Cardiovascular outcomes 50 years after antenatal exposure to betamethasone: Follow-up of a randomised double-blind, placebo-controlled trial.

BACKGROUND: Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids. METHODS AND FINDINGS: We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments. CONCLUSIONS: There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.

The Ighmbp2D564N mouse model is the first SMARD1 model to demonstrate respiratory defects.

Spinal muscular atrophy with respiratory distress type I (SMARD1) is a neurodegenerative disease defined by respiratory distress, muscle atrophy and sensory and autonomic nervous system defects. SMARD1 is a result of mutations within the IGHMBP2 gene. We have generated six Ighmbp2 mouse models based on patient-derived mutations that result in SMARD1 and/or Charcot-Marie Tooth Type 2 (CMT2S). Here we describe the characterization of one of these models, Ighmbp2D564N (human D565N). The Ighmbp2D564N/D564N mouse model mimics important aspects of the SMARD1 disease phenotype, including motor neuron degeneration and muscle atrophy. Ighmbp2D564N/D564N is the first SMARD1 mouse model to demonstrate respiratory defects based on quantified plethysmography analyses. SMARD1 disease phenotypes, including the respiratory defects, are significantly diminished by intracerebroventricular (ICV) injection of ssAAV9-IGHMBP2 and the extent of phenotypic restoration is dose-dependent. Collectively, this model provides important biological insight into SMARD1 disease development.

A novel non-recurrent CNV deletion involving TBX4 and leaving TBX2 intact causes congenital alveolar dysplasia.

Congenital alveolar dysplasia (CAD) belongs to rare lethal lung developmental disorders (LLDDs) in neonates, manifesting with acute respiratory failure and pulmonary arterial hypertension refractory to treatment. The majority of CAD cases have been associated with copy-number variant (CNV) deletions at 17q23.1q23.2 or 5p12. Most CNV deletions at 17q23.1q23.2 were recurrent and encompassed two closely located genes, TBX4 and TBX2. In a few CAD cases, intragenic frameshifting deletions or single-nucleotide variants (SNVs) involved TBX4 but not TBX2. Here, we describe a male neonate who died at 27 days of life from acute respiratory failure caused by lung growth arrest along the spectrum of CAD confirmed by histopathological assessment. Trio-based genome sequencing revealed in the proband a novel non-recurrent ~1.07 Mb heterozygous CNV deletion at 17q23.2, encompassing TBX4 that arose de novo on the paternal chromosome. This is the first report of a larger-sized CNV deletion in a CAD patient involving TBX4 and leaving TBX2 intact. Our results, together with previous reports, indicate that perturbations of TBX4, rather than TBX2, cause severe lung phenotypes in humans.

Inspiratory-expiratory variation of pleural line thickness in neonates with and without acute respiratory failure.

BACKGROUND: There are relatively few data about the ultrasound evaluation of pleural line in patients with respiratory failure. We measured the pleural line thickness during different phases of the respiratory cycle in neonates with and without acute respiratory failure as we hypothesized that this can significantly change. METHODS: Prospective, observational, cohort study performed in an academic tertiary neonatal intensive care unit recruiting neonates with transient tachypnoea of the neonate (TTN), respiratory distress syndrome (RDS) or neonatal acute respiratory distress syndrome (NARDS). Neonates with no lung disease (NLD) were also recruited as controls. Pleural line thickness was measured with high-frequency ultrasound at end-inspiration and end-expiration by two different raters. RESULTS: Pleural line thickness was slightly but significantly higher at end-expiration (0.53 [0.43-0.63] mm) than at end-inspiration (0.5 [0.4-0.6] mm; p = 0.001) for the whole population. End-inspiratory (NLD: 0.45 [0.38-0.53], TTN: 0.49 [0.43-0.59], RDS: 0.53 [0.41-0.62], NARDS: 0.6 [0.5-0.7] mm) and -expiratory (NLD: 0.47 [0.42-0.56], TTN: 0.48 [0.43-0.61], RDS: 0.53 [0.46-0.65], NARDS: 0.61 [0.54-0.72] mm) thickness were significantly different (overall p = 0.021 for both), between the groups although the absolute differences were small. The inter-rater agreement was optimal (ICC: 0.95 (0.94-0.96)). Coefficient of variation was 2.8% and 2.5% for end-inspiratory and end-expiratory measurements, respectively. These findings provide normative data of pleural line thickness for the most common forms of neonatal acute respiratory failure and are useful to design future studies to investigate possible clinical applications.

A comparison of 2 doses of antenatal dexamethasone for the prevention of respiratory distress syndrome: an open-label, noninferiority, pragmatic randomized trial.

BACKGROUND: Antenatal corticosteroids have been used for the prevention of respiratory complications, intraventricular hemorrhage, necrotizing enterocolitis, and other adverse neonatal outcomes for over 50 years, with limited evidence about their optimal doses. Higher steroid doses or frequencies of antenatal corticosteroids in preterm newborns pose adverse effects such as prolonged adrenal suppression, negative effects on fetal programming and metabolism, and increased risks of neurodevelopmental and neuropsychological impairments. Conversely, lower doses of antenatal corticosteroids may be an effective alternative to induce fetal lung maturation with less risk to the fetus. Late preterm births represent the largest population of all preterm neonates, with a respiratory distress syndrome risk of 8.83%. Therefore, determining the optimal antenatal corticosteroid dosage is of particular importance for this population. OBJECTIVE: This study aimed to compare the efficacy of 5-mg and 6-mg dexamethasone in preventing neonatal respiratory distress syndrome in women with preterm births at 320 to 366 weeks of gestation. STUDY DESIGN: This was an open-label, randomized, controlled, noninferiority trial. Singleton pregnant women (n=370) at 320 to 366 weeks of gestation with spontaneous preterm labor or preterm premature rupture of membranes were enrolled. They were randomly assigned (1:1) to a 5-mg or 6-mg dexamethasone group. Dexamethasone was administered intramuscularly every 12 hours for 4 doses or until delivery. The primary outcome was the reduction in neonatal respiratory distress syndrome cases, whereas the secondary outcomes were any adverse maternal or neonatal events. RESULTS: Between December 2020 and April 2022, 370 eligible women, anticipating deliveries within the gestational range of 32 0/7 to 36 6/7 weeks, willingly participated in the study. They were evenly split, with 185 women assigned to the 5-mg group and 185 to the 6-mg group. The study revealed that the demographic profiles of the participants in the 2 groups were remarkably similar, with no statistically significant disparities (P>.05). It is noteworthy that most of these women gave birth after 34 weeks of gestation. Despite a substantial proportion not completing the full course of steroid treatment, the 5-mg dose exhibited noninferiority compared with the 6-mg dose of dexamethasone, as indicated by a modest proportional difference of 0.5% (95% confidence interval, -2.8 to 43.9). Neonatal respiratory distress syndrome occurred in a relatively low percentage of newborns in both groups, affecting 2.2% in the 5-mg group and 1.6% in the 6-mg group. Notably, the risk difference of 0.6% fell comfortably within the predefined noninferiority threshold of 10%. CONCLUSION: Our study suggests that a 5-mg dexamethasone dose is noninferior to a standard 6-mg dose in preventing neonatal respiratory distress syndrome in preterm births.

Evaluation of a respiratory care protocol including less invasive surfactant administration in preterm infants.

BACKGROUND: Respiratory care protocol including less invasive ssurfactant administration (LISA) in ≤29 weeks' gestational age (GA) infants introduced in October 2018. METHODS: Retrospective study of infants admitted on continuous positive airway pressure (CPAP) October 2018 to December 2021. Maternal and neonatal variables were compared between infants managed on CPAP with and without LISA. Infants who received LISA and subsequently required mechanical ventilation (MV) within 72 h of life (HOL) [LISA failure (LF)] were compared with those who required no MV [LISA success (LS)]. RESULTS: 249 infants were admitted on CPAP, 5 were intubated prior to LISA, 143 required LISA and 101 remained on CPAP without surfactant. Of those receiving LISA, 108 were LS and 35 were LF. Compared to LS, LF infants were of lower GA and birth weight, required higher fractional inspired oxygen (FiO2), and CPAP level at birth, admission, one HOL, and an hour after LISA. Moreover, LF infants had higher mortality and morbidity. Together GA ≤ 25 weeks' and FiO2 ≥ 0.3 an hour after LISA best predicted LF. CONCLUSIONS: Over 80% of infants admitted on CPAP avoided MV within 72 HOL. Early predictors of LF provide targets for future interventions to decrease need for MV in preterm infants. IMPACT: Less invasive surfactant administration (LISA) decreases the need for mechanical ventilation (MV) and improves outcomes. However, some infants require MV within 72 h of life (HOL) despite LISA (LISA failure). Over 80% of ≤29 weeks' gestational age (GA) infants can be successfully managed on CPAP with or without surfactant in the first 72 HOL. A combination of factors including ≤25 weeks' GA and fraction of inspired oxygen ≥0.3 an hour after LISA predict LISA failure. Evaluation of a noninvasive respiratory support strategy including LISA provides targets for intervention to decrease need for MV in preterm infants.

Antenatal corticosteroids and newborn respiratory outcomes in twins: A regression discontinuity study.

OBJECTIVE: To estimate the effect of antenatal corticosteroids on newborn respiratory morbidity in twins. DESIGN: Regression discontinuity applied to population-based birth registry data. SETTING: British Columbia, Canada, 2008-2018. POPULATION: Twin pregnancies admitted for birth between 31+0 and 36+6 weeks of gestation. METHODS: During our study period, Canadian clinical practice guidelines recommended antenatal corticosteroid administration for imminent preterm birth up to 33+6 weeks. We used a logistic model to compare the predicted risks of our outcomes among pregnancies admitted for birth immediately before this clinical cut-point (higher probability of exposure to antenatal corticosteroids) versus immediately after it (lower probability). MAIN OUTCOME MEASURES: Our primary outcome was a composite of newborn respiratory distress or in-hospital death. Our secondary outcome was a composite of newborn respiratory intervention or in-hospital death. RESULTS: Among 2524 pregnancies (5035 liveborn twins), 47% of admissions before 34+0 weeks of gestation were exposed to antenatal corticosteroids but only 4.2% of admissions after this cut-point were exposed. The risk of newborn respiratory distress or in-hospital mortality increased abruptly at 34+0 weeks, corresponding to a protective effect of treatment (risk ratio [RR] 0.69, 95% CI 0.53-0.90; risk difference [RD] -12 cases per 100 births, 95% CI -20 to -4.1). There was no clear evidence for or against an effect on newborn respiratory intervention or in-hospital death (RR 0.89, 95% CI 0.70-1.13; RD -4.2 per 100, 95% CI -13 to +4.2). CONCLUSIONS: Our findings provide evidence for the effectiveness of antenatal corticosteroids in preventing adverse newborn respiratory outcomes in twins.

Diagnostic value of bedside lung ultrasound and 12-zone score in the 65 cases of neonatal respiratory distress syndrome and its severity.

OBJECTIVE: To explore the predictive value of bedside lung ultrasound score in the severity of neonatal respiratory distress syndrome (NRDS) and mechanical ventilation and extubation. METHODS: The clinical data of 65 neonates with NRDS and invasive mechanical ventilation diagnosed in the neonatal intensive care unit of our hospital from July 2021 to July 2022 were retrospectively analyzed. 65 neonates were included in the NRDS group, and 40 neonates with other common lung diseases were selected as the other lung disease groups. All neonates underwent lung ultrasound and X-ray examination. The correlation between lung ultrasound scores and arterial blood gas indexes was analyzed by Pearson. The efficacy of successful evacuation of mechanical ventilation was evaluated by lung ultrasound analysis by ROC curve analysis. RESULTS: The positive rates of lung consolidation and white lung in NRDS group were higher than the other lung disease groups (P < 0.05). The positive rates of bronchial inflation sign and double lung points were lower than these in the other lung disease groups (P < 0.05). The ultrasound scores of both lungs, left lung, right lung, bilateral lung and double basal lung in the NRDS group were significantly higher than those in the other lung disease groups (P < 0.05). There was a significant positive correlation between lung ultrasound score and X-ray grade (r = 0.841, P < 0.001). The area under the curve (AUC) of lung ultrasound score for the differential diagnosis of NRDS and common lung diseases was 0.907. The AUC of lung ultrasound score in the differential diagnosis of mild and moderate, and moderate and severe NRDS were 0.914 and 0.933, respectively, which had high clinical value. The lung ultrasound score was positively correlated with the level of PaCO2 (r = 0.254, P = 0.041), and negatively correlated with the levels of SpO2 and PaO2 (r = - 0.459, - 0.362, P = 0.001, 0.003). The AUC of successful mechanical ventilation withdrawal predicted by the pulmonary ultrasound score before extubation was 0.954 (95% CI 0.907-1.000). The predictive value of successful extubation was 10 points of the pulmonary ultrasound score, with a sensitivity of 93.33% and a specificity of 88.00%. CONCLUSION: The bedside lung ultrasound score can intuitively reflect the respiratory status of neonates, which provides clinicians with an important basis for disease evaluation.

The influence of chorioamnionitis on respiratory drive and spontaneous breathing of premature infants at birth: a narrative review.

Most very premature infants breathe at birth but require respiratory support in order to stimulate and support their breathing. A significant proportion of premature infants are affected by chorioamnionitis, defined as an umbrella term for antenatal inflammation of the foetal membranes and umbilical vessels. Chorioamnionitis produces inflammatory mediators that potentially depress the respiratory drive generated in the brainstem. Such respiratory depression could maintain itself by delaying lung aeration, hampering respiratory support at birth and putting infants at risk of hypoxic injury. This inflammatory-mediated respiratory depression may contribute to an association between chorioamnionitis and increased requirement of neonatal resuscitation in premature infants at birth. This narrative review summarises mechanisms on how respiratory drive and spontaneous breathing could be influenced by chorioamnionitis and provides possible interventions to stimulate spontaneous breathing.  Conclusion: Chorioamnionitis could possibly depress respiratory drive and spontaneous breathing in premature infants at birth. Interventions to stimulate spontaneous breathing could therefore be valuable. What is Known: • A large proportion of premature infants are affected by chorioamnionitis, antenatal inflammation of the foetal membranes and umbilical vessels. What is New: • Premature infants affected by chorioamnionitis might be exposed to higher concentrations of respiratory drive inhibitors which could depress breathing at birth. • Premature infants affected by chorioamnionitis seem to be associated with a higher and more extensive requirement of resuscitation at birth.

Global, Regional and National Trends in the Burden of Neonatal Respiratory Failure and essentials of its diagnosis and management from 1992 to 2022: a scoping review.

Neonatal respiratory failure (NRF) is an emergency which has not been examined extensively. We critically synthesized the contemporary in-hospital prevalence, mortality rate, predictors, aetiologies, diagnosis and management of NRF to better formulate measures to curb its burden. We searched MEDLINE and Google Scholar from 01/01/1992 to 31/12/2022 for relevant publications. We identified 237 papers from 58 high-income and low-and middle-income countries (LMICs). NRF prevalence ranged from 0.64 to 88.4% with some heterogeneity. The prevalence was highest in Africa, the Middle East and Asia. Globally as well as in Asia and the Americas, respiratory distress syndrome (RDS) was the leading aetiology of NRF. Neonatal sepsis was first aetiology in Africa, whereas in both Europe and the Middle East it was transient tachypnoea of the newborn. Independent predictors of NRF were prematurity, male gender, ethnicity, low/high birth weight, young/advanced maternal age, primiparity/multiparity, maternal smoking, pregestational/gestational diabetes mellitus, infectious anamneses, antepartum haemorrhage, gestational hypertensive disorders, multiple pregnancy, caesarean delivery, antenatal drugs, foetal distress, APGAR score, meconium-stained amniotic fluid and poor pregnancy follow-up. The NRF-related in-hospital mortality rate was 0.21-57.3%, highest in Africa, Asia and the Middle East. This death toll was primarily due to RDS globally and in all regions. Clinical evaluation using the Silverman-Anderson score was widely used and reliable. Initial resuscitation followed by specific management was the common clinical practice. CONCLUSION: NRF has a high burden globally, driven by RDS, especially in LIMCs where more aggressive treatment and innovations, preferably subsidized, are warranted to curb its alarming burden. WHAT IS KNOWN: • Neonatal respiratory failure is a frequent emergency associated with a significant morbidity and mortality, yet there is no comprehensive research paper summarizing its global burden. • Neonatal respiratory failure needs prompt diagnosis and treatment geared at improving neonatal survival. WHAT IS NEW: • Neonatal respiratory failure has an alarmingly high global burden largely attributed to Respiratory distress syndrome. Low resource settings are disproportionately affected by the burden of neonatal respiratory failure. • Independent preditors of neonatal respiratory failure are several but can be classified into foetal, maternal and obstetrical factors. An illustrative pedagogical algorithm is provided to facilitate diagnosis and management of neonatal respiratory failure by healthcare providers.

Impact on cerebral hemodynamics of the use of volume guarantee combined with high frequency oscillatory ventilation in a neonatal animal respiratory distress model.

High-frequency oscillatory ventilation (HFOV) is an alternative to conventional mechanical ventilation (CMV). Recently, the use of volume guarantee (VG) combined with HFOV has been suggested as a safe strategy capable of reducing the damage induced by ventilation in immature lungs. However, the possible impact of this new ventilation technique on cerebral hemodynamics is unknown. To evaluate the cerebral hemodynamics effect of HFOV combined with VG in an experimental animal model of neonatal respiratory distress syndrome (RDS) due to surfactant deficiency compared with HFOV and CMV+VG (control group). Eighteen newborn piglets were randomized, before and after the induction of RDS by bronchoalveolar lavage, into 3 mechanical ventilation groups: CMV, HFOV and HFOV with VG. Changes in cerebral oxygen transport and consumption and cerebral blood flow were analyzed by non-invasive regional cerebral oxygen saturation (CrSO2), jugular venous saturation (SjO2), the calculated cerebral oxygen extraction fraction (COEF), the calculated cerebral fractional tissue oxygen extraction (cFTOE) and direct measurement of carotid artery flow. To analyze the temporal evolution of these variables, a mixed-effects linear regression model was constructed. After randomization, the following statistically significant results were found in every group: a drop in carotid artery flow: at a rate of -1.7 mL/kg/min (95% CI: -2.5 to -0.81; p < 0.001), CrSO2: at a rate of -6.2% (95% CI: -7.9 to -4.4; p < 0.001) and SjO2: at a rate of -20% (95% CI: -26 to -15; p < 0.001), accompanied by an increase in COEF: at a rate of 20% (95% CI: 15 to 26; p < 0.001) and cFTOE: at a rate of 0.07 (95% CI: 0.05 to 0.08; p < 0.001) in all groups. No statistically significant differences were found between the HFOV groups. CONCLUSION: No differences were observed at cerebral hemodynamic between respiratory assistance in HFOV with and without VG, being the latter ventilatory strategy equally safe. WHAT IS KNOWN: • Preterm have a situation of fragility of cerebral perfusion wich means that any mechanical ventilation strategy can have a significant influence. High-frequency oscillatory ventilation (HFOV) is an alternative to conventional mechanical ventilation (CMV). Recently, the use of volume guarantee (VG) combined with HFOV has been suggested as a safe strategy capable of reducing the damage induced by ventilation in immature lungs. Several studies have compared CMV and HFOV and their effects at hemodynamic level. It is known that the use of high mean airway pressure in HFOV can cause an increase in pulmonary vascular resistance with a decrease in thoracic venous return. WHAT IS NEW: • The possible impact of VAFO + VG on cerebral hemodynamics is unknown. Due the lack of studies and the existing controversy, we have carried out this research project in an experimental animal model with the aim of evaluating the cerebral hemodynamic repercussion of the use of VG in HFOV compared to the classic strategy without VG.

Assessing the diagnostic accuracy of lung ultrasound in determining invasive ventilation needs in neonates on non-invasive ventilation: An observational study from a tertiary NICU in India.

Effective management of neonatal respiratory distress requires timely recognition of when to transition from non-invasive to invasive ventilation. Although the lung ultrasound score (LUS) is useful in evaluating disease severity and predicting the need for surfactants, its efficacy in identifying neonates requiring invasive ventilation has only been explored in a few studies. This study aims to assess the accuracy of LUS in determining the need for invasive ventilation in neonates on non-invasive ventilation (NIV) support. From July 2021 to June 2023, we conducted a prospective study on 192 consecutively admitted neonates with respiratory distress needing NIV within 24 h of birth at our NICU in Hyderabad, India. The primary objective was the diagnostic accuracy of LUS in determining the need for invasive ventilation within 72 h of initiating NIV. We calculated LUS using the scoring system of Brat et al. (JAMA Pediatr 169:e151797, [10]). Treating physicians' assessments of the need for invasive ventilation served as the reference standard for evaluating LUS effectiveness. Out of 192 studied neonates, 31 (16.1%) required invasive ventilation. The median LUS was 5 (IQR: 2-8) for those on NIV and 10 (IQR: 7-12) for those needing invasive ventilation. The LUS had a strong discriminative ability for invasive ventilation with an AUC (area under the curve) of 0.825 (CI: 0.75-0.86, p = 0.0001). An LUS > 7 had 77.4% sensitivity (95% CI: 58.9-90.8%), 75.1% specificity (95% CI: 67.8-81.7%), 37.5% positive predictive value (PPV) (95% CI: 30.15-45.5%), 94.5% negative predictive value (NPV) (95% CI: 89.9-97.1%), 3.1 positive likelihood ratio (PLR) (95% CI: 2.2-4.3), 0.3 negative likelihood ratio (NLR) (95% CI: 0.15-0.58), and 75.5% overall accuracy (95% CI: 68.8-81.4%) for identifying invasive ventilation needs. In contrast, SAS, with a cutoff point greater than 5, has an AUC of 0.67. It demonstrates 62.5% sensitivity, 61.9% specificity, 24.7% PPV, 89.2% NPV, and an overall diagnostic accuracy of 61.9%. The DeLong test confirms the significance of this difference (AUC difference: 0.142, p = 0.04), underscoring LUS's greater reliability for NIV failure.  Conclusion: This study underscores the diagnostic accuracy of the LUS cutoff of > 7 in determining invasive ventilation needs during the initial 72 h of NIV. Importantly, while lower LUS values typically rule out the need for ventilation, higher values, though indicative, are not definitive. What is known? • The effectiveness of lung ultrasound in evaluating disease severity and the need for surfactants in neonates with respiratory distress is well established. However, traditional indicators for transitioning from non-invasive to invasive ventilation, like respiratory distress and oxygen levels, have limitations, underscoring the need for reliable, non-invasive assessment tools. What is new? • This study reveals that a LUS over 7 accurately discriminates between neonates requiring invasive ventilation and those who do not. Furthermore, the lung ultrasound score outperformed the Silverman Andersen score for NIV failure in our population.

Neonatal point-of-care lung ultrasound: what should be known and done out of the NICU?

Lung ultrasound is rapidly becoming a useful tool in the care of neonates: its ease of use, reproducibility, low cost, and negligible side effects make it a very suitable tool for the respiratory care of all neonates. This technique has been extensively studied by different approaches in neonatal intensive care unit (NICU), both for diagnostic and prognostic aims and to guide respiratory treatments. However, many neonates are being born in level I/II hospitals without NICU facilities so all pediatricians, not just neonatal intensivists, should be aware of its potential. This is made possible by the increasing access to ultrasound machines in a modern hospital setting. In this review, we describe the ultrasonographic characteristics of the normal neonatal lung. We also discuss the ultrasound features of main neonatal respiratory diseases: transient tachypnea of the neonate (TTN), respiratory distress syndrome (RDS), meconium aspiration syndrome (MAS), pneumothorax (PNX), pleural effusion (PE), or pneumonia. Finally, we mention two functional approaches to lung ultrasound: 1. The use of lung ultrasound in level I delivery centers as a mean to assess the severity of neonatal respiratory distress and request a transport to a higher degree structure in a timely fashion. 2. The prognostic accuracy of lung ultrasound for early and targeted surfactant replacement. CONCLUSION:  LU is still a useful tool in level I/II neonatal units, both for diagnostic and functional issues. WHAT IS KNOWN: • Neonatal lung ultrasound has been recently introduced in the usual care in many Neonatal Intensive Care Units. WHAT IS NEW: • It also has many advantages in level I/II neonatal units, both for neonatologist or even pediatricians that treat neonates in those sites.

Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome.

BACKGROUND: Laryngeal mask airway surfactant administration (S-LMA) has the potential benefit of surfactant administration whilst avoiding endotracheal intubation and ventilation, ventilator-induced lung injury and bronchopulmonary dysplasia (BPD). OBJECTIVES: To evaluate the benefits and harms of S-LMA either as prophylaxis or treatment (rescue) compared to placebo, no treatment, or intratracheal surfactant administration via an endotracheal tube (ETT) with the intent to rapidly extubate (InSurE) or extubate at standard criteria (S-ETT) or via other less-invasive surfactant administration (LISA) methods on morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome (RDS). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trial registries in December 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster- or quasi-RCTs of S-LMA compared to placebo, no treatment, or other routes of administration (nebulised, pharyngeal instillation of surfactant before the first breath, thin endotracheal catheter surfactant administration or intratracheal surfactant instillation) on morbidity and mortality in preterm infants at risk of RDS. We considered published, unpublished and ongoing trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included eight trials (seven new to this update) recruiting 510 newborns. Five trials (333 infants) compared S-LMA with surfactant administration via ETT with InSurE. One trial (48 infants) compared S-LMA with surfactant administration via ETT with S-ETT, and two trials (129 infants) compared S-LMA with no surfactant administration. We found no studies comparing S-LMA with LISA techniques or prophylactic or early S-LMA. S-LMA versus surfactant administration via InSurE S-LMA may have little or no effect on the composite outcome of death or BPD at 36 weeks' postmenstrual age (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.27 to 8.34, I 2 = not applicable (NA) as 1 study had 0 events; risk difference (RD) 0.02, 95% CI -0.07 to 0.10; I 2 = 0%; 2 studies, 110 infants; low-certainty evidence). There may be a reduction in the need for mechanical ventilation at any time (RR 0.53, 95% CI 0.36 to 0.78; I 2 = 27%; RD -0.14, 95% CI -0.22 to -0.06, I 2 = 89%; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 5 to 17; 5 studies, 333 infants; low-certainty evidence). However, this was limited to four studies (236 infants) using analgesia or sedation for the InSurE group. There was little or no difference for air leak during first hospitalisation (RR 1.39, 95% CI 0.65 to 2.98; I 2 = 0%; 5 studies, 333 infants (based on 3 studies as 2 studies had 0 events); low-certainty evidence); BPD among survivors to 36 weeks' PMA (RR 1.28, 95% CI 0.47 to 3.52; I 2 = 0%; 4 studies, 264 infants (based on 3 studies as 1 study had 0 events); low-certainty evidence); or death (all causes) during the first hospitalisation (RR 0.28, 95% CI 0.01 to 6.60; I 2 = NA as 2 studies had 0 events; 3 studies, 203 infants; low-certainty evidence). Neurosensory disability was not reported. Intraventricular haemorrhage ( IVH) grades III and IV were reported among the study groups (1 study, 50 infants). S-LMA versus surfactant administration via S-ETT No study reported death or BPD at 36 weeks' PMA. S-LMA may reduce the use of mechanical ventilation at any time compared with S-ETT (RR 0.47, 95% CI 0.31 to 0.71; RD -0.54, 95% CI -0.74 to -0.34; NNTB 2, 95% CI 2 to 3; 1 study, 48 infants; low-certainty evidence). We are very uncertain whether S-LMA compared with S-ETT reduces air leak during first hospitalisation (RR 2.56, 95% CI 0.11 to 59.75), IVH grade III or IV (RR 2.56, 95% CI 0.11 to 59.75) and death (all causes) during the first hospitalisation (RR 0.17, 95% CI 0.01 to 3.37) (1 study, 48 infants; very low-certainty evidence). No study reported BPD to 36 weeks' PMA or neurosensory disability. S-LMA versus no surfactant administration Rescue surfactant could be used in both groups. There may be little or no difference in death or BPD at 36 weeks (RR 1.65, 95% CI 0.85 to 3.22; I 2 = 58%; RD 0.08, 95% CI -0.03 to 0.19; I 2 = 0%; 2 studies, 129 infants; low-certainty evidence). There was probably a reduction in the need for mechanical ventilation at any time with S-LMA compared with nasal continuous positive airway pressure without surfactant (RR 0.57, 95% CI 0.38 to 0.85; I 2 = 0%; RD -0.24, 95% CI -0.40 to -0.08; I 2 = 0%; NNTB 4, 95% CI 3 to 13; 2 studies, 129 infants; moderate-certainty evidence). There was little or no difference in air leak during first hospitalisation (RR 0.65, 95% CI 0.23 to 1.88; I 2 = 0%; 2 studies, 129 infants; low-certainty evidence) or BPD to 36 weeks' PMA (RR 1.65, 95% CI 0.85 to 3.22; I 2 = 58%; 2 studies, 129 infants; low-certainty evidence). There were no events in either group for death during the first hospitalisation (1 study, 103 infants) or IVH grade III and IV (1 study, 103 infants). No study reported neurosensory disability. AUTHORS' CONCLUSIONS: In preterm infants less than 36 weeks' PMA, rescue S-LMA may have little or no effect on the composite outcome of death or BPD at 36 weeks' PMA. However, it may reduce the need for mechanical ventilation at any time. This benefit is limited to trials reporting the use of analgesia or sedation in the InSurE and S-ETT groups. There is low- to very-low certainty evidence for no or little difference in neonatal morbidities and mortality. Long-term outcomes are largely unreported. In preterm infants less than 32 weeks' PMA or less than 1500 g, there are insufficient data to support or refute the use of S-LMA in clinical practice. Adequately powered trials are required to determine the effect of S-LMA for prevention or early treatment of RDS in extremely preterm infants. S-LMA use should be limited to clinical trials in this group of infants.

Non-invasive high-frequency ventilation in newborn infants with respiratory distress.

BACKGROUND: Respiratory distress occurs in up to 7% of newborns, with respiratory support (RS) provided invasively via an endotracheal (ET) tube or non-invasively via a nasal interface. Invasive ventilation increases the risk of lung injury and chronic lung disease (CLD). Using non-invasive strategies, with or without minimally invasive surfactant, may reduce the need for mechanical ventilation and the risk of lung damage in newborn infants with respiratory distress. OBJECTIVES: To evaluate the benefits and harms of nasal high-frequency ventilation (nHFV) compared to invasive ventilation via an ET tube or other non-invasive ventilation methods on morbidity and mortality in preterm and term infants with or at risk of respiratory distress. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and three trial registries in April 2023. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster- or quasi-RCTs of nHFV in newborn infants with respiratory distress compared to invasive or non-invasive ventilation. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials for inclusion, extracted data, assessed the risk of bias, and undertook GRADE assessment. MAIN RESULTS: We identified 33 studies, mostly in low- to middle-income settings, that investigated this therapy in 5068 preterm and 46 term infants. nHFV compared to invasive respiratory therapy for initial RS We are very uncertain whether nHFV reduces mortality before hospital discharge (RR 0.67, 95% CI 0.20 to 2.18; 1 study, 80 infants) or the incidence of CLD (RR 0.38, 95% CI 0.09 to 1.59; 2 studies, 180 infants), both very low-certainty. ET intubation, death or CLD, severe intraventricular haemorrhage (IVH) and neurodevelopmental disability (ND) were not reported. nHFV vs nasal continuous positive airway pressure (nCPAP) used for initial RS We are very uncertain whether nHFV reduces mortality before hospital discharge (RR 1.00, 95% CI 0.41 to 2.41; 4 studies, 531 infants; very low-certainty). nHFV may reduce ET intubation (RR 0.52, 95% CI 0.33 to 0.82; 5 studies, 571 infants), but there may be little or no difference in CLD (RR 1.35, 95% CI 0.80 to 2.27; 4 studies, 481 infants); death or CLD (RR 2.50, 95% CI 0.52 to 12.01; 1 study, 68 participants); or severe IVH (RR 1.17, 95% CI 0.36 to 3.78; 4 studies, 531 infants), all low-certainty evidence. ND was not reported. nHFV vs nasal intermittent positive-pressure ventilation (nIPPV) used for initial RS nHFV may result in little to no difference in mortality before hospital discharge (RR 1.86, 95% CI 0.90 to 3.83; 2 studies, 84 infants; low-certainty). nHFV may have little or no effect in reducing ET intubation (RR 1.33, 95% CI 0.76 to 2.34; 5 studies, 228 infants; low-certainty). There may be a reduction in CLD (RR 0.63, 95% CI 0.42 to 0.95; 5 studies, 307 infants; low-certainty). A single study (36 infants) reported no events for severe IVH. Death or CLD and ND were not reported. nHFV vs high-flow nasal cannula (HFNC) used for initial RS We are very uncertain whether nHFV reduces ET intubation (RR 2.94, 95% CI 0.65 to 13.27; 1 study, 37 infants) or reduces CLD (RR 1.18, 95% CI 0.46 to 2.98; 1 study, 37 participants), both very low-certainty. There were no mortality events before hospital discharge or severe IVH. Other deaths, CLD and ND, were not reported. nHFV vs nCPAP used for RS following planned extubation nHFV probably results in little or no difference in mortality before hospital discharge (RR 0.92, 95% CI 0.52 to 1.64; 6 studies, 1472 infants; moderate-certainty). nHFV may result in a reduction in ET reintubation (RR 0.42, 95% CI 0.35 to 0.51; 11 studies, 1897 infants) and CLD (RR 0.78, 95% CI 0.67 to 0.91; 10 studies, 1829 infants), both low-certainty. nHFV probably has little or no effect on death or CLD (RR 0.90, 95% CI 0.77 to 1.06; 2 studies, 966 infants) and severe IVH (RR 0.80, 95% CI 0.57 to 1.13; 3 studies, 1117 infants), both moderate-certainty. We are very uncertain whether nHFV reduces ND (RR 0.92, 95% CI 0.37 to 2.29; 1 study, 74 infants; very low-certainty). nHFV versus nIPPV used for RS following planned extubation nHFV may have little or no effect on mortality before hospital discharge (RR 1.83, 95% CI 0.70 to 4.79; 2 studies, 984 infants; low-certainty). There is probably a reduction in ET reintubation (RR 0.69, 95% CI 0.54 to 0.89; 6 studies, 1364 infants), but little or no effect on CLD (RR 0.88, 95% CI 0.75 to 1.04; 4 studies, 1236 infants); death or CLD (RR 0.92, 95% CI 0.79 to 1.08; 3 studies, 1070 infants); or severe IVH (RR 0.78, 95% CI 0.55 to 1.10; 4 studies, 1162 infants), all moderate-certainty. One study reported there might be no difference in ND (RR 0.88, 95% CI 0.35 to 2.16; 1 study, 72 infants; low-certainty). nHFV versus nIPPV following initial non-invasive RS failure nHFV may have little or no effect on mortality before hospital discharge (RR 1.44, 95% CI 0.10 to 21.33); or ET intubation (RR 1.23, 95% CI 0.51 to 2.98); or CLD (RR 1.01, 95% CI 0.70 to 1.47); or severe IVH (RR 0.47, 95% CI 0.02 to 10.87); 1 study, 39 participants, all low- or very low-certainty. Other deaths or CLD and ND were not reported. AUTHORS' CONCLUSIONS: For initial RS, we are very uncertain if using nHFV compared to invasive respiratory therapy affects clinical outcomes. However, nHFV may reduce intubation when compared to nCPAP. For planned extubation, nHFV may reduce the risk of reintubation compared to nCPAP and nIPPV. nHFV may reduce the risk of CLD when compared to nCPAP. Following initial non-invasive respiratory support failure, nHFV when compared to nIPPV may result in little to no difference in intubation. Large trials, particularly in high-income settings, are needed to determine the role of nHFV in initial RS and following the failure of other non-invasive respiratory support. Also, the optimal settings of nHVF require further investigation.

The use of late preterm antenatal corticosteroids in women with gestational diabetes : a puzzle worth solving.

BACKGROUND: To investigate the association between late preterm antenatal corticosteroid treatment and outcome in late preterm neonates born to mothers with gestational diabetes mellitus, METHODS: All patients with gestational diabetes mellitus who had a late preterm delivery at Etlik Lady Zübeyde Hospital between 2017 and 2021 were included. Women who met the inclusion criteria and were not given antenatal corticosteroid treatment during current pregnancy before 34 0/7 weeks of gestation were divided into two groups according to whether or not they received late preterm antenatal corticosteroid treatment. The two groups were compared in terms of adverse neonatal complications. The main outcomes were composite respiratory outcome and composite neonatal outcome. Logistic regression analysis was used to determine additional potential predictors of neonatal outcome. RESULTS: This retrospective cohort study included a total of 400 participants with gestational diabetes mellitus who had a late preterm delivery within the study period. Of these women, 196 (49%) received late preterm antenatal corticosteroid treatment. Main outcomes showed no difference. Decreasing gestational age at birth was identified as an independent risk factor predicting both composite respiratory outcome and composite neonatal outcome in multivariate logistic regression analysis. CONCLUSIONS: Antenatal corticosteroid treatment at or after 34 0/7 weeks of gestation in women with gestational diabetes mellitus who had a late preterm delivery was not associated with improvement in adverse neonatal outcomes. Decreasing gestational age at birth was the only independent risk factor predicting composite neonatal and composite respiratory outcomes.

Does the use of antenatal corticosteroids reduce respiratory morbidity in babies born in late preterm period?

BACKGROUND: The aim of this study is to determine the effectiveness of antenatal corticosteroid in reducing respiratory morbidity in babies born in the late preterm period. METHODS: Two hundred and eighty-six pregnant women at risk of having a late preterm delivery were studied. One hundred and forty-three (143) served as the cases and were given 2 doses of 12 mg intramuscular dexamethasone 12 h apart, while 143 served as the controls and were given a similar quantity of placebo. The women were followed up prospectively and data were collected on the pregnant women and their newborns on a standardized form. The neonates were assessed for acute respiratory distress syndrome and transient tachypnea of the newborn based on clinical signs, symptoms, and chest x-ray results (when indicated). The primary outcome was the occurrence of neonatal respiratory morbidity. RESULTS: The primary outcome occurred in 5 out of 130 infants (3.8%) in the dexamethasone group and 31 out of 122 (25.4%) in the placebo group (P value = 0.000003). Birth asphyxia, neonatal intensive care admission and need for active resuscitation at birth also occurred significantly less frequently in the dexamethasone group (P value 0.004, 0.009, 0.014 respectively). There were no significant group differences in the incidence of neonatal sepsis, neonatal jaundice, hypoglycemia and feeding difficulties. CONCLUSIONS: Administration of dexamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications, neonatal intensive care unit admission, and need for active resuscitation at birth. TRIAL REGISTRATION: PACTR ( www.pactr.org ) Registration Number: PACTR202304579281358. The study was retrospectively registered on April 19, 2023.

Construction and evaluation of neonatal respiratory failure risk prediction model for neonatal respiratory distress syndrome.

BACKGROUND: Neonatal respiratory distress syndrome (NRDS) is a common respiratory disease in preterm infants, often accompanied by respiratory failure. The aim of this study was to establish and validate a nomogram model for predicting the probability of respiratory failure in NRDS patients. METHODS: Patients diagnosed with NRDS were extracted from the MIMIC-iv database. The patients were randomly assigned to a training and a validation cohort. Univariate and stepwise Cox regression analyses were used to determine the prognostic factors of NRDS. A nomogram containing these factors was established to predict the incidence of respiratory failure in NRDS patients. The area under the receiver operating characteristic curve (AUC), receiver operating characteristic curve (ROC), calibration curves and decision curve analysis were used to determine the effectiveness of this model. RESULTS: The study included 2,705 patients with NRDS. Univariate and multivariate stepwise Cox regression analysis showed that the independent risk factors for respiratory failure in NRDS patients were gestational age, pH, partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), hemoglobin, blood culture, infection, neonatal intracranial hemorrhage, Pulmonary surfactant (PS), parenteral nutrition and respiratory support. Then, the nomogram was constructed and verified. CONCLUSIONS: This study identified the independent risk factors of respiratory failure in NRDS patients and used them to construct and evaluate respiratory failure risk prediction model for NRDS. The present findings provide clinicians with the judgment of patients with respiratory failure in NRDS and help clinicians to identify and intervene in the early stage.

Exploring the diagnostic value of ultrasound radiomics for neonatal respiratory distress syndrome.

BACKGROUND: Neonatal respiratory distress syndrome (NRDS) is a prevalent cause of respiratory failure and death among newborns, and prompt diagnosis is imperative. Historically, diagnosis of NRDS relied mostly on typical clinical manifestations, chest X-rays, and CT scans. However, recently, ultrasound has emerged as a valuable and preferred tool for aiding NRDS diagnosis. Nevertheless, evaluating lung ultrasound imagery necessitates rigorous training and may be subject to operator-dependent bias, limiting its widespread use. As a result, it is essential to investigate a new, reliable, and operator-independent diagnostic approach that does not require subjective factors or operator expertise. This article aims to explore the diagnostic potential of ultrasound-based radiomics in differentiating NRDS from other non-NRDS lung disease. METHODS: A total of 150 neonatal lung disease cases were consecutively collected from the department of neonatal intensive care unit of the Quanzhou Maternity and Children's Hospital, Fujian Province, from September 2021 to October 2022. Of these patients, 60 were diagnosed with NRDS, whereas 30 were diagnosed with neonatal pneumonia, meconium aspiration syndrome (MAS), and transient tachypnea (TTN). Two ultrasound images with characteristic manifestations of each lung disease were acquired and divided into training (n = 120) and validation cohorts (n = 30) based on the examination date using an 8:2 ratio. The imaging texture features were extracted using PyRadiomics and, after the screening, machine learning models such as random forest (RF), logistic regression (LR), K-nearest neighbors (KNN), support vector machine (SVM), and multilayer perceptron (MLP) were developed to construct an imaging-based diagnostic model. The diagnostic efficacy of each model was analyzed. Lastly, we randomly selected 282 lung ultrasound images and evaluated the diagnostic efficacy disparities between the optimal model and doctors across differing levels of expertise. RESULTS: Twenty-two imaging-based features with the highest weights were selected to construct a predictive model for neonatal respiratory distress syndrome. All models exhibited favorable diagnostic performances. Analysis of the Youden index demonstrated that the RF model had the highest score in both the training (0.99) and validation (0.90) cohorts. Additionally, the calibration curve indicated that the RF model had the best calibration (P = 0.98). When compared to the diagnostic performance of experienced and junior physicians, the RF model had an area under the curve (AUC) of 0.99; however, the values for experienced and junior physicians were 0.98 and 0.85, respectively. The difference in diagnostic efficacy between the RF model and experienced physicians was not statistically significant (P = 0.24), whereas that between the RF model and junior physicians was statistically significant (P < 0.0001). CONCLUSION: The RF model exhibited excellent diagnostic performance in the analysis of texture features based on ultrasound radiomics for diagnosing NRDS.

The association between sex and neonatal respiratory distress syndrome.

BACKGROUND: To investigate the association between sex and neonatal respiratory distress syndrome (NRDS). METHODS: Neonates born at our hospital and transferred to the neonatal department within 1 h were retrospectively analyzed. Depending on whether they developed NRDS during their hospital stay, the neonates was divided into NRDS and non-NRDS groups. There were 142 neonates in the NRDS group (95 males and 47 females) and 310 neonates in the non-NRDS group (180 males and 140 females). The neonates' data on gestational age (GA), sex, birth weight, white blood cell count (WBC), platelet count (PLT), C-reactive protein (CRP), total immunoglobulin M (total IgM), gestational diabetes mellitus(GDM), antenatal steroids use, meconium-stained amniotic fluid, and preterm premature rupture of membranes(PPROM) were gathered. RESULTS: 452 neonates (265 males and 187 females) were involved for the purpose of collecting basic characteristic. Multivariate analysis, males had a 1.87 times higher risk of NRDS than females (P < 0.05) after controlling for the confounding effects of GA, birth weight, WBC, PLT, CRP, total IgM, GDM, antenatal steroids use, meconium-stained amniotic fluid, and PPROM. CONCLUSIONS: Sex was associated with NRDS; males had a considerably higher risk of NRDS than females.