Metabolic and Microbial Dysregulation in Preterm Infants with Neonatal Respiratory Distress Syndrome: An Early Developmental Perspective.

Neonatal respiratory distress syndrome (NRDS) is one of the most severe respiratory disorders in preterm infants (PTIs) due to immature lung development. To delineate the serum metabolic alterations and gut microbiota variations in NRDS and assess their implications on neonatal development, we enrolled 13 NRDS neonates and 12 PTIs and collected fecal and serum specimens after birth. Longitudinal fecal sampling was conducted weekly for a month in NRDS neonates. NRDS neonates were characterized by notably reduced gestational ages and birth weights and a higher rate of asphyxia at birth relative to PTIs. Early postnatal disturbances in tryptophan metabolism were evident in the NRDS group, concomitant with elevated relative abundance of Haemophilus, Fusicatenibacter, and Vibrio. Integrative multiomics analyses revealed an inverse relationship between tryptophan concentrations and Blautia abundance. At one-week old, NRDS neonates exhibited cortisol regulation anomalies and augmented hepatic catabolism. Sequential microbial profiling revealed distinct gut microbiota evolution in NRDS subjects, characterized by a general reduction in potentially pathogenic bacteria. The acute perinatal stress of NRDS leads to mitochondrial compromise, hormonal imbalance, and delayed gut microbiota evolution. Despite the short duration of NRDS, its impact on neonatal development is significant and requires extended attention.

Supervised contrastive learning enhances graph convolutional networks for predicting neurodevelopmental deficits in very preterm infants using brain structural connectome.

Very preterm (VPT) infants (born at less than 32 weeks gestational age) are at high risk for various adverse neurodevelopmental deficits. Unfortunately, most of these deficits cannot be accurately diagnosed until the age of 2-5 years old. Given the benefits of early interventions, accurate diagnosis and prediction soon after birth are urgently needed for VPT infants. Previous studies have applied deep learning models to learn the brain structural connectome (SC) to predict neurodevelopmental deficits in the preterm population. However, none of these models are specifically designed for graph-structured data, and thus may potentially miss certain topological information conveyed in the brain SC. In this study, we aim to develop deep learning models to learn the SC acquired at term-equivalent age for early prediction of neurodevelopmental deficits at 2 years corrected age in VPT infants. We directly treated the brain SC as a graph, and applied graph convolutional network (GCN) models to capture complex topological information of the SC. In addition, we applied the supervised contrastive learning (SCL) technique to mitigate the effects of the data scarcity problem, and enable robust training of GCN models. We hypothesize that SCL will enhance GCN models for early prediction of neurodevelopmental deficits in VPT infants using the SC. We used a regional prospective cohort of ∼280 VPT infants who underwent MRI examinations at term-equivalent age from the Cincinnati Infant Neurodevelopment Early Prediction Study (CINEPS). These VPT infants completed neurodevelopmental assessment at 2 years corrected age to evaluate cognition, language, and motor skills. Using the SCL technique, the GCN model achieved mean areas under the receiver operating characteristic curve (AUCs) in the range of 0.72∼0.75 for predicting three neurodevelopmental deficits, outperforming several competing models. Our results support our hypothesis that the SCL technique is able to enhance the GCN model in our prediction tasks.

Clinical Decision Support for Improved Neonatal Care: The Development of a Machine Learning Model for the Prediction of Late-onset Sepsis and Necrotizing Enterocolitis.

OBJECTIVE: To develop an artificial intelligence-based software system for predicting late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in infants admitted to the neonatal intensive care unit (NICU). STUDY DESIGN: Single-center, retrospective cohort study, conducted in the NICU of the Antwerp University Hospital. Continuous monitoring data of 865 preterm infants born at <32 weeks gestational age, admitted to the NICU in the first week of life, were used to train an XGBoost machine learning (ML) algorithm for LOS and NEC prediction in a cross-validated setup. Afterward, the model's performance was assessed on an independent test set of 148 patients (internal validation). RESULTS: The ML model delivered hourly risk predictions with an overall sensitivity of 69% (142/206) for all LOS/NEC episodes and 81% (67/83) for severe LOS/NEC episodes. The model showed a median time gain of ≤10 hours (IQR, 3.1-21.0 hours), compared with historical clinical diagnosis. On the complete retrospective dataset, the ML model made 721 069 predictions, of which 9805 (1.3%) depicted a LOS/NEC probability of ≥0.15, resulting in a total alarm rate of <1 patient alarm-day per week. The model reached a similar performance on the internal validation set. CONCLUSIONS: Artificial intelligence technology can assist clinicians in the early detection of LOS and NEC in the NICU, which potentially can result in clinical and socioeconomic benefits. Additional studies are required to quantify further the effect of combining artificial and human intelligence on patient outcomes in the NICU.

Hypertensive Disorders of Pregnancy and Risk of Early Brain Abnormalities on Magnetic Resonance Imaging at Term among Infants Born at ≤32 Weeks' Gestational Age.

OBJECTIVE: To evaluate the proximal effects of hypertensive disorders of pregnancy (HDP) on a validated measure of brain abnormalities in infants born at ≤32 weeks' gestational age (GA) using magnetic resonance imaging at term-equivalent age. STUDY DESIGN: In a multisite prospective cohort study, 395 infants born at ≤32 weeks' GA, underwent 3T magnetic resonance imaging scan between 39 and 44 weeks' postmenstrual age. A single neuroradiologist, blinded to clinical history, evaluated the standardized Kidokoro global brain abnormality score as the primary outcome. We classified infants as HDP-exposed by maternal diagnosis of chronic hypertension, gestational hypertension, pre-eclampsia, or eclampsia. Linear regression analysis identified the independent effects of HDP on infant brain abnormalities, adjusting for histologic chorioamnionitis, maternal smoking, antenatal steroids, magnesium sulfate, and infant sex. Mediation analyses quantified the indirect effect of HDP mediated via impaired intrauterine growth and prematurity and remaining direct effects on brain abnormalities. RESULTS: A total of 170/395 infants (43%) were HDP-exposed. Adjusted multivariable analyses revealed HDP-exposed infants had 27% (95% CI 5%-53%) higher brain abnormality scores than those without HDP exposure (P = .02), primarily driven by increased white matter injury/abnormality scores (P = .01). Mediation analyses showed HDP-induced impaired intrauterine growth significantly (P = .02) contributed to brain abnormality scores (22% of the total effect). CONCLUSIONS: Maternal hypertension independently increased the risk for early brain injury and/or maturational delays in infants born at ≤32 weeks' GA with an indirect effect of 22% resulting from impaired intrauterine growth. Enhanced prevention/treatment of maternal hypertension may mitigate the risk of infant brain abnormalities and potential neurodevelopmental impairments.

Predicting Extubation Readiness in Preterm Infants Utilizing Machine Learning: A Diagnostic Utility Study.

OBJECTIVE: The objective of this study was to predict extubation readiness in preterm infants using machine learning analysis of bedside pulse oximeter and ventilator data. STUDY DESIGN: This is an observational study with prospective recordings of oxygen saturation (SpO2) and ventilator data from infants <30 weeks of gestation age. Research pulse oximeters collected SpO2 (1 Hz sampling rate) to quantify intermittent hypoxemia (IH). Continuous ventilator metrics were collected (4-5-minute sampling) from bedside ventilators. Data modeling was completed using unbiased machine learning algorithms. Three model sets were created using the following data source combinations: (1) IH and ventilator (IH + SIMV), (2) IH, and (3) ventilator (SIMV). Infants were also analyzed separated by postnatal age (infants <2 or ≥2 weeks of age). Models were compared by area under the receiver operating characteristic curve (AUC). RESULTS: A total of 110 extubation events from 110 preterm infants were analyzed. Infants had a median gestation age and birth weight of 26 weeks and 825 g, respectively. Of the 3 models presented, the IH + SIMV model achieved the highest AUC of 0.77 for all infants. Separating infants by postnatal age increased accuracy further achieving AUC of 0.94 for <2 weeks of age group and AUC of 0.83 for ≥2 weeks group. CONCLUSIONS: Machine learning analysis has the potential to enhance prediction accuracy of extubation readiness in preterm infants while utilizing readily available data streams from bedside pulse oximeters and ventilators.

Gut microbial network signatures of early colonizers in preterm neonates with extrauterine growth restriction.

BACKGROUND: Extrauterine growth restriction (EUGR) represents a prevalent condition observed in preterm neonates, which poses potential adverse implications for both neonatal development and long-term health outcomes. The manifestation of EUGR has been intricately associated with perturbations in microbial and metabolic profiles. This study aimed to investigate the characteristics of the gut microbial network in early colonizers among preterm neonates with EUGR. METHODS: Twenty-nine preterm infants participated in this study, comprising 14 subjects in the EUGR group and 15 in the normal growth (AGA) group. Meconium (D1) and fecal samples were collected at postnatal day 28 (D28) and 1 month after discharge (M1). Subsequently, total bacterial DNA was extracted and sequenced using the Illumina MiSeq system, targeting the V3-V4 hyper-variable regions of the 16S rRNA gene. RESULTS: The outcomes of principal coordinates analysis (PCoA) and examination of the microbial network structure revealed distinctive developmental trajectories in the gut microbiome during the initial three months of life among preterm neonates with and without EUGR. Significant differences in microbial community were observed at the D1 (P = 0.039) and M1 phases (P = 0.036) between the EUGR and AGA groups, while a comparable microbial community was noted at the D28 phase (P = 0.414). Moreover, relative to the AGA group, the EUGR group exhibited significantly lower relative abundances of bacteria associated with secretion of short-chain fatty acids, including Lactobacillus (P = 0.041) and Parabacteroides (P = 0.033) at the D1 phase, Bifidobacterium at the D28 phase, and genera Dysgonomonas (P = 0.042), Dialister (P = 0.02), Dorea (P = 0.042), and Fusobacterium (P = 0.017) at the M1 phase. CONCLUSION: Overall, the present findings offer crucial important insights into the distinctive gut microbial signatures exhibited by earlier colonizers in preterm neonates with EUGR. Further mechanistic studies are needed to establish whether these differences are the cause or a consequence of EUGR.

Preterm Birth Alters the Regional Development and Structural Covariance of Cerebellum at Term-Equivalent Age.

Preterm birth is associated with increased risk for a spectrum of neurodevelopmental disabilities. The cerebellum is implicated in a wide range of cognitive functions extending beyond sensorimotor control and plays an increasingly recognized role in brain development. Morphometric studies based on volume analyses have revealed impaired cerebellar development in preterm infants. However, the structural covariance between the cerebellum and cerebral cortex has not been studied during the neonatal period, and the extent to which structural covariance is affected by preterm birth remains unknown. In this study, using the structural MR images of 52 preterm infants scanned at term-equivalent age and 312 full-term controls from the Developing Human Connectome Project, we compared volumetric growth, local cerebellum shape development and cerebello-cerebral structural covariance between the two groups. We found that although there was no significant difference in the overall volume measurements between preterm and full-term infants, the shape measurements were different. Compared with the control infants, preterm infants had significantly larger thickness in the vermis and lower thickness in the lateral portions of the bilateral cerebral hemispheres. The structural covariance between the cerebellum and frontal and parietal lobes was significantly greater in preterm infants than in full-term controls. The findings in this study suggested that cerebellar development and cerebello-cerebral structural covariance may be affected by premature birth.

One-year anthropometric follow-up of South African preterm infants in kangaroo mother care: Which early-life factors predict malnutrition?

BACKGROUND: Preterm infants often have poor short- and long-term growth. Kangaroo mother care supports short-term growth, but longer-term outcomes are unclear. METHODS: This study analysed longitudinally collected routine clinical data from a South African cohort of preterm infants (born <37 weeks gestation) attending the outpatient follow-up clinic of a tertiary-level hospital (Tshwane District, South Africa) for 1 year between 2012 and 2019. At 1 year, small-for-gestational age (SGA) and appropriate-for-gestational age (AGA) infants were compared with regard to age-corrected anthropometric z-scores (weight-for-age [WAZ], length-for-age [LAZ], weight-for-length [WLZ] and BMI-for-age [BMIZ]) and rates of underweight (WAZ < -2), stunting (LAZ < -2), wasting (WLZ < -2) and overweight (BMIZ> + 2). Multiple regression analysis was used to investigate associations between maternal/infant characteristics and rates of underweight, stunting, wasting and overweight. RESULTS: At 1 year, compared with AGA infants (n = 210), SGA infants (n = 111) had lower WAZ (-1.26 ± 1.32 vs. -0.22 ± 1.24, p < 0.001), LAZ (-1.50 ± 1.11 vs. -0.60 ± 1.06, p < 0.001), WLZ (-0.66 ± 1.31 vs. 0.11 ± 1.24, p < 0.001) and BMIZ (-0.55 ± 1.31 vs. 1.06 ± 1.23, p < 0.001), despite larger WAZ gains from birth (+0.70 ± 1.30 vs. +0.05 ± 1.30, p < 0.001). SGA infants had significantly more stunting (34.2% vs. 9.1%; p < 0.001), underweight (31.2% vs. 7.2%; p < 0.001) and wasting (12.6% vs. 4.3%, p = 0.012), with no difference in overweight (4.5% vs. 7.7%, p = 0.397). In multiple regression analysis, birth weight-for-GA z-score more consistently predicted 1-year malnutrition than SGA. CONCLUSION: Preterm-born SGA infants remain more underweight, stunted and wasted than their preterm-born AGA peers at 1 year, despite greater WAZ gains. Interventions for appropriate catch-up growth especially for SGA preterm infants are needed.

Short apneas and periodic breathing in preterm infants in the neonatal intensive care unit-Effects of sleep position, sleep state, and age.

This observational study investigated the effects of sleep position and sleep state on short apneas and periodic breathing in hospitalized preterm infants longitudinally, in relation to postmenstrual age. Preterm infants (25-31 weeks gestation, n = 29) were studied fortnightly after birth until discharge, in prone and supine positions, and in quiet sleep and active sleep. The percentage of time spent in each sleep state (percentage of time in quiet sleep and percentage of time in active sleep), percentage of total sleep time spent in short apneas and periodic breathing, respectively, the percentage of falls from baseline in heart rate, arterial oxygen saturation and cerebral tissue oxygenation index during short apneas and periodic breathing, and the associated percentage of total sleep time with systemic (arterial oxygen saturation < 90%) and cerebral hypoxia (cerebral tissue oxygenation index < 55%) were analysed using a linear mixed model. Results showed that the prone position decreased (improved) the percentage of falls from baseline in arterial oxygen saturation during both short apneas and periodic breathing, decreased the proportion of infants with periodic breathing and the periodic breathing-associated percentage of total sleep time with cerebral hypoxia. The percentage of time in quiet sleep was higher in the prone position. Quiet sleep decreased the percentage of total sleep time spent in short apneas, the short apneas-associated percentage of falls from baseline in heart rate, arterial oxygen saturation, and proportion of infants with systemic hypoxia. Quiet sleep also decreased the proportion of infants with periodic breathing and percentage of total sleep time with cerebral hypoxia. The effects of sleep position and sleep state were not related to postmenstrual age. In summary, when sleep state is controlled for, the prone sleeping position has some benefits during both short apneas and periodic breathing. Quiet sleep improves cardiorespiratory stability and is increased in the prone position at the expense of active sleep, which is critical for brain maturation. This evidence should be considered in positioning preterm infants.

Characteristics of red blood cell transfusion among very preterm infants in China.

BACKGROUND AND OBJECTIVES: National-level data on the incidence of red blood cell (RBC) transfusions and outcomes among very preterm infants (VPIs) are lacking in China. This study aims to describe the use and variation of RBC transfusion among VPIs in China. MATERIALS AND METHODS: This cohort study was conducted among 70 tertiary hospitals participating in the Chinese Neonatal Network (CHNN) from 2019 to 2020 across China. All VPIs admitted to the CHNN neonatal intensive care units (NICUs) were included. RESULTS: A total of 13,447 VPIs were enrolled, of whom 7026 (52.2%) received ≥1 RBC transfusions. The mean number of transfusions per infant was 2 (interquartile range [IQR] 1-4 times) and the median age at first transfusion was 15 days (IQR 3-27 days). The transfusion rate was higher in critically ill infants compared with non-critically ill infants (70.5% vs. 39.3%). The transfusion rate varied widely (13.5%-95.0%) between different NICUs. The prevalence of death, severe intra-ventricular haemorrhage, necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP), sepsis, bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (ROP) and cystic periventricular leukomalacia (cPVL) was significantly higher in the transfused group. Among non-critically ill infants, RBC transfusion was independently associated with BPD, severe ROP and cPVL. CONCLUSION: Our study, providing the first baseline data on RBC transfusions among VPIs in China, shows an alarmingly high RBC transfusion rate with significant site variations. There is an urgent need for national guidelines on RBC transfusions for VPIs in China.

Incidence of brain injuries in a large cohort of very preterm and extremely preterm infants at term-equivalent age: results of a single tertiary neonatal care center over 10 years.

OBJECTIVES: Cerebral magnetic resonance imaging (cMRI) at term-equivalent age (TEA) can detect brain injury (BI) associated with adverse neurological outcomes in preterm infants. This study aimed to assess BI incidences in a large, consecutive cohort of preterm infants born < 32 weeks of gestation, the comparison between very (VPT, ≥ 28 + 0 to < 32 + 0 weeks of gestation) and extremely preterm infants (EPT, < 28 + 0 weeks of gestation) and across weeks of gestation. METHODS: We retrospectively analyzed cMRIs at TEA of VPT and EPT infants born at a large tertiary center (2009-2018). We recorded and compared the incidences of BI, severe BI, intraventricular hemorrhage (IVH), periventricular hemorrhagic infarction (PVHI), cerebellar hemorrhage (CBH), cystic periventricular leukomalacia (cPVL), and punctate white matter lesions (PWML) between VPTs, EPTs, and across weeks of gestation. RESULTS: We included 507 preterm infants (VPT, 335/507 (66.1%); EPT, 172/507 (33.9%); mean gestational age (GA), 28 + 2 weeks (SD 2 + 2 weeks); male, 52.1%). BIs were found in 48.3% of the preterm infants (severe BI, 12.0%) and increased with decreasing GA. IVH, PVHI, CBH, cPVL, and PWML were seen in 16.8%, 0.8%, 10.5%, 3.4%, and 18.1%, respectively. EPT vs. VPT infants suffered more frequently from BI (59.3% vs. 42.7%, p < 0.001), severe BI (18.6% vs. 8.7%, p = 0.001), IVH (31.9% vs. 9.0%, p < 0.001), and CBH (18.0% vs. 6.6%, p < 0.001). CONCLUSION: Brain injuries are common cMRI findings among preterm infants with a higher incidence of EPT compared to VPT infants. These results may serve as reference values for clinical management and research. CLINICAL RELEVANCE STATEMENT: Our results with regard to gestational age might provide valuable clinical insights, serving as a key reference for parental advice, structured follow-up planning, and enhancing research and management within the Neonatal Intensive Care Unit. KEY POINTS: • Brain injury is a common cMRI finding in preterm infants seen in 48.3% individuals. • Extremely preterm compared to very preterm infants have higher brain injury incidences driven by brain injuries such as intraventricular and cerebellar hemorrhage. • Reference incidence values are crucial for parental advice and structured follow-up planning.

Effect of maturation at birth on the clinical features of neonatal cow's milk protein allergy: A retrospective study.

Neonatal immune regulation transitions from fetal immunity and varies with maturation status, but its role in neonatal cow's milk protein allergy (CMPA) remains unknown. We studied the association between maturation status at birth and neonatal CMPA. Clinical and laboratory data of neonates presenting with CMPA symptoms were retrospectively collected from two tertiary hospitals. Patients were assessed according to gestational age at birth: preterm, late-preterm, and full-term. Fifty-five infants (26 females, 14 preterm, 15 late-preterm, and 26 full-term) were included; 44 were negative for milk-specific immunoglobulin E. Neonatal CMPA was common during moderately premature periods. Preterm infants exhibited longer latency from initial CM exposure to disease onset, lower incidence of bloody stool, and absence of elevated monocyte counts. However, immunoreactivity to CM antigens was retained in all infants. Neonatal CMPA features varied with infant maturation status at birth. Our results improve the understanding of intestinal immunity development, fetal/neonatal immune regulation, and CMPA pathogenesis.

Differences in neonatal gastric tubes during insertion into a 3D model in relation to risk of potential perforation.

OBJECTIVES: Perforation of esophagus or stomach is a potential complication during and after insertion of a gastric tube in neonates. The aim of this study was to analyze different types of gastric tubes in a three-dimensional (3D) model of neonatal esophagus and stomach regarding potential perforations. METHODS: A 3D model of esophagus and stomach was created based on computed tomography data of a term neonate. Three types of gastric tubes were inserted into the 3D model, the localization was examined by radioscopy and the behavior, stiffness and manageability of each gastric tube was evaluated. RESULTS: Insertion of gastric tubes with higher stiffness was easier. The rates of correct localization differed significantly between the gastric tubes with the highest rate of correct localization in the softest tube (48.5%) and the lowest rate in the tube with the highest stiffness (21.2%). Additionally, the softest tube showed the lowest rate of localization of its tip at the stomach wall. CONCLUSIONS: The study illustrates differences between various types of gastric tubes regarding stiffness, behavior and resiliency. Softer gastric tubes may be beneficial. These differences may be relevant in neonatal care of very immature and very sick infants.

Music therapy and weight gain in preterm infants: Secondary analysis of the randomized controlled LongSTEP trial.

OBJECTIVES: This study assessed the association between MT and weight gain among preterm infants hospitalized in Neonatal Intensive Care Units. METHODS: Data collected during the international, randomized, Longitudinal Study of Music Therapy's Effectiveness for Premature Infants and their Caregivers (LongSTEP) study were compared between the MT group and the standard care (SC) group. Weights were recorded at birth, enrollment, and discharge. Weight percentiles, Z-scores, weight gain velocity, and extrauterine growth restriction (EUGR) were calculated. RESULTS: Among 201 preterm infants included, no significant differences in weight parameters (weight, weight percentiles, weight Z-scores; all p ≥ 0.23) were found between the MT group (n = 104) and the SC (n = 97) group at birth, enrollment, or discharge. No statistical differences in EUGR represented by change in Z-scores from birth to discharge were recorded between MT and SC (0.8 vs. 0.7). Among perinatal parameters, younger gestational age (p = 0.005) and male sex (p = 0.012) were associated with increased risk of EUGR at discharge. Antenatal steroid treatment, systemic infection, bronchopulmonary dysplasia, neurological morbidities, retinopathy of prematurity, necrotizing enterocolitis, parental factors (amount of skin-to-skin care, bonding, anxiety, and depression questionnaire scores), and type of enteral nutrition did not significantly influence weight gain parameters (all p > 0.05). CONCLUSIONS: In the LongSTEP study, MT for preterm infants and families was not associated with better weight parameters compared to the SC group. The degree of prematurity remains the main risk factor for unfavorable weight parameters.

Association between viral infection and bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis.

Bronchopulmonary dysplasia (BPD) is the most common serious complication of very preterm infants (VPI) or very low birth weight (VLBW) infants. Studies implicate viral infections in etiopathogenesis. The aim of this study was to summarize the relationship between viral infections and BPD through a systematic review and meta-analysis. We searched PubMed, Embase, the Web of Science Core Collection, and the Cochrane Database on December 19, 2023. We included observational studies that examined the association between viral infections and BPD in preterm infants. We extracted data on study methods, participant characteristics, exposure assessment, and outcome measures. We assessed study risk of bias using the Newcastle-Ottawa Scale (NOS). We included 17 and 15 studies in the qualitative review and meta-analysis, respectively. The meta-analysis showed a significant association between viral infection and BPD diagnosed at 36 weeks postmenstrual age (odds ratio (OR): 2.42, 95% confidence interval: 1.89-3.09, 13 studies, very low certainty of evidence). In a subgroup analysis of specific viruses, cytomegalovirus (CMV) proved to be significantly associated with BPD diagnosed at 36 weeks postmenstrual age (OR: 2.34, 95% confidence interval: 1.80-3.05, 11 studies). We did not find an association between viral infection and BPD diagnosed on the 28th day of life, probably due to the small sample size of the included prospective studies.  Conclusion: Viral infections, especially CMV, are associated with an increased risk of BPD in preterm infants. Methodologically reliable prospective studies with large samples are needed to validate our conclusions, and high-quality randomized controlled studies are needed to explore the effect of prevention or treatment of viral infections on the incidence of BPD. What is Known: • Studies have attempted to identify viral infections and bronchopulmonary dysplasia in preterm infants; however, results have been inconsistent. What is New: • Systematic demonstration that viral infections, particularly cytomegalovirus, are positively associated with bronchopulmonary dysplasia diagnosed in preterm infants at the 36th week of postmenstrual age. • The importance of screening for viral infections in preterm infants, especially cytomegalovirus. More high-quality studies should be produced in the future to investigate the causal relationship between viral infections and bronchopulmonary dysplasia.

Effects of early-life gut microbiota on the neurodevelopmental outcomes of preterm infants: a multi-center, longitudinal observational study in China.

To prospectively investigate associations between the features of gut microbiota at the fourth week after birth in preterm infants and neurodevelopment from 1 month of corrected age to 6 months of corrected age (MCA). Seventy-seven preterm infants were recruited from three NICUs of three tertiary hospitals between Apr 2021 to Sep 2022. Stool samples were collected during the fourth week after birth. Illumina MiSeq high-throughput sequencing technology was used to detect the composition and diversity of gut microbiota. Neurodevelopment assessments of preterm infants were conducted at 1, 3, and 6 MCA using the Ages and Stages Questionnaire, the third edition (ASQ-3). Spearman correlation, a generalized linear mixed model (GLMM), and permutational multivariate analysis of variance (PERMANOVA) analysis were used to horizontally and prospectively explore the associations between gut microbial and ASQ-3 dimension scores at each time point. The GLMM showed no significant associations between the alpha diversity and neurodevelopmental trajectory from 1 to 6 MCA. The beta diversity was significantly associated with gross motor scores at 1, 3, and 6 MCA (R2 = 0.067, p = 0.001; R2 = 0.039, p = 0.020; R2 = 0.031, p = 0.047); communication scores at 3 MCA (R2 = 0.030, p = 0.040); and fine motor scores at 6 MCA (R2 = 0.035, p = 0.022). After adjusting for covariates, the GLMM showed that the relative abundance of Klebsiella was negatively associated with gross motor score trajectory from 1 to 6 MCA (ß = - 1.449; 95% CI, - 2.275 to - 0.572; p = 0.001), while the relative abundance of Lactobacillus displayed a positive association (ß = 1.421; 95% CI, 0.139 to 2.702; p = 0.030). Moreover, the relative abundance of Streptococcus was negatively associated with fine motor trajectory from 1 to 6 MCA (ß = - 1.669; 95% CI, - 3.305 to - 0.033; p = 0.046). CONCLUSION: Our results suggest a possible association between the neonatal gut microbial diversity; the relative abundance of Klebsiella, Streptococcus, and Lactobacillus; and neurodevelopment from 1 to 6 MCA. In the future, clinical staff can focus on the window period of gut microbiota colonization, and implement probiotics targeted at the dominant genera to improve the neurodevelopment of preterm infants. WHAT IS KNOWN: • In the fields of biology and medicine, current studies suggest that gut microbiota may play an important role in the critical window period of neurodevelopment through the gut-brain axis pathway. • Extensive preclinical research has implied the vital role of the initial gut colonization in the long-term neurodevelopment of children. WHAT IS NEW: • The early-life gut microbiota was associated with neurodevelopment in preterm infants within 6 months of corrected age (MCA).

Synergistic effects of achieving perinatal interventions on bronchopulmonary dysplasia in preterm infants.

To investigate the effect of perinatal interventions on the risk of severe BPD (sBPD) and death in extremely preterm infants (EPIs) and their synergistic effects. This was a secondary analysis of the prospective cohort Chinese Neonatal Network (CHNN). Infants with a birth weight of 500 to 1250 g or 24-28 weeks completed gestational age were recruited. The impacts and the synergistic effects of six evidence-based perinatal interventions on the primary outcomes of sBPD and death were assessed by univariate and multivariable logistic regression modeling. Totally, 6568 EPIs were finally enrolled. Antenatal corticosteroid (adjusted OR, aOR, 0.74; 95%CI, 0.65-083), birth in centers with tertiary NICU (aOR, 0.64; 95%CI, 0.57-0.72), preventing intubation in the delivery room (aOR, 0.65; 95%CI, 0.58-0.73), early caffeine therapy (aOR, 0.59; 95%CI, 0.52-0.66), and early extubating (aOR, 0.42; 95%CI 0.37-0.47), were strongly associated with a lower risk of sBPD and death while early surfactant administration was associated with a lower risk of death (aOR, 0.84; 95%CI, 0.72, 0.98). Compared with achieving 0/1 perinatal interventions, achieving more than one intervention was associated with decreased rates (46.6% in 0/1 groups while 38.5%, 29.6%, 22.2%, 16.2%, and 11.7% in 2/3/4/5/6-intervention groups respectively) and reduced risks of sBPD/death with aORs of 0.76(0.60, 0.96), 0.55(0.43, 0.69), 0.38(0.30, 0.48), 0.28(0.22, 0.36), and 0.20(0.15, 0.27) in 2, 3, 4, 5, and 6 intervention groups respectively. Subgroup analyses showed consistent results. CONCLUSION: Six perinatal interventions can effectively reduce the risk of sBPD and death in a synergistic form. WHAT IS KNOWN: • Bronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease associated with prematurity. The effective management of BPD requires a comprehensive set of interventions. However, the extent to which these interventions can mitigate the risk of severe outcomes, such as severe BPD or mortality, or if they possess synergistic effects remains unknown. WHAT IS NEW: • The implementation of various perinatal interventions, such as prenatal steroids, birth in centers with tertiary NICU, early non-Invasive respiratory support, surfactant administration within 2 hours after birth, early caffeine initiation within 3 days, and early extubation within 7 days after birth has shown promising results in the prevention of severe bronchopulmonary dysplasia (BPD) or mortality in extremely preterm infants. Moreover, these interventions have demonstrated synergistic effects when implemented in combination.

Criteria for discharge of preterm infants from Canadian neonatal intensive care units.

Initial discharge from a neonatal intensive care unit (NICU) to home is a crucial milestone that impacts preterm infants, their families, and NICUs. Standardized discharge programs individualized for family needs can ensure a safe transfer of care to parents, decrease the length of stay and hospital costs, and improve parents' satisfaction. To assess the degree of variability in the current discharge criteria of preterm infants less than 34 weeks' gestation among Canadian NICUs, explore different institution-specific guidelines and degree of adherence to the Canadian Paediatric Society (CPS) guidelines. A clinical representative of each of the 117 level 2-4 Canadian NICUs was contacted via email to participate in an anonymous survey link regarding the discharge criteria of preterm infants. Responders from ninety-eight NICUs (84%), representing all Canadian provinces, completed the survey. Most were nurse practitioners (43%) and neonatologists (31%) with > 5 years of experience (87%). Level 3 and 4 NICUs represented 63% of responses. Units varied widely in many discharge criteria and in their adherence to CPS guidelines. Most of the units (81%) lack written discharge guidelines; 60% do not have a dedicated discharge coordinator, and 45% do not have a post-discharge clinic. Only 25% routinely teach parents CPR and only half of the surveyed units provide parental support programs.   Conclusion: There is a significant heterogeneity in discharge practices of preterm infants among Canadian NICUs. This survey provides a basis for benchmarking and knowledge sharing. What is Known: • Discharging preterm infants from the NICU impacts preterm infants, their families, and NICUs. • All efforts should ensure a safe transfer of care to parents, decrease the length of stay, better utilize resources, and improve parents' satisfaction. What is New: • The discharge criteria of preterm infants vary widely among NICUs. • This survey provides benchmark information and exposes the need to better standardize discharge practices and the subsequent support for infants and parents.

Impact of macronutrients intake on glycemic homeostasis of preterm infants: evidence from continuous glucose monitoring.

Nutritional intake could influence the blood glucose profile during early life of preterm infants. We investigated the impact of macronutrient intake on glycemic homeostasis using continuous glucose monitoring (CGM). We analyzed macronutrient intake in infants born ≤ 32 weeks gestational age (GA) and/or with birth weight ≤ 1500 g. CGM was started within 48 h of birth and maintained for 5 days. Mild and severe hypoglycemia were defined as sensor glucose (SG) < 72 mg/dL and <47 mg/dL, respectively, while mild and severe hyperglycemia were SG > 144 mg/dL and >180 mg/dL. Data from 30 participants were included (age 29.9 weeks (29.1; 31.2), birthweight 1230.5 g (1040.0; 1458.6)). A reduced time in mild hypoglycemia was associated to higher amino acids intake (p = 0.011) while increased exposure to hyperglycemia was observed in the presence of higher lipids intake (p = 0.031). The birthweight was the strongest predictor of neonatal glucose profile with an inverse relationship between the time spent in hyperglycemia and birthweight (p = 0.007).  Conclusions: Macronutrient intakes influence neonatal glucose profile as described by continuous glucose monitoring. CGM might contribute to adjust nutritional intakes in preterm infants. What is Known: • Parenteral nutrition may affect glucose profile during the first days of life of preterm infants. What is New: • Continuous glucose monitoring describes the relationship between daily parenteral nutrient intakes and time spent in hypo and hyperglycemic ranges.

Lower plasma melatonin levels in non-hypoxic premature newborns associated with neonatal pain.

We analyzed plasma melatonin levels in different groups of preterm newborns without hypoxia and their relationship with several perinatal variables like gestational age or neonatal pain. Prospective cohort study of preterm newborns (PTNB) without perinatal hypoxia, Apgar > 6 at 5 min, and oxygen needs on the third day of life. We compared melatonin levels at day 3 of life in different groups of non-hypoxic preterm infants (Student's t-tests, Mann-Whitney U, and chi2) and analyzed the relationship of melatonin with GA, birth weight, neonatal pain (Premature Infant Pain Profile (PIPP) scale), caffeine treatment, parenteral nutrition, or the development of free radical diseases (correlation study, linear regression) and factors associated with moderate/intense pain and free radical diseases (logistic regression analysis). Sixty-one preterm infants with gestational age (GA) of 30.7 ± 2.0 weeks with no oxygen requirements at day 3 of life were studied with plasma melatonin levels of 33.8 ± 12.01 pg/ml. Preterm infants weighing < 1250 g at birth had lower plasma melatonin levels (p = 0.05). Preterm infants with moderate or severe pain (PPIPP > 5) have lower melatonin levels (p = 0.01), and being preterm with PIPP > 5 is associated with lower plasma melatonin levels (p = 0.03). Being very preterm (GA < 32 GS), having low weight for gestational age (LWGA), receiving caffeine treatment, or requiring parenteral nutrition did not modify melatonin levels in non-hypoxic preterm infants (p = NS). Melatonin on day 3 of life in non-hypoxic preterm infants is not associated with later development of free radical diseases (BPD, sepsis, ROP, HIV, NEC). CONCLUSION: We observed that preterm infants with moderate to severe pain have lower melatonin levels. These findings are relevant because they reinforce the findings of other authors that melatonin supplementation decreases pain and oxidative stress in painful procedures in premature infants. Further studies are needed to evaluate whether melatonin could be used as an analgesic in painful procedures in preterm infants. TRIAL REGISTRATION: Trial registration was not required since this was an observational study. WHAT IS KNOWN: • Melatonin is a potent antioxidant and free radical scavenger in newborns under stress conditions: hypoxia, acidosis, hypotension, painful procedures, or parenteral nutrition. • Pain stimulates the production of melatonin. • Various studies conclude that melatonin administration decreases pain during the neonatal period. WHAT IS NEW: • Non-hypoxic preterm infants with moderate to severe pain (PIPP>5) have lower levels of melatonin. • Administration of caffeine and treatment with parenteral nutrition do not modify melatonin levels in non-hypoxic preterm infants.