Lung ultrasound score as a tool to predict severity of bronchopulmonary dysplasia in neonates born ≤25 weeks of gestational age.

OBJECTIVE: The primary aim was to evaluate whether the addition of the posterior lung aided in diagnostic accuracy of predicting bronchopulmonary dysplasia (BPD) vs moderate-severe BPD (msBPD); the secondary aim was to explore the diagnostic accuracy of two protocols for BPD vs msBPD. STUDY DESIGN: This was a single-center prospective observational study. Preterm infants with a gestational age ≤ 25 weeks were included. Two LUS score protocols were evaluated on the 14th day of life (DOL): (A) evaluating the anterolateral (LUS score-al) lung and (B) the anterolateral combined with posterior (LUS score-alp) lung. The LUS score range for the two protocols was 0-32 and 0-48, respectively. RESULTS: A total of eighty-nine infants were enrolled. Both the LUS score-al and LUS score-alp were higher in neonates developing BPD and msBPD than in the rest of the cohort (LUS score-al 24 (23,26) vs 22 (20,23); LUS score-alp 36 (34,39) vs 28 (25,32)) (LUS score-al 25 (24,26) vs 23 (21,24); LUS score-alp 40 (39,40) vs 34 (28,36)). The LUS score-al on the 14th DOL showed a moderate diagnostic accuracy to predict BPD and msBPD (AUC 95% CI: 0.797 [0.697-0.896]; 0.811[0.713-0.909]), while the LUS score-alp significantly improved diagnostic accuracy of BPD and msBPD (AUC 95% CI: 0.902 [0.834-0.970]; 0.922 [0.848-0.996]). A cutoff of 25 points in the LUS score-al provided a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 76.9%, 79.4%, 3.7, and 0.3 respectively to predict msBPD. Meanwhile, that of 39 points in the LUS score-alp provided a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 81%, 98.4%, 50.5 and 0.19 to predict msBPD, respectively. CONCLUSIONS: The LUS score on the 14th DOL can predict BPD and msBPD with moderate diagnostic accuracy. Apart from that, scanning posterior enhanced diagnostic accuracy.

Association between plasma lysophosphatidic acid levels and bronchopulmonary dysplasia in extremely preterm infants: A prospective study.

BACKGROUND: Lysophosphatidic acid (LPA) is implicated in bronchopulmonary dysplasia (BPD) pathogenesis, but clinical evidence is lacking. This study aimed to investigate LPA levels in preterm infants with and without BPD and explore LPA as a biomarker for predicting BPD occurrence. METHODS: Premature infants with a gestational age of <28 weeks or a birth weight of <1000 g were enrolled. Blood samples were collected at postnatal day (PD) 7, 28, and postmenstrual age (PMA) 36 weeks, and plasma LPA levels were measured using a commercial ELISA kit. Receiver operating characteristic curve (ROC) curve analysis determined the PD 28 cutoff for LPA, and multivariable regression analyzed LPA's independent contribution to BPD and exploratory outcomes. RESULT: Among the 91 infants enrolled in this study, 35 were classified into the non-BPD group and 56 into the BPD group. Infants with BPD had higher plasma LPA levels at PD 28 (6.467 vs. 4.226 µg/mL, p = 0.034) and PMA 36 weeks (2.330 vs. 1.636 µg/mL, p = 0.001). PD 28 LPA level of 6.132 µg/mL was the cutoff for predicting BPD development. Higher PD 28 LPA levels (≥6.132 µg/mL) independently associated with BPD occurrence (OR 3.307, 95% CI 1.032-10.597, p = 0.044). Higher LPA levels correlated with longer oxygen therapy durations [regression coefficients (ß) 0.147, 95% CI 0.643-16.133, p = .034]. CONCLUSIONS: Infants with BPD had higher plasma LPA levels at PD 28 and PMA 36 weeks. Higher PD 28 LPA levels independently associated with an increased BPD risk.

The value of hematocrit for predicting bronchopulmonary dysplasia in very low birth weight preterm infants.

To determine hematocrit (HCT) and to identify independent risk factors for predicting bronchopulmonary dysplasia (BPD) in preterm infants with very low birth weight (VLBW) infants. This retrospective study included 296 premature infants with VLBW in the neonatal intensive care unit of the First Affiliated Hospital of the University of Science and Technology of China between January 2015 and December 2019. Maternal pregnant information and clinical information as well as hematological parameters of preterm babies were collected and compared. Then the maximum area under the curve of receiver operating characteristic curve was developed to estimate the predictive indicator in the blood. Finally, differential variables together with the predictive index were screened for multiple logistic regression analysis to determine independent prognostic factors for BPD. Infants were divided into a BPD group (134 cases) and a non-BPD group (162 cases). The area under the curve of HCT at postnatal 1 week was 0.737 with the sensitivity of 52.30 % and the specificity of 86.00%. Birth weight (BW) <1.12 kg, gestational age <28.4 weeks, newborn respiratory distress syndrome, mechanical ventilation ≥ 7 days, ventilation associated pneumonia, patent arterial duct, PaO2/FiO2 <300 mm Hg and HCT <0.455 at postnatal 1 week were risk factors for BPD of VLBW infants. HCT levels below 0.455 at 1 week after birth serve as a valuable indicator for the potential development of BPD.

Lung ultrasound score predicts patent ductus arteriosus ligation among neonates ≤25 weeks.

BACKGROUND: This prospective study aimed to investigate whether lung ultrasound score (LUSs) can predict the patent ductus arteriosus (PDA) ligation. METHODS: Preterm infants ≤25 weeks of gestational age (GA) were enrolled. A lung ultrasound was performed on the 14th day of life. Each lung zone was given a score between 0 and 4. A receiver-operating characteristic (ROC) curve was constructed to evaluate the ability of the LUSs for predicting ligation. RESULTS: A total of 81 infants were eligible with a median GA and birth weight (BW) of 25 weeks (24.1-25.2) and 710 g (645-770), respectively. The median time from birth to ligation was 35 days (32-51). Those who underwent ligation had a longer time of mechanical ventilation (34 [26-39] vs. 19 [12-30], p < 0.001), shorter time of noninvasive respiratory support (39 [32-51] vs. 50 [41.5-57], p < 0.01), higher incidence of the bronchopulmonary dysplasia (BPD) (p < 0.01), and severe BPD (p < 0.001). The LUSs had an area under the ROC of 0.96 (95% confidence interval: 0.93-0.99) for the prediction of ligation. A LUSs cutoff of 36 has a sensitivity and specificity of 96% and 86% and positive and negative predictive values of 82% and 98%, respectively. CONCLUSIONS: LUSs at an early stage of life can predict PDA ligation in extremely preterm infants. It would be helpful to reduce morbidity by reducing the duration and magnitude of respiratory support.

Association of Ureaplasma infection pattern and azithromycin treatment effect with bronchopulmonary dysplasia in Ureaplasma positive infants: a cohort study.

BACKGROUND: It is unclear whether Ureaplasma-associated pneumonia and azithromycin treatment affect the risk for bronchopulmonary dysplasia (BPD). METHODS: A retrospective cohort study was performed in very low birth weight (VLBW) infants who tested positive for Ureaplasma within 72 h after birth in a tertiary unit. Chest X-ray (CXR) and laboratory test were performed before and after azithromycin treatment. Multivariate logistic regression analysis was used to identify the independent association between BPD and Ureaplasma-associated pneumonia, as well as BPD and effective azithromycin treatment. RESULTS: A total of 118 infants were included in the current study, of whom 36 developed BPD (defined as supplemental oxygen needed at postmenstrual age 36 weeks or discharge). The rate of BPD was significantly higher in infants with Ureaplasma-associated pneumonia (44.6%) compared to infants with Ureaplasma colonization (17.7%, P = 0.002). After adjusting for confounders, an effective azithromycin treatment was significantly associated with reduced risk of BPD [odd ratio (OR) 0.011; 95% confidence interval (CI): 0.000-0.250), whereas Ureaplasma-associated pneumonia was not significantly associated with BPD (OR 1.835; 95% CI: 0.548-6.147). CONCLUSION: Effective Azithromycin treatment in Ureaplasma positive VLBW infants was associated with a reduced risk of BPD.

Early Antibiotic Use and Neonatal Outcomes Among Preterm Infants Without Infections.

OBJECTIVES: To determine whether use, duration, and types of early antibiotics were associated with neonatal outcomes and late antibiotic use in preterm infants without infection-related diseases. METHODS: This cohort study enrolled infants admitted to 25 tertiary NICUs in China within 24 hours of birth during 2015-2018. Death, discharge, or infection-related morbidities within 7 days of birth; major congenital anomalies; and error data on antibiotic use were excluded. The composite outcome was death or adverse morbidities. Late antibiotic use indicated antibiotics used after 7 days of age. Late antibiotic use rate was total antibiotic use days divided by the days of hospital stay after the first 7 days of life. RESULTS: Among 21 540 infants, 18 302 (85.0%) received early antibiotics. Early antibiotics was related to increased bronchopulmonary dysplasia (BPD) (adjusted odds ratio [aOR], 1.28; 95% confidence interval [CI], 1.05-1.56), late antibiotic use (aOR, 4.64; 95% CI, 4.19-5.14), and late antibiotic use rate (adjusted mean difference, 130 days/1000 patient-days; 95% CI, 112-147). Each additional day of early antibiotics was associated with increased BPD (aOR, 1.07; 95% CI, 1.04-1.10) and late antibiotic use (aOR, 1.41; 95% CI, 1.39-1.43). Broad-spectrum antibiotics showed larger effect size on neonatal outcomes than narrow-spectrum antibiotics. The correlation between early antibiotics and outcomes was significant among noncritical infants but disappeared for critical infants. CONCLUSIONS: Among infants without infection, early antibiotic use was associated with increased risk of BPD and late antibiotic use. Judicious early antibiotic use, especially avoiding prolonged duration and broad-spectrum antibiotics among noncritical infants, may improve neonatal outcomes and overall antibiotic use in NICUs.

Vascular and pulmonary effects of ibuprofen on neonatal lung development.

BACKGROUND: Ibuprofen is a nonsteroidal anti-inflammatory drug that is commonly used to stimulate closure of a patent ductus arteriosus (PDA) in very premature infants and may lead to aberrant neonatal lung development and bronchopulmonary dysplasia (BPD). METHODS: We investigated the effect of ibuprofen on angiogenesis in human umbilical cord vein endothelial cells (HUVECs) and the therapeutic potential of daily treatment with 50 mg/kg of ibuprofen injected subcutaneously in neonatal Wistar rat pups with severe hyperoxia-induced experimental BPD. Parameters investigated included growth, survival, lung histopathology and mRNA expression. RESULTS: Ibuprofen inhibited angiogenesis in HUVECs, as shown by reduced tube formation, migration and cell proliferation via inhibition of the cell cycle S-phase and promotion of apoptosis. Treatment of newborn rat pups with ibuprofen reduced pulmonary vessel density in the developing lung, but also attenuated experimental BPD by reducing lung inflammation, alveolar enlargement, alveolar septum thickness and small arteriolar wall thickening. CONCLUSIONS: In conclusion, ibuprofen has dual effects on lung development: adverse effects on angiogenesis and beneficial effects on alveolarization and inflammation. Therefore, extrapolation of the beneficial effects of ibuprofen to premature infants with BPD should be done with extreme caution.

Decreased plasma levels of PDGF-BB, VEGF-A, and HIF-2α in preterm infants after ibuprofen treatment.

Introduction: Ibuprofen is one of the most common non-steroidal anti-inflammatory drugs used to close patent ductus arteriosus (PDA) in preterm infants. PDA is associated with bronchopulmonary dysplasia (BPD), while PDA closure by ibuprofen did not reduce the incidence of BPD or death. Previous studies have indicated an anti-angiogenesis effect of ibuprofen. This study investigated the change of angiogenic factors after ibuprofen treatment in preterm infants. Methods: Preterm infants with hemodynamically significant PDA (hsPDA) were included. After confirmed hsPDA by color doppler ultrasonography within 1 week after birth, infants received oral ibuprofen for three continuous days. Paired plasma before and after the ibuprofen treatment was collected and measured by ELISA to determine the concentrations of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor A (VEGF-A), and hypoxia-inducible factor-2α (HIF-2α). Results: 17 paired plasma from infants with hsPDA were collected. The concentration of PDGF-BB and VEGF-A significantly decreased after ibuprofen treatment (1,908 vs. 442 pg/mL for PDGF-BB, 379 vs. 174 pg/mL for VEGF-A). HIF-2α level showed a tendency to decrease after ibuprofen treatment, although the reduction was not statistically significant (p = 0.077). Conclusion: This study demonstrated decreased vascular growth factors after ibuprofen exposure in hsPDA infants.

Platelets are indispensable for alveolar development in neonatal mice.

Previous studies suggest that platelets are involved in fetal and adult lung development, but their role in postnatal lung development especially after premature birth is elusive. There is an urgent need to scrutinize this topic because the incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease after premature birth, remains high. We have previously shown impaired platelet biogenesis in infants and rats with BPD. In this study, we investigated the role of anti-CD41 antibody-induced platelet depletion during normal postnatal lung development and thrombopoietin (TPO)-induced platelet biogenesis in mice with experimental BPD. We demonstrate that platelet deficient mice develop a BPD-like phenotype, characterized by enlarged alveoli and vascular remodeling of the small pulmonary arteries, resulting in pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). Vascular remodeling was potentially caused by endothelial dysfunction demonstrated by elevated von Willebrand factor (vWF) concentration in plasma and reduced vWF staining in lung tissue with platelet depletion. Furthermore, TPO-induced platelet biogenesis in mice with experimental BPD improved alveolar simplification and ameliorated vascular remodeling. These findings demonstrate that platelets are indispensable for normal postnatal lung development and attenuation of BPD, probably by maintaining endothelial function.

Dose-dependent immunomodulatory effects of metformin on human neonatal monocyte-derived macrophages.

While the association of inflammation with bronchopulmonary dysplasia (BPD) has long been appreciated, M1 proinflammatory macrophage population is emerging as the key element in driving the BPD inflammatory environment. Previous study suggests that low-dose metformin elicits an anti-inflammatory response, possibly through modulating macrophages, to improve disease outcome in a rat BPD model. To investigate this concept further, we examined the dose-dependent immunomodulatory function of metformin directly on human macrophages derived from cord blood (CB) monocytes. We demonstrate that low-dose metformin promotes expansion of M2 anti-inflammatory macrophages, contrasted with high-dose treatment, which exacerbates inflammation by favoring M1 polarization and restricting M2 phenotype. These findings highlight that metformin hold immunomodulatory ability by regulating macrophage polarization in a dose-dependent manner, and only when applied at low dose, exhibiting potential for beneficial anti-inflammatory adjuvant in BPD setting.

The Value of Lung Ultrasound Score in Neonatology.

Point-of-care lung ultrasound (LUS) is increasingly applied in the neonatal intensive care unit (NICU). Diagnostic applications for LUS in the NICU contain the diagnosis of many common neonatal pulmonary diseases (such as Respiratory distress syndrome, Transient tachypnea of the newborn, Meconium aspiration syndrome, Pneumonia, Pneumothorax, and Pleural effusion) which have been validated. In addition to being employed as a diagnostic tool in the classical sense of the term, recent studies have shown that the number and type of artifacts are associated with lung aeration. Based on this theory, over the last few years, LUS has also been used as a semi-quantitative method or as a "functional" tool. Scores have been proposed to monitor the progress of neonatal lung diseases and to decide whether or not to perform a specific treatment. The semi-quantitative LUS scores (LUSs) have been developed to predict the demand for surfactant therapy, the need of respiratory support and the progress of bronchopulmonary dysplasia. Given their ease of use, accuracy and lack of invasiveness, the use of LUSs is increasing in clinical practice. Therefore, this manuscript will review the application of LUSs in neonatal lung diseases.

The Association of Human Milk Feeding With Short-Term Health Outcomes Among Chinese Very/Extremely Low Birth Weight Infants.

BACKGROUND: There is limited evidence about the influence of human milk feeding on short-term outcomes in a large preterm infant population. RESEARCH AIMS: To explore the influences of human milk feeding on the primary outcome of necrotizing enterocolitis and secondarily sepsis, bronchial pulmonary dysplasia, severe retinopathy of prematurity, death, and the time to achieve full enteral feeding at discharge in very/extremely low-birth-weight infants. METHODS: This study was a retrospective, longitudinal, observational two-group comparison cohort study. A total of 4470 very/extremely low-birth-weight infants from 25 neonatal intensive care units in China, between April 2015 and May 2018, were enrolled in this study. Exclusive human milk-fed and formula-fed participants were matched using propensity scores. After matching, human milk-fed participants (n = 1379) and formula-fed participants (n = 1378) were included in the analyses. The likelihood of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, severe retinopathy of prematurity, death, and the time to achieve full enteral feeding were compared between the two groups. RESULTS: Exclusive human milk feeding was associated with lower odds of necrotizing enterocolitis (2.90% vs. 8.42%, OR 0.33, 95% CI [0.22, 0.47]), bronchopulmonary dysplasia (15.74% vs. 20.26%, OR 0.69, 95% CI [0.56, 0.86]), severe retinopathy of prematurity (1.45% vs. 2.39%, OR 0.50, 95% CI [0.27, 0.93]), and death (6.02% vs. 10.38%, OR 0.44, 95% CI [0.32, 0.61]) compared with formula feeding. No significant differences in the time to achieve full enteral feeding or the odds of sepsis were found between the two groups. CONCLUSION: Exclusive human milk feeding is associated with a reduction in necrotizing enterocolitis, bronchopulmonary dysplasia, severe retinopathy of prematurity, and mortality among very/extremely low-birth-weight infants. TRIAL REGISTRATION: Clinicaltrials.gov on November 9, 2015 (NCT02600195).

Prognostic Role of Biomarkers for Pulmonary Arterial Hypertension Associated with Bronchopulmonary Dysplasia in Extremely Premature Infants.

To explore the association of the biochemical markers after birth with BPD-PAH, factors independently predicting BPD-PAH risk were identified by multivariate logistic regression. Cut off values were determined by plotting receiver-operator curve (ROC), for the sake of dichotomizing continuous variables that showed independent relation with BPD-PAH risk. The results show that uric acid (UC) and blood urea nitrogen (BUN) contents markedly increased among infants experiencing BPD-PAH in comparison with those without BPD-PAH (11.6 vs. 9.7 mmol/L, P = 0.006 and 482.0 vs. 249.0 µmol/L, P < 0.001, separately). As shown by multivariate logistic regression, serum BUN levels (OR = 1.143) and uric acid levels (OR = 1.034) were important risk factors for BPD-PAH. Through a lot of experiments, the effectiveness and the advanced nature of the framework proposed in this paper are proved effectively. The framework proposed in this paper can provide some reference and thinking for follow-up research.

Clinical treatment outcomes and their changes in extremely preterm twins: a multicenter retrospective study in Guangdong Province, China. / è¶ æœªæˆç†ŸåŒèƒŽå„¿ä¸´åºŠæ•‘æ²»ç»“å±€åŠå˜åŒ–åˆ†æžï¼šä¸€é¡¹å¹¿ä¸œçœå¤šä¸­å¿ƒå›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS: There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.

Influence of Alveolar Fluid on Aquaporins and Na+/K+-ATPase and Its Possible Theoretical or Clinical Significance.

OBJECTIVE: Pulmonary edema is the most common pathophysiological change in pulmonary disease. Aquaporins (AQPs) and Na+/K+-ATPase play pivotal roles in alveolar fluid clearance. This study aimed to explore the influence of increased alveolar fluid on the absorption of lung fluid. STUDY DESIGN: Eighty New Zealand rabbits were randomly divided into eight groups (n = 10 in each group), and models of different alveolar fluid contents were established by the infusion of different volumes of normal saline (NS) via the endotracheal tube. Five animals in each group were sacrificed immediately after infusion to determine the wet/dry ratio, while the remaining animals in each group were killed 4 hours later to determine the wet/dry ratio at 4 hours. Additionally, lung specimens were collected from each group, and quantitative real-time PCR (qRT-PCR), western blot, and immunohistochemical (IHC) analyses of AQPs and Na+/K+-ATPase were performed. RESULTS: The qRT-PCR analysis and western blot studies showed markedly decreased mRNA and protein levels of AQP1 and Na+/K+-ATPase when the alveolar fluid volume was ≥6 mL/kg, and the mRNA level of AQP5 was significantly reduced when the alveolar fluid volume was ≥4 mL/kg. In addition, IHC analysis showed the same results. At 4 hours, the lung wet/dry ratio was significantly increased when the alveolar fluid volume was ≥6 mL/kg; however, compared with 0 hours after NS infusion, there was still a significant absorption of alveolar fluid for a period of 4 hours. CONCLUSION: The results of this study suggest that increased alveolar fluid may induce the downregulation of the mRNA and protein expression of AQPs and Na+/K+-ATPase, which appear to affect alveolar fluid clearance in rabbit lungs. Early intervention is required to avoid excessive alveolar fluid accumulation. KEY POINTS: · The expression levels of AQPs and Na+/K+--ATPase were significantly decreased as alveolar fluid increased.. · At 4 hours, wet/dry ratio was significantly increased when infusion volume was ≥ 6 mL/kg.. · Early intervention is required to avoid excessive alveolar fluid accumulation..

Bronchopulmonary dysplasia in extremely premature infant with congenital lobar emphysema: a case report.

BACKGROUND: Congenital lobar emphysema (CLE) is a congenital pulmonary cystic disease, characterized by overinflation of the pulmonary lobe and compression of the surrounding areas. Most patients with symptoms need an urgent surgical intervention. Caution and alertness for CLE is required in cases of local emphysema on chest X-ray images of extremely premature infants with bronchopulmonary dysplasia (BPD). CASE PRESENTATION: Here, we report a case of premature infant with 27 + 4 weeks of gestational age who suddenly presented with severe respiratory distress at 60 days after birth. Chest X-ray and computed tomography (CT) indicated emphysema in the middle lobe of the right lung. The diagnosis of CLE was confirmed by histopathological examinations. CONCLUSIONS: Although extremely premature infants have high-risk factors of bronchopulmonary dysplasia due to their small gestational age, alertness for CLE is necessary if local emphysema is present. Timely pulmonary CT scan and surgical interventions should be performed to avoid the delay of the diagnosis and treatment.

Close Association Between Platelet Biogenesis and Alveolarization of the Developing Lung.

Bronchopulmonary dysplasia (BPD) is a neonatal chronic lung disease characterized by an arrest in alveolar and vascular development. BPD is secondary to lung immaturity, ventilator-induced lung injury, and exposure to hyperoxia in extremely premature infants, leading to a lifelong impairment of lung function. Recent studies indicate that the lung plays an important role in platelet biogenesis. However, the dynamic change of platelet production during lung development and BPD pathogenesis remains to be elucidated. We investigated the dynamic change of platelet parameters in extremely premature infants during BPD development, and in newborn rats during their normal development from birth to adulthood. We further studied the effect of hyperoxia exposure on platelet production and concomitant pulmonary maldevelopment in an experimental BPD rat model induced by prolonged exposure to hyperoxia. We detected a physiological increase in platelet count from birth to 36 weeks postmenstrual age in extremely premature infants, but platelet counts in extremely premature infants who developed BPD were persistently lower than gestational age-matched controls. In line with clinical findings, exposure to hyperoxia significantly decreased the platelet count in neonatal rats. Lung morphometry analysis demonstrated that platelet counts stabilized with the completion of lung alveolarization in rats. Our findings indicate a close association between platelet biogenesis and alveolarization in the developing lung. This phenomenon might explain the reduced platelet count in extremely premature infants with BPD.

Mortality and Morbidity of Infants Born Extremely Preterm at Tertiary Medical Centers in China From 2010 to 2019.

Importance: Extreme prematurity is associated with a substantial burden on health care systems worldwide. However, little is known about the prognosis of infants born extremely preterm in developing countries, such as China. Objective: To describe survival and major morbidity among infants born extremely preterm in China over the past decade. Design, Setting, and Participants: This retrospective cohort study was conducted from January 1, 2010, through December 31, 2019. Included individuals were infants with gestational age less than 28 weeks discharged from 1 of 68 neonatal intensive care units located in 31 provinces in China. Data were analyzed from August through October 2020. Exposure: Extremely preterm birth. Main Outcomes and Measures: Survival to discharge and major morbidity (ie, bronchopulmonary dysplasia, grades III-IV intraventricular hemorrhage, white matter injury, stage II-III necrotizing enterocolitis, sepsis, or severe retinopathy of prematurity) were measured. Results: Among 8514 eligible infants, 5295 (62.2%) were male and 116 infants (2.0%) were small for gestational age (SGA). Overall, 5302 infants (62.3%) survived to discharge. The survival rate was 1 of 21 infants (4.8%) at 22 weeks, 13 of 71 infants (18.3%) at 23 weeks, 144 of 408 infants (35.3%) at 24 weeks, 480 of 987 infants (48.6%) at 25 weeks, 1423 of 2331 infants (61.0%) at 26 weeks, and 3241 of 4692 infants (69.1%) at 27 weeks. Survival increased from 136 of 241 infants (56.4%; 95% CI, 50.1%-62.7%) in 2010 to 1110 of 1633 infants (68.0%; 95% CI, 65.7%-70.2%) in 2019 for infants born at 24 to 27 weeks (mean difference, 11.5%; 95% CI, 4.9%-18.2%; P < .001), without a significant change for infants born at less than 24 weeks. Major morbidity was found in 5999 of 8281 infants overall, for a rate of 72.4%, which increased from 116 of 223 infants (52.0%; 95% CI, 45.4%-58.6%) to 1363 of 1656 infants (82.3%; 95% CI, 80.5%-84.1%) from 2010 to 2019 (mean difference, 30.3%; 95% CI, 23.5%-37.1%, P < .001). Regional variations in survival were identified, with an almost 2-fold increase (1.94-fold; 95% CI, 1.66-2.27; P < .001) from 188 of 474 infants (39.7%) in northwest China to 887 of 1153 infants (76.9%) in north China. Gestational age (adjusted risk ratio [aRR], 1.084; 95% CI, 1.063-1.105; P < .001), birth weight (aRR, 1.028; 95% CI, 1.020-1.036; P < .001), premature rupture of membranes (aRR, 1.025; 95% CI, 1.002-1.048; P = .03), and antenatal steroids (aRR, 1.029; 95% CI, 1.004-1.055; P = .02) were associated with improved survival, while being born SGA (aRR, 0.801; 95% CI, 0.679-0.945; P = .01), being male (aRR, 0.975; 95% CI, 0.954-0.997; P = .02), multiple birth (aRR, 0.955; 95% CI, 0.929-0.982; P = .001), having a mother with gestational diabetes (aRR, 0.946; 95% CI, 0.913-0.981; P = .002), and low Apgar score (aRR, 0.951; 95% CI, 0.925-0.977; P < .001) were found to be risk factors associated with decreased chances of survival. Conclusions and Relevance: This study found that infants born extremely preterm were at increased risk of mortality and morbidity in China, with a survival rate that improved over time and a major morbidity rate that increased. These findings suggest that more active and effective treatment strategies are needed, especially for infants born at gestational age 25 to 27 weeks.

Simultaneous detection of fungal (1,3)-ß-d-glucan and procalcitonin using a dual-label time-resolved fluorescence immunoassay.

Neonatal infectious diseases are a serious threat to the health of newborns. The aim was to establish a new detection method for the simultaneous measurement of (1,3)-ß-d-glucan and procalcitonin in serum for the early screening and efficacy testing of neonatal infectious diseases. We established a sandwich dual-label time-resolved fluorescence immunoassay (TRFIA): anti-(1,3)-ß-d-glucan/procalcitonin antibodies immobilized on 96-well plates captured (1,3)-ß-d-glucan/procalcitonin antigens and then banded together with the detection antibodies labeled with europium(III) (Eu3+ )/samarium(III) (Sm3+ ) chelates. Finally, time-resolved fluorometry was used to measure the fluorescence intensity. The linear correlation coefficient (R2 ) of the (1,3)-ß-d-glucan standard curve was 0.9913, and the R2 of the procalcitonin standard curve was 0.9911. The detection sensitivity for (1,3)-ß-d-glucan was 0.4 pg/mL (dynamic range: 0.6-90 pg/mL), and the average recovery was 101.55%. The detection sensitivity for procalcitonin was 0.02 ng/mL (dynamic range: 0.05-95 ng/mL), and the average recovery was 104.61%. There was a high R2 between the present TRFIA method and a commercially available assay (R2  = 0.9829 for (1,3)-ß-d-glucan and R2  = 0.9704 for procalcitonin). Additionally, the cutoff values for (1,3)-ß-d-glucan and procalcitonin were 23.95 pg/mL and 0.055 ng/mL, respectively. The present TRFIA method has high sensitivity, accuracy, and specificity and is an effective method for early screening and efficient testing of neonatal invasive fungal infection.

Epidemiology and microbiology of late-onset sepsis among preterm infants in China, 2015-2018: A cohort study.

OBJECTIVE: To describe the incidence, case-fatality rate and pathogen distribution of late-onset sepsis (LOS) among preterm infants in China. To investigate risk factors and short-term outcomes associated with LOS caused by Gram-positive bacteria, Gram-negative bacteria and fungi. METHODS: This cohort study included all infants born at <34 weeks' gestation and admitted to 25 tertiary hospitals in 19 provinces in China from May, 2015 to April, 2018. Infants were excluded who died or were discharged within 3 days of being born. RESULTS: A total of 1199 episodes of culture-positive LOS were identified in 1133 infants, with an incidence of 4.4% (1133/25,725). Overall, 15.4% (175/1133) of infants with LOS died and 10.0% (113/1133) of infants died within 7 days of LOS onset. Among 1214 isolated pathogens, Gram-negative bacteria were the most common (51.8%, 629/1214) and fungi accounted for 17.1% (207/1214). Use of central lines, longer duration of antibiotics and previous carbapenem exposure were related to increased risk of fungal LOS compared with Gram-positive bacteria. Gram-negative bacteria LOS was independently associated with increased risk of death, periventricular leukomalacia, bronchopulmonary dysplasia, and necrotizing enterocolitis. Fungal LOS was independently associated with increased risk of periventricular leukomalacia, bronchopulmonary dysplasia and necrotizing enterocolitis. CONCLUSIONS: Late-onset sepsis was a significant cause of morbidity and mortality in Chinese neonatal intensive care units, with a distinct pathogen distribution from industrial countries. Clinical guidelines on the prevention and treatment of LOS should be developed and tailored to these LOS characteristics in Chinese neonatal intensive care units.