weeks' postmenstrual age modified the association between postnatal corticosteroid therapy and death or disability at 2 years' corrected age in extremely preterm infants.
Design, setting, and participants:
This cohort study analyzed data on 482 matched pairs of infants from 45 participating US hospitals in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database (GDB). Infants were included in the cohort if they were born at less than 27 weeks' gestation between April 1, 2011, and March 31, 2017; survived the first 7 postnatal days; and had 2-year death or developmental follow-up data collected between January 2013 and December 2019. Corticosteroid-treated infants were propensity score matched with untreated controls. Data were analyzed from September 1, 2019, to November 30, 2022.
Exposure:
Systemic corticosteroid therapy to prevent BPD that was initiated between day 8 and day 42 after birth.
Main outcomes and measures:
The primary outcome was death or moderate to severe neurodevelopmental impairment at 2 years' corrected age. The secondary outcome was death or moderate to severe cerebral palsy at 2 years' corrected age.
Results:
A total of 482 matched pairs of infants (mean [SD] gestational age, 24.1 [1.1] weeks]; 270 males [56.0%]) were included from 656 corticosteroid-treated infants and 2796 potential controls. Most treated infants (363 [75.3%]) received dexamethasone. The risk of death or disability associated with corticosteroid therapy was inversely associated with the estimated pretreatment probability of death or grade 2 or 3 BPD. The risk difference for death or neurodevelopmental impairment associated with corticosteroids decreased by 2.7% (95% CI, 1.9%-3.5%) for each 10% increase in the pretreatment risk of death or grade 2 or 3 BPD. This risk transitioned from estimated net harm to benefit when the pretreatment risk of death or grade 2 or 3 BPD exceeded 53% (95% CI, 44%-61%). For death or cerebral palsy, the risk difference decreased by 3.6% (95% CI, 2.9%-4.4%) for each 10% increase in the risk of death or grade 2 or 3 BPD and transitioned from estimated net harm to benefit at a pretreatment risk of 40% (95% CI, 33%-46%).
Conclusions and relevance:
Results of this study suggested that corticosteroids were associated with a reduced risk of death or disability in infants at moderate to high pretreatment risk of death or grade 2 or 3 BPD but with possible harm in infants at lower risk.
Preeclampsia (PE) is a leading cause of maternal and fetal mortality worldwide. The immune system plays a critical role in normal pregnancy progression; however, inappropriate inflammatory responses have been consistently linked with PE pathophysiology. This inflammatory phenotype consists of activation of the innate immune system, adaptive immune system, and increased inflammatory mediators in circulation. Moreover, recent studies have shown that the inflammatory profile seen in PE persists into the postpartum period. This manuscript aims to highlight recent advances in research relating to inflammation in PE as well as the inflammation that persists postpartum in women after a PE pregnancy. With the advent of the COVID-19 pandemic, there has been an increase in obstetric disorders associated with COVID-19 infection during pregnancy. This manuscript also aims to shed light on the relationship between COVID-19 infection during pregnancy and the increased incidence of PE in these women.
Retinopathy of prematurity (ROP), a vasoproliferative vitreoretinal disorder, is the leading cause of childhood blindness worldwide. Although angiogenic pathways have been the main focus, cytokine-mediated inflammation is also involved in ROP etiology. Herein, we illustrate the characteristics and actions of all cytokines involved in ROP pathogenesis. The two-phase (vaso-obliteration followed by vasoproliferation) theory outlines the evaluation of cytokines in a time-dependent manner. Levels of cytokines may even differ between the blood and the vitreous. Data from animal models of oxygen-induced retinopathy are also valuable. Although conventional cryotherapy and laser photocoagulation are well established and anti-vascular endothelial growth factor agents are available, less destructive novel therapeutics that can precisely target the signaling pathways are required. Linking the cytokines involved in ROP to other maternal and neonatal diseases and conditions provides insights into the management of ROP. Suppressing disordered retinal angiogenesis via the modulation of hypoxia-inducible factor, supplementation of insulin-like growth factor (IGF)-1/IGF-binding protein 3 complex, erythropoietin, and its derivatives, polyunsaturated fatty acids, and inhibition of secretogranin III have attracted the attention of researchers. Recently, gut microbiota modulation, non-coding RNAs, and gene therapies have shown promise in regulating ROP. These emerging therapeutics can be used to treat preterm infants with ROP.
Preterm birth is a major contributor to neonatal morbidity and mortality. Complications of prematurity such as bronchopulmonary dysplasia (BPD, affecting the lung), pulmonary hypertension associated with BPD (BPD-PH, heart), white matter injury (WMI, brain), retinopathy of prematurity (ROP, eyes), necrotizing enterocolitis (NEC, gut) and sepsis are among the major causes of long-term morbidity in infants born prematurely. Though the origins are multifactorial, inflammation and in particular the imbalance of pro- and anti-inflammatory mediators is now recognized as a key driver of the pathophysiology underlying these illnesses. Here, we review the involvement of the interleukin (IL)-1 family in perinatal inflammation and its clinical implications, with a focus on the potential of these cytokines as therapeutic targets for the development of safe and effective treatments for early life inflammatory diseases.
Necrotizing enterocolitis (NEC) is a devastating, multifactorial disease mainly affecting the intestine of premature infants. Recent discoveries have significantly enhanced our understanding of risk factors, as well as, cellular and genetic mechanisms of this complex disease. Despite these advancements, no essential, single risk factor, nor the mechanism by which each risk factor affects NEC has been elucidated. Nonetheless, recent research indicates that maternal factors, antibiotic exposure, feeding, hypoxia, and altered gut microbiota pose a threat to the underdeveloped immunity of preterm infants. Here we review predisposing factors, status of unwarranted immune responses, and microbial pathogenesis in NEC based on currently available scientific evidence. We additionally discuss novel techniques and models used to study NEC and how this research translates from the bench to the bedside into potential treatment strategies.
The comparative efficacy and safety of restrictive with liberal transfusion thresholds remain controversial in anemic preterm infants. This meta-analysis aimed to compare the efficacy and safety of these two transfusion thresholds for anemic preterm infants. We searched PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) for relevant randomized controlled trials (RCTs) comparing restrictive with liberal transfusion thresholds in anemic preterm infants through April 30, 2022. Two independent investigators screened literature, extracted data, and appraised the methodological quality of eligible studies. Meta-analysis was conducted using RevMan version 5.3.5. Twelve RCTs with 4380 preterm infants were included. Liberal transfusion threshold significantly increased the level of hemoglobin after transfusion (mean difference (MD): −10.03; 95% confidence interval (CI): −15.98 to −4.08; p=0.001; I2=94%) and hematocrit (MD: −3.62; 95%CI: −6.78 to −0.46; p=0.02; I2=80%) compared with restrictive transfusion. Infants’ age at first transfusion in restrictive transfusion group was higher than that of infants in liberal transfusion group (MD: 5.08; 95%CI: 2.27 to7.89; p=0.004; I2=54%); however, restrictive transfusion was associated with more time on supplemental oxygen (MD: 3.56; 95%CI: 1.93 to 5.18; p<0.001; I2=62%) and ventilator or CPAP (MD: 3.31; 95%CI: 1.42 to 5.20; p=0.006; I2=75%). For the remaining outcomes, two transfusion strategies were comparable. Furthermore, a series of sensitivity analyses confirmed the robustness of the level of hemoglobin after transfusion, age at first transfusion, time on ventilator or CPAP, and safety outcomes. Evidence with substantial heterogeneity indicates that liberal and restrictive transfusion thresholds are effective and safe blood cell transfusion strategies in anemic preterm infants, but the liberal strategy may be more effective in shortening the length of necessary respiratory support.
Despite advances in neonatal care Necrotising Enterocolitis (NEC) continues to have a significant mortality and morbidity rate, and with increasing survival of those more immature infants the population at risk of NEC is increasing. Ischaemia, reperfusion, and inflammation underpin diseases affecting intestinal blood flow causing gut injury including Necrotising Enterocolitis. There is increasing interest in tissue biomarkers of gut injury in neonates, particularly those representing changes in intestinal wall barrier and permeability, to determine whether these could be useful biomarkers of gut injury. This article reviews current and newly proposed markers of gut injury, the available literature evidence, recent advances and considers how effective they are in clinical practice. We discuss each biomarker in terms of its effectiveness in predicting NEC onset and diagnosis or predicting NEC severity and then those that will aid in surveillance and identifying those infants are greatest risk of developing NEC.
Background
Bronchopulmonary dysplasia (BPD), its complication pulmonary hypertension (BPD-PH) and preterm brain and gut injury lead to significant morbidity and mortality in infants born extremely prematurely. There is extensive evidence that the pro-inflammatory cytokine interleukin 1 (IL-1) plays a key role in the pathophysiology of these illnesses. Two decades of clinical use in paediatric and adult medicine have established an excellent safety and efficacy record for IL-1 blockade with IL-1 receptor antagonist (IL-1Ra, medication name anakinra). Building on robust pre-clinical evidence, the Anakinra Pilot trial aims to demonstrate safety and feasibility of administering anakinra to preterm infants, and to establish pharmacokinetics in this population. Its ultimate goal is to facilitate large studies that will test whether anakinra can ameliorate early-life inflammation, thus alleviating multiple complications of prematurity.
Methods and analysis
Anakinra Pilot is an investigator-initiated, single arm, safety and feasibility dose-escalation trial in extremely preterm infants born between 24 weeks 0 days (24⁰) and 27⁶ weeks of gestational age (GA). Enrolled infants will receive anakinra intravenously over the first 21 days after birth, starting in the first 24 h after birth. In the first phase, dosing is 1 mg/kg every 48 h, and dosage will increase to 1.5 mg/kg every 24 h in the second phase. Initial anakinra dosing was determined through population pharmacokinetic model simulations. During the study, there will be a interim analysis to confirm predictions before undertaking dose assessment. Anakinra therapy will be considered safe if the frequency of adverse outcomes/events does not exceed that expected in infants born at 24⁰-27⁶ weeks GA.
Clinical Trial Registration
https://clinicaltrials.gov/, identifier NCT05280340.
In clinical settings, oxygen therapy is administered to preterm neonates and to adults with acute and chronic conditions such as COVID-19, pulmonary fibrosis, sepsis, cardiac arrest, carbon monoxide poisoning, and acute heart failure. In non-clinical settings, divers and astronauts may also receive supplemental oxygen. In addition, under current standard cell culture practices, cells are maintained in atmospheric oxygen, which is several times higher than what most cells experience in vivo. In all the above scenarios, the elevated oxygen levels (hyperoxia) can lead to increased production of reactive oxygen species from mitochondria, NADPH oxidases, and other sources. This can cause cell dysfunction or death. Acute hyperoxia injury impairs various cellular functions, manifesting ultimately as physiological deficits. Chronic hyperoxia, particularly in the neonate, can disrupt development, leading to permanent deficiencies. In this review, we discuss the cellular activities and pathways affected by hyperoxia, as well as strategies that have been developed to ameliorate injury.
Graphical abstract
• Hyperoxia promotes overproduction of reactive oxygen species (ROS).
• Hyperoxia dysregulates a variety of signaling pathways, such as the Nrf2, NF-κB and MAPK pathways.
• Hyperoxia causes cell death by multiple pathways.
• Antioxidants, particularly, mitochondria-targeted antioxidants, have shown promising results as therapeutic agents against oxygen toxicity in animal models.
Background
Bronchopulmonary dysplasia (BPD) is one of the most common and serious sequelae of prematurity. Prompt diagnosis using prediction tools is crucial for early intervention and prevention of further adverse effects. This study aims to develop a BPD-free survival prediction tool based on the concept of the developmental origin of BPD with machine learning.
Methods
Datasets comprising perinatal factors and early postnatal respiratory support were used for initial model development, followed by combining the two models into a final ensemble model using logistic regression. Simulation of clinical scenarios was performed.
Results
Data from 689 infants were included in the study. We randomly selected data from 80% of infants for model development and used the remaining 20% for validation. The performance of the final model was assessed by receiver operating characteristics which showed 0.921 (95% CI: 0.899–0.943) and 0.899 (95% CI: 0.848–0.949) for the training and the validation datasets, respectively. Simulation data suggests that extubating to CPAP is superior to NIPPV in BPD-free survival. Additionally, successful extubation may be defined as no reintubation for 9 days following initial extubation.
Conclusions
Machine learning-based BPD prediction based on perinatal features and respiratory data may have clinical applicability to promote early targeted intervention in high-risk infants.
Formula feeding is an important risk factor for the development of necrotizing enterocolitis in preterm infants. The potential harmful effects of different preterm formulas on the developing intestinal tract remain incompletely understood. Here we demonstrate that feeding newborn mouse pups with various preterm formulas resulted in differing effects on intestinal inflammation, apoptosis, and activation of the pro-inflammatory transcription factor NFκB. 16S rRNA sequencing revealed that each preterm formula resulted in significant gut microbial alterations that were different from dam-fed controls. Formula feeding with EleCare and Similac Special Care caused greater intestinal injury compared to NeoSure. Pre-treatment with Lactobacillus rhamnosus GG ameliorated severity of intestinal injury from EleCare and Similac Special Care. Our findings indicate that not all preterm formulas are the same, and different formulations can have varying effects on intestinal inflammation, apoptosis, and microbiome composition.
Ureaplasma and Prevotella infections are well-known bacteria associated with preterm birth. However, with the development of metagenome sequencing techniques, it has been found that not all Ureaplasma and Prevotella colonizations cause preterm birth. The purpose of this study was to determine the association between Ureaplasma and Prevotella colonization with the induction of preterm birth even in the presence of Lactobacillus. In this matched case–control study, a total of 203 pregnant Korean women were selected and their cervicovaginal fluid samples were collected during mid-pregnancy. The microbiome profiles of the cervicovaginal fluid were analyzed using 16S rRNA gene amplification. Sequencing data were processed using QIIME1.9.1. Statistical analyses were performed using R software, and microbiome analysis was performed using the MicrobiomeAnalyst and Calypso software. A positive correlation between Ureaplasma and other genera was highly related to preterm birth, but interestingly, there was a negative correlation with Lactobacillus and term birth, with the same pattern observed with Prevotella. Ureaplasma and Prevotella colonization with Lactobacillus abundance during pregnancy facilitates term birth, although Ureaplasma and Prevotella are associated with preterm birth. Balanced colonization between Lactobacillus and Ureaplasma and Prevotella is important to prevent preterm birth.
Even more than 50 years after its initial description, bronchopulmonary dysplasia (BPD) remains one of the most important and lifelong sequelae following premature birth. Tremendous efforts have been undertaken since then to reduce this ever-increasing disease burden but a therapeutic breakthrough preventing BPD is still not in sight. The inflammatory response provoked in the immature lung is a key driver of distorted lung development and impacts the formation of alveolar, mesenchymal, and vascular structures during a particularly vulnerable time-period. During the last 5 years, new scientific insights have led to an improved pathomechanistic understanding of BPD origins and disease drivers. Within the framework of current scientific progress, concepts involving disruption of the balance of key inflammatory and lung growth promoting pathways by various stimuli, take center stage. Still today, the number of efficient therapeutics available to prevent BPD is limited to a few, well-established pharmacological interventions including postnatal corticosteroids, early caffeine administration, and vitamin A. Recent advances in the clinical care of infants in the neonatal intensive care unit (NICU) have led to improvements in survival without a consistent reduction in the incidence of BPD. Our update provides latest insights from both preclinical models and clinical cohort studies and describes novel approaches to prevent BPD.
Purpose
Perinatal Ureaplasma infection is associated with a variety of adverse outcomes and neonatal diseases. This meta-analysis is to evaluate current evidence evaluating the association between Ureaplasma and adverse pregnancy outcomes and bronchopulmonary dysplasia (BPD) in preterm infants.
Methods
We searched for published articles on Ureaplasma, preterm and BPD in PubMed, the Cochrane Library, and Embase databases posted before August 28, 2021. In addition, the references of these articles were screened. A random/fixed-effect model was used to synthesize predefined outcomes.
Results
A total of 19 cohort studies involving 11,990 pregnancy women met our inclusion criteria. Pregnancy Ureaplasma positive increased the risk of preterm birth [odds ratios (OR) 2.76, 95% confidence intervals (CI) 1.63–4.68], BPD (OR 2.39 95% CI 1.73–3.30), chorioamnionitis (OR 2.71, 95% CI 2.02–3.64) and premature rupture of membranes (PROM, OR 2.19, 95% CI 1.34–3.58).
Conclusions
Pregnancy Ureaplasma positive may increase the risk of developing preterm birth, chorioamnionitis, PROM and BPD in the preterm infant. The evidence base is, however, of low quality and well-designed studies are needed.
Retinopathy of prematurity (ROP) is the main risk factor for vision-threatening disease in premature infants with low birth weight. An accumulating number of independent studies have focused on ROP pathogenesis and have demonstrated that laser photocoagulation therapy and/or anti-VEGF treatment are effective. However, early diagnosis of ROP is still critical. At present, the main method of ROP screening is based on binocular indirect ophthalmoscopy. However, the judgment of whether ROP occurs and whether treatment is necessary depends largely on ophthalmologists with a great deal of experience. Therefore, it is essential to develop a simple, accurate and effective diagnostic method. This review describes recent findings on novel biomarkers for the prediction, diagnosis and prognosis of ROP patients. The novel biomarkers were separated into the following categories: metabolites, cytokines and growth factors, non-coding RNAs, iconography, gut microbiota, oxidative stress biomarkers, and others. Biomarkers with high sensitivity and specificity are urgently needed for the clinical applications of ROP. In addition, using non-invasive or minimally invasive methods to obtain samples is also important. Our review provides an overview of potential biomarkers of ROP.
High concentration oxygen is widely used in the treatment of neonates, which has a significant effect on improving blood oxygen concentration in neonates with respiratory distress. The adverse effects of hyperoxia therapy on the lung, retina, and neurodevelopment of newborns have been extensively studied, but less attention has been paid to intestinal damage caused by hyperoxia therapy. In this review, we focus on the physical, immune, and microorganism barriers of the intestinal tract and discuss neonatal intestinal tract damage caused by hyperoxia therapy and analyze the molecular mechanism of intestinal damage caused by hyperoxia in combination with necrotizing enterocolitis.
Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.
Preterm babies are highly susceptible to oxidative stress (OS) due to an imbalance between the oxidant and antioxidant systems. The generation of free radicals (FR) induces oxidative damage to multiple body organs and systems. OS is the main factor responsible for the development of typical premature infant diseases, such as bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, kidney damage, eryptosis, and also respiratory distress syndrome and patent ductus arteriosus. Many biomarkers have been detected to early identify newborns at risk of developing a free radical-mediated disease and to investigate new antioxidant strategies. This review reports the current knowledge on OS in the preterm newborns and the newest findings concerning the use of OS biomarkers as diagnostic tools, as well as in implementing antioxidant therapeutic strategies for the prevention and treatment of these diseases and their sequelae.
Bronchopulmonary dysplasia (BPD) is a common, severe chronic respiratory disease that affects very preterm infants. In utero and postnatal exposure to proinflammatory stimuli contribute to the pathophysiology of BPD. Corticosteroids, because of their potent anti-inflammatory properties, may decrease respiratory morbidity and reduce the risk of BPD in very preterm infants. However, these medications can have adverse effects on the developing brain and other organ systems. This review examines current evidence on the risks and benefits of postnatal corticosteroids used to prevent BPD in preterm infants.
Purpose: To analyze the effect of different feeding types on bronchopulmonary dysplasia (BPD) in very low birth weight preterm infants. Methods: The Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, China Biomedical Literature Database (CBM) were searched for literature related to breastfeeding and BPD, with a search period from their inception to January 2023. Two researchers independently screened the literature, extracted data, and assessed the quality of included studies before analyzing the data using Stata16 and RevMan5.4.1 software. Results: A total of 17 studies were included. The results showed that there was no significant difference in the frequency of BPD between human milk (HM) and donor human milk (DHM) (OR = 0.54, 95% CI: 0.29-1.03, p = 0.07). However, DHM had a significant effect in reducing the frequency of BPD compared to preterm formula (PF) (OR = 0.62, 95% CI: 0.41-0.94, p = 0.02). Exclusive HM also had a significant effect in reducing the frequency of BPD compared to exclusive PF (OR = 0.51, 95% CI: 0.34-0.78, p = 0.002), as well as compared to any PF (OR = 0.57, 95% CI: 0.37-0.88, p = 0.01). Furthermore, mainly (>50%) HM had a significant effect in reducing the frequency of BPD compared to mainly PF (OR = 0.72, 95% CI: 0.55-0.93, p = 0.01). However, there was no statistically significant difference between any HM and exclusive PF (OR = 0.88, 95% CI: 0.62-1.23, p = 0.46). Conclusions: Our study findings suggest that both HM and DHM have a significant protective effect in reducing the frequency of BPD occurrence compared to PF. Furthermore, even when the amount of HM is insufficient, feeding more than 50% of the HM volume still provides a protective effect against the frequency of BPD. Therefore, we recommend feeding infants with more than 50% of HM to harness the protective effect of HM against BPD occurrence.
Red blood cell (RBC) transfusions are common in neonates requiring intensive care. Recent studies have compared restricted versus liberal transfusion guidelines, but limitations exist on evaluations of outcomes in populations that never required a transfusion compared to those receiving any transfusion. Although there are well-established risks associated with RBC transfusions, new data has emerged that suggests additional clinically relevant associations, including adverse neurodevelopmental outcomes, donor sex differences, and inflammation or immunosuppression. Further research is needed to delineate the magnitude of these risks and to further improve the safety of transfusions. The goal of this review is to highlight underappreciated, yet clinically important risks associated with neonatal RBC transfusions and to introduce several areas in which neonates may uniquely benefit from alterations in practice.
Background:
Despite considerable improvement in outcomes for preterm infants, rates of bronchopulmonary dysplasia (BPD) remain high, affecting an estimated 33% of very low birthweight infants, with corresponding long-term respiratory and neurosensory issues. Systemic corticosteroids can address the inflammation underlying BPD, but the optimal regimen for prevention of this disease, balancing of the benefits with the potentially meaningful risks of systemic corticosteroids, continues to be a medical quandary. Numerous studies have shown that systemic corticosteroids, particularly dexamethasone and hydrocortisone, effectively treat or prevent BPD. However, concerning short and long-term side effects have been reported and the optimal approach to corticosteroid treatment remains unclear.
Objectives:
To determine whether differences in efficacy and safety exist between high-dose dexamethasone, moderate-dose dexamethasone, low-dose dexamethasone, hydrocortisone, and placebo in the prevention of BPD, death, the composite outcome of death or BPD, and other relevant morbidities, in preterm infants through a network meta-analysis, generating both pairwise comparisons between all treatments and rankings of the treatments.
Search methods:
We searched the Cochrane Library for all systematic reviews of systemic corticosteroids for the prevention of BPD and searched for completed and ongoing studies in the following databases in January 2023: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial databases.
Selection criteria:
We included randomized controlled trials (RCTs) in preterm infants (< 37 weeks' gestation) at risk for BPD that evaluated systemic corticosteroids (high-dose [≥ 4 mg/kg cumulative dose] dexamethasone, moderate-dose [≥ 2 to < 4 mg/kg] dexamethasone, low-dose [< 2 mg/kg] dexamethasone, or hydrocortisone) versus control or another systemic corticosteroid.
Data collection and analysis:
Our main information sources were the systematic reviews, with reference to the original manuscript only for data not included in these reviews. Teams of two paired review authors independently performed data extraction, with disagreements resolved by discussion. Data were entered into Review Manager 5 and exported to R software for network meta-analysis (NMA). NMA was performed using a frequentist model with random-effects. Two separate networks were constructed, one for early (< seven days) initiation of treatment and one for late (≥ seven days) treatment initiation, to reflect the different patient populations evaluated. We assessed the certainty of evidence derived from the NMA for our primary outcomes using principles of the GRADE framework modified for application to NMA.
Main results:
We included 59 studies, involving 6441 infants, in our analyses. Only six of the included studies provided direct comparisons between any of the treatment (dexamethasone or hydrocortisone) groups, forcing network comparisons between treatments to rely heavily on indirect evidence through comparisons with placebo/no treatment groups. Thirty-one studies evaluated early corticosteroid treatment, 27 evaluated late corticosteroid treatment, and one study evaluated both early and late corticosteroid treatments. Early treatment (prior to seven days after birth): Benefits:NMA for early treatment showed only moderate-dose dexamethasone to decrease the risk of BPD at 36 weeks' postmenstrual age (PMA) compared with control (RR 0.56, 95% CI 0.39 to 0.80; moderate-certainty evidence), although the other dexamethasone dosing regimens may have similar effects compared with control (high-dose dexamethasone, RR 0.71, 95% CI 0.50 to 1.01; low-certainty evidence; low-dose dexamethasone, RR 0.83, 95% CI 0.67 to 1.03; low-certainty evidence). Other early treatment regimens may have little or no effect on the risk of death at 36 weeks' PMA. Only moderate-dose dexamethasone decreased the composite outcome of death or BPD at 36 weeks' PMA compared with control (RR 0.77, 95% CI 0.60 to 0.98; moderate-certainty evidence).
Harms:
Low-dose dexamethasone increased the risk for cerebral palsy (RR 1.92, 95% CI 1.12 to 3.28; moderate-certainty evidence) compared with control. Hydrocortisone may decrease the risk of major neurosensory disability versus low-dose dexamethasone (RR 0.65, 95% CI 0.41 to 1.01; low-certainty evidence). Late treatment (at seven days or later after birth): Benefits: NMA for late treatment showed high-dose dexamethasone to decrease the risk of BPD both versus hydrocortisone (RR 0.66, 95% CI 0.51 to 0.85; low-certainty evidence) and versus control (RR 0.72, CI 0.59 to 0.87; moderate-certainty evidence). The late treatment regimens evaluated may have little or no effect on the risk of death at 36 weeks' PMA. High-dose dexamethasone decreased risk for the composite outcome of death or BPD compared with all other treatments (control, RR 0.69, 95% CI 0.59 to 0.80, high-certainty evidence; hydrocortisone, RR 0.69, 95% CI 0.58 to 0.84, low-certainty evidence; low-dose dexamethasone, RR 0.73, 95% CI 0.60 to 0.88, low-certainty evidence; moderate-dose dexamethasone, RR 0.76, 95% CI 0.62 to 0.93, low-certainty evidence).
Harms:
No effect was observed for the outcomes of major neurosensory disability or cerebral palsy. The evidence for the primary outcomes was of overall low certainty, with notable deductions for imprecision and heterogeneity across the networks.
Authors' conclusions:
While early treatment with moderate-dose dexamethasone or late treatment with high-dose dexamethasone may lead to the best effects for survival without BPD, the certainty of the evidence is low. There is insufficient evidence to guide this therapy with regard to plausible adverse long-term outcomes. Further RCTs with direct comparisons between systemic corticosteroid treatments are needed to determine the optimal treatment approach, and these studies should be adequately powered to evaluate survival without major neurosensory disability.
Retinopathy of prematurity (ROP) is a leading cause of preventable vision loss in preterm infants. While appropriate screening is crucial for early identification and treatment of ROP, current screening guidelines remain limited by inter-examiner variability in screening modalities, absence of local protocol for ROP screening in some settings, a paucity of resources and an increased survival of younger and smaller infants. This review summarizes the advancements and challenges of current innovative technologies, artificial intelligence (AI), and predictive biomarkers for the diagnosis and management of ROP. We provide a contemporary overview of AI-based models for detection of ROP, its severity, progression, and response to treatment. To address the transition from experimental settings to real-world clinical practice, challenges to the clinical implementation of AI for ROP are reviewed and potential solutions are proposed. The use of optical coherence tomography (OCT) and OCT angiography (OCTA) technology is also explored, providing evaluation of subclinical ROP characteristics that are often imperceptible on fundus examination. Furthermore, we explore several potential biomarkers to reduce the need for invasive procedures, to enhance diagnostic accuracy and treatment efficacy. Finally, we emphasize the need of a symbiotic integration of biologic and imaging biomarkers and AI in ROP screening, where the robustness of biomarkers in early disease detection is complemented by the predictive precision of AI algorithms.
Intravenous lipid emulsions (ILEs) are a source of nonprotein calories and fatty acids and help promote growth in preterm infants and infants with intestinal failure. An ILE dose and oil source determines its fatty acid, phytosterol, and vitamin E delivery. These factors play a role in the infant's risk for essential fatty acid deficiency and cholestasis, and help modulate inflammation, immunity, and organ development. This article reviews different ILEs and their constituents and their relationship with neonatal health.
Mechanical ventilation is necessary to maintain oxygenation and ventilation in many preterm infants. Unfortunately, even short periods of mechanical ventilation can cause lung and airway injury, and initiate the lung inflammation that contributes to the development of bronchopulmonary dysplasia (BPD). The mechanical stretch leads to airway cell differentiation and simplification of the alveoli, and releases cytokines that cause systemic response in other organs. Mechanical ventilation also leads to brain injury (IVH, white and gray matter) and neuronal inflammation that can affect the neurodevelopment of preterm infants. In efforts to decrease BPD, corticosteroids have been used for both prevention and treatment of lung inflammation. Corticosteroids have also been demonstrated to cause neuronal injury, so the clinician must balance the negative effects of both mechanical ventilation and steroids on the brain and lungs. Predictive models for BPD can help assess the infants who will benefit most from corticosteroid exposure. This review describes the lung and brain injury from mechanical ventilation in the delivery room and chronic mechanical ventilation in animal models. It provides updates on the current guidelines for use of postnatal corticosteroids (dexamethasone, hydrocortisone, budesonide, budesonide with surfactant) for the prevention and treatment of BPD, and the effects the timing of each steroid regimen has on neurodevelopment.
Over the last 20 years, stem cells of varying origin and their associated secretome have been investigated as a therapeutic option for a myriad of neonatal models of disease, with very promising results. Despite the devastating nature of some of these disorders, translation of the preclinical evidence to the bedside has been slow. In this review, we explore the existing clinical evidence for stem cell therapies in neonates, highlight the barriers faced by researchers and suggest potential solutions to move the field forward.
Preterm birth and intrapartum related complications account for a substantial amount of mortality and morbidity in the neonatal period despite significant advancements in neonatal-perinatal care. Currently, there is a noticeable lack of curative or preventative therapies available for any of the most common complications of prematurity including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia and retinopathy of prematurity or hypoxic-ischemic encephalopathy, the main cause of perinatal brain injury in term infants. Mesenchymal stem/stromal cell-derived therapy has been an active area of investigation for the past decade and has demonstrated encouraging results in multiple experimental models of neonatal disease. It is now widely acknowledged that mesenchymal stem/stromal cells exert their therapeutic effects via their secretome, with the principal vector identified as extracellular vesicles. This review will focus on summarizing the current literature and investigations on mesenchymal stem/stromal cell-derived extracellular vesicles as a treatment for neonatal diseases and examine the considerations to their application in the clinical setting.
Immune-mediated inflammatory diseases (IMIDs) are characterized by excessive and uncontrolled inflammation and thrombosis, both of which are responsible for organ damage, morbidity and death. Platelets have long been known for their role in primary haemostasis, but they are now also considered to be components of the immune system and to have a central role in the pathogenesis of IMIDs. In patients with IMIDs, platelets are activated by disease-specific factors, and their activation often reflects disease activity. Here we summarize the evidence showing that activated platelets have an active role in the pathogenesis and the progression of IMIDs. Activated platelets produce soluble factors and directly interact with immune cells, thereby promoting an inflammatory phenotype. Furthermore, platelets participate in tissue injury and promote abnormal tissue healing, leading to fibrosis. Targeting platelet activation and targeting the interaction of platelets with the immune system are novel and promising therapeutic strategies in IMIDs. In addition to their well-established role in haemostasis, platelets also have an active role in the immune response. Here the authors summarize the evidence linking platelet activation to immune dysregulation and organ damage in immune-mediated inflammatory diseases, and discuss the therapeutic potential of targeting platelets.
Necrotizing enterocolitis (NEC) continues to be a major cause of morbidity and mortality in preterm infants. Despite decades of research in NEC, no reliable biomarkers can accurately diagnose NEC or predict patient prognosis. The recent emergence of multi-omics could potentially shift NEC biomarker discovery, particularly when evaluated using systems biology techniques. Furthermore, the use of machine learning and artificial intelligence in analyzing this 'big data' could enable novel interpretations of NEC subtypes, disease progression, and potential therapeutic targets, allowing for integration with personalized medicine approaches. In this review, we evaluate studies using omics technologies and machine learning in the diagnosis of NEC. Future implications and challenges inherent to the field are also discussed.
Background:
Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks' postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation may be an effective and safe alternative.
Objectives:
To assess the benefits and harms of inhaled corticosteroids versus placebo, initiated between seven days of postnatal life and 36 weeks' postmenstrual age, to preterm infants at risk of developing bronchopulmonary dysplasia.
Search methods:
We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trials registries to August 2022. We searched conference proceedings and the reference lists of retrieved articles for additional studies.
Selection criteria:
We included randomised controlled trials (RCTs) comparing inhaled corticosteroids to placebo, started between seven days' postnatal age (PNA) and 36 weeks' PMA, in infants at risk of BPD. We excluded trials investigating systemic corticosteroids versus inhaled corticosteroids.
Data collection and analysis:
We collected data on participant characteristics, trial methodology, and inhalation regimens. The primary outcomes were mortality, BPD, or both at 36 weeks' PMA. Secondary outcomes included short-term respiratory outcomes (mortality or BPD at 28 days' PNA, failure to extubate, total days of mechanical ventilation and oxygen use, and need for systemic corticosteroids) and adverse effects. We contacted the trial authors to verify the validity of extracted data and to request missing data. We analysed all data using Review Manager 5. Where possible, we reported the results of meta-analyses using risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, along with their 95% confidence intervals (CIs). We analysed ventilated and non-ventilated participants separately. We used the GRADE approach to assess the certainty of the evidence.
Main results:
We included seven trials involving 218 preterm infants in this review. We identified no new eligible studies in this update. The evidence is very uncertain regarding whether inhaled corticosteroids affects the combined outcome of mortality or BPD at 36 weeks' PMA (RR 1.10, 95% CI 0.74 to 1.63; RD 0.07, 95% CI -0.21 to 0.34; 1 study, 30 infants; very low-certainty) or its separate components: mortality (RR 3.00, 95% CI 0.35 to 25.78; RD 0.07, 95% CI -0.08 to 0.21; 3 studies, 61 infants; very low-certainty) and BPD (RR 1.00, 95% CI 0.59 to 1.70; RD 0.00, 95% CI -0.31 to 0.31; 1 study, 30 infants; very low-certainty) at 36 weeks' PMA. Inhaled corticosteroids may reduce the need for systemic corticosteroids, but the evidence is very uncertain (RR 0.51, 95% CI 0.26 to 1.00; RD -0.22, 95% CI -0.42 to -0.02; number needed to treat for an additional beneficial outcome 5, 95% CI 2 to 115; 4 studies, 74 infants; very low-certainty). There was a paucity of data on short-term and long-term adverse effects. Despite a low risk of bias in the individual studies, we considered the certainty of the evidence for all comparisons discussed above to be very low, because the studies had few participants, there was substantial clinical heterogeneity between studies, and only three studies reported the primary outcome of this review.
Authors' conclusions:
Based on the available evidence, we do not know if inhaled corticosteroids initiated from seven days of life in preterm infants at risk of developing BPD reduces mortality or BPD at 36 weeks' PMA. There is a need for larger randomised placebo-controlled trials to establish the benefits and harms of inhaled corticosteroids.
Bronchopulmonary dysplasia (BPD) is one of the most common pulmonary sequelae of extreme preterm birth, with long-lasting respiratory symptoms and reduced lung function. A reliable predictive tool of BPD development is urgent and its search remains one of the major challenges for neonatologists approaching the upcoming arrival of possible new preventive therapies. Biomarkers, identifying an ongoing pathogenetic pathway, could allow both the selection of preterm infants with an evolving disease and potentially the therapeutic targets of the indicted pathogenesis. The “omic” sciences represent well-known promising tools for this objective. In this review, we resume the current laboratoristic, metabolomic, proteomic, and microbiomic evidence in the prediction of BPD.
Key Points
Purpose of review:
Premature neonates are frequently transfused red blood cells (RBCs) or platelets to raise hemoglobin or platelet counts. However, these transfusions may have unintended effects on the immune system. This review will summarize the newest discoveries on the immunologic effects of RBC and platelet transfusions in neonates, and their potential impact on neonatal outcomes.
Recent findings:
Neonatal RBC transfusions are associated with increases in plasma pro-inflammatory cytokines, but recent findings suggest sex-specific differential responses. At least one cytokine (monocyte chemoattractant protein-1) rises in females receiving RBC transfusions, but not in males. These inflammatory responses correlate with poorer neurodevelopmental outcomes in heavily transfused female infants, while preterm male infants seem to be more sensitive to severe anemia. Platelet transfusions in preterm neonates are associated with increased neonatal mortality and morbidity. The underlying mechanisms are unknown, but likely related to the immune/inflammatory effects of transfused platelets. Adult platelets are different from neonatal platelets, with the potential to be more pro-inflammatory. Early preclinical data suggest that platelet transfusions alter the neonatal systemic inflammatory response and enhance immune cell migration.
Summary:
RBC and platelet transfusions alter neonatal immune and inflammatory responses. Their pro-inflammatory effects might worsen neonatal disease or affect neurodevelopmental outcomes.
The American Academy of Pediatrics continues to provide guidance on the use of postnatal corticosteroids to manage or prevent chronic lung disease following preterm birth (formerly referred to as bronchopulmonary dysplasia). Since the last revision of such guidance in 2010, several prospective randomized trials have been published. This revision provides a review of those studies as well as updated recommendations, which include the use of systemic low-dose corticosteroid in preterm neonates with or at high risk for chronic lung disease. High-dose dexamethasone (≥0.5 mg/kg per day) is not recommended. New evidence suggests that inhaled corticosteroids may confer benefit if provided with surfactant as a vehicle, but safety data are lacking. Evidence remains insufficient to make any recommendations regarding routine use of postnatal corticosteroids in preterm infants. Neonatologists and other hospital care providers must continue to use their clinical judgment in individual patients, balancing the potential adverse effects of corticosteroid treatment with those of chronic lung disease. The decision to use postnatal corticosteroids for this purpose should be made together with the infant’s parents, and the care providers should document their discussions with parents in the patient’s medical record.
Background:
Advances in technology, data availability, and analytics have helped improve quality of care in the neonatal intensive care unit.
Objective:
To provide an in-depth review of artificial intelligence (AI) and machine learning techniques being utilized to predict neonatal outcomes.
Methods:
The PRISMA protocol was followed that considered articles from established digital repositories. Included articles were categorized based on predictions of: (a) major neonatal morbidities such as sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity; (b) mortality; and (c) length of stay.
Results:
A total of 366 studies were considered; 68 studies were eligible for inclusion in the review. The current set of predictor models are primarily built on supervised learning and mostly used regression models built on retrospective data.
Conclusion:
With the availability of EMR data and data-sharing of NICU outcomes across neonatal research networks, machine learning algorithms have shown breakthrough performance in predicting neonatal disease.
Necrotizing enterocolitis (NEC) is the leading cause of death and disability from gastrointestinal disease in premature infants. Recent discoveries have shed light on a unifying theorem to explain the pathogenesis of NEC, suggesting that specific treatments might finally be forthcoming. A variety of experiments have highlighted how the interaction between bacterial signalling receptors on the premature intestine and an abnormal gut microbiota incites a pro-inflammatory response in the intestinal mucosa and its underlying endothelium that leads to NEC. Central amongst the bacterial signalling receptors implicated in NEC development is the lipopolysaccharide receptor Toll-like receptor 4 (TLR4), which is expressed at higher levels in the premature gut than in the full-term gut. The high prenatal intestinal expression of TLR4 reflects the role of TLR4 in the regulation of normal gut development, and supports additional studies indicating that NEC develops in response to signalling events that occur in utero. This Review provides new evidence explaining the pathogenesis of NEC, explores new findings indicating that NEC development has origins before birth, and discusses future questions and opportunities for discovery in this field.
Background:
Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown.
Methods:
We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age.
Results:
We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups.
Conclusions:
In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).
Importance:
Despite improvement during recent decades, extremely preterm infants continue to contribute disproportionately to neonatal mortality and childhood morbidity.
Objective:
To review survival, in-hospital morbidities, care practices, and neurodevelopmental and functional outcomes at 22-26 months' corrected age for extremely preterm infants.
Design, setting, and participants:
Prospective registry for extremely preterm infants born at 19 US academic centers that are part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. The study included 10 877 infants born at 22-28 weeks' gestational age between January 1, 2013, and December 31, 2018, including 2566 infants born before 27 weeks between January 1, 2013, and December 31, 2016, who completed follow-up assessments at 22-26 months' corrected age. The last assessment was completed on August 13, 2019. Outcomes were compared with a similar cohort of infants born in 2008-2012 adjusting for gestational age.
Exposures:
Extremely preterm birth.
Main outcomes and measures:
Survival and 12 in-hospital morbidities were assessed, including necrotizing enterocolitis, infection, intracranial hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia. Infants were assessed at 22-26 months' corrected age for 12 health and functional outcomes, including neurodevelopment, cerebral palsy, vision, hearing, rehospitalizations, and need for assistive devices.
Results:
The 10 877 infants were 49.0% female and 51.0% male; 78.3% (8495/10848) survived to discharge, an increase from 76.0% in 2008-2012 (adjusted difference, 2.0%; 95% CI, 1.0%-2.9%). Survival to discharge was 10.9% (60/549) for live-born infants at 22 weeks and 94.0% (2267/2412) at 28 weeks. Survival among actively treated infants was 30.0% (60/200) at 22 weeks and 55.8% (535/958) at 23 weeks. All in-hospital morbidities were more likely among infants born at earlier gestational ages. Overall, 8.9% (890/9956) of infants had necrotizing enterocolitis, 2.4% (238/9957) had early-onset infection, 19.9% (1911/9610) had late-onset infection, 14.3% (1386/9705) had severe intracranial hemorrhage, 12.8% (1099/8585) had severe retinopathy of prematurity, and 8.0% (666/8305) had severe bronchopulmonary dysplasia. Among 2930 surviving infants with gestational ages of 22-26 weeks eligible for follow-up, 2566 (87.6%) were examined. By 2-year follow-up, 8.4% (214/2555) of children had moderate to severe cerebral palsy, 1.5% (38/2555) had bilateral blindness, 2.5% (64/2527) required hearing aids or cochlear implants, 49.9% (1277/2561) had been rehospitalized, and 15.4% (393/2560) required mobility aids or other supportive devices. Among 2458 fully evaluated infants, 48.7% (1198/2458) had no or mild neurodevelopmental impairment at follow-up, 29.3% (709/2419) had moderate neurodevelopmental impairment, and 21.2% (512/2419) had severe neurodevelopmental impairment.
Conclusions and relevance:
Among extremely preterm infants born in 2013-2018 and treated at 19 US academic medical centers, 78.3% survived to discharge, a significantly higher rate than for infants born in 2008-2012. Among infants born at less than 27 weeks' gestational age, rehospitalization and neurodevelopmental impairment were common at 2 years of age.
Circulating cell-free mitochondrial DNA (ccf-mtDNA) released upon cell injury or death stimulates diverse pattern recognition receptors to activate innate immune responses and initiate systemic inflammation. In this review, we discuss the temporal changes of ccf-mtDNA during pregnancy and its potential contribution to adverse pregnancy outcomes in pregnancy complications.
Bronchopulmonary dysplasia (BPD) is the most significant respiratory complication of prematurity, and its consequences last from birth into adulthood. Unfortunately, the dramatic improvements in the management of premature infants have not led to a decreased incidence of BPD, or to breakthroughs in treatments offered for this long-lasting chronic respiratory disorder. Over recent decades the pathological picture of BPD has changed from inflammation, interstitial fibrosis and emphysema attributed to volu-, barotrauma and oxygen toxicity to larger, simplified alveoli and dysmorphic vessels related to arrested alveolarization and vasculogenesis with inflammation maintaining a central role. Corticosteroids play a key role in the development of respiratory epithelial cells and lung maturation. These potent anti-inflammatory agents have long been used for the prevention and treatment of BPD; however the risk/benefit ratio of their use remains unresolved. Corticosteroids administered antenatally have contributed to reduce mortality and respiratory distress syndrome, no such effect on BPD reduction has been observed. Postnatal systemic corticosteroids reduced the rate and severity of BPD, yet their long-term neurodevelopmental and respiratory consequences markedly limit routine administration. This is the first in a two-part State-of-the-Art series that reviews the latest relevant clinical trials investigating the short-term and long-term effects of corticosteroids in the prevention and treatment of BPD.
This article is protected by copyright. All rights reserved.
Objective
To address the effectiveness and safety of early airway combined utilization of budesonide and surfactant for bronchopulmonary dysplasia (BPD) prevention in premature infants with respiratory distress syndrome (RDS).
Methods
Literature retrieval was carried out in the PubMed, Web of Science, EMBASE, Cochrane Library, Wanfang, CQ VIP and China National Knowledge Infrastructure databases, searching from the inception to Sep 2021. Stata 16.0 software was used for statistical analysis.
Results
This meta-analysis suggested that early combined utilization of budesonide and surfactant by airway have a superiority on BPD incidence [risk ratio (RR)=0.62;95%CI:0.54~0.71, P<0.001], mortality (RR=0.64;95%CI:0.45~0.92, P=0.016), the composite outcome of BPD or mortality (RR=0.58;95%CI:0.50~0.68, P<0.001), the additional doses of surfactant (RR=0.53; 95%CI:0.44~0.63, P<0.001), the duration of assisted ventilation [standard mean difference (SMD) =-1.14;95%CI: -1.58 ~ -0.70, P<0.001], duration of invasive ventilation(SMD=-1.77;95%CI: -2.61~-0.93, P<0.001), and hospital stays (SMD=-1.11;95%CI: -1.73~-0.49, P=0.001) in preterm infants with RDS. And these benefits were not associated with increased adverse outcomes. Furthermore, a decreased incidence of patent ducts arterious (PDA) (RR=0.79; 95%CI:0.65~0.97, P=0.028) was found in premature infants treated with budesonide and surfactant. Subgroup analysis based on budesonide delivery methods (inhalation or intratracheal instillation) indicated that the decrease of mortality (RR=0.63; 95%CI:0.43~0.93, P=0.019), duration of assisted ventilation (SMD=-0.95;95%CI: -1.30~-0.61, P<0.001), hospital stays (SMD=-1.23;95%CI: -2.05~-0.41, P=0.003) and PDA incidence (RR=0.80; 95%CI:0.65~0.99, P=0.044) were mainly in budesonide intratracheal instillation subgroup, rather than in budesonide inhalation subgroup.
Conclusions
This meta-analysis suggested that early combined utilization of budesonide and surfactant by airway might be an effective and safe clinical practice for BPD prevention in premature infants with RDS, especially when budesonide was delivered by intratracheal instillation. However, many of the included studies were small and were from Asian origin. More well-designed randomized controlled trials (RCTs) with larger sample sizes and longer follow-up from all over the world ought to be conducted in the future.
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