End-tidal carbon monoxide concentrations measured within 48 hours of birth predict hemolytic hyperbilirubinemia.

OBJECTIVES: To determine, among neonates at-risk for hyperbilirubinemia, whether measuring end-tidal carbon monoxide concentration (ETCOc) twice before 48 hours could identify those who would develop hyperbilirubinemia and differentiate hemolytic vs. non-hemolytic causes. METHODS: Prospective study on neonates meeting criteria "at-risk for hyperbilirubinemia." Routine bilirubin measurements and 10-day follow-up were used to categorize neonates as; (1) normal (no hyperbilirubinemia, all bilirubins <95th percentile of Bhutani nomogram), (2) having hemolytic hyperbilirubinemia (bilirubin ≥95th percentile, DAT+, elevated retic, or G6PD+), or (3) having non-hemolytic hyperbilirubinemia. RESULTS: 386 neonates were enrolled. 321 (83%) did not develop hyperbilirubinemia and 65 (17%) did, of which 29 were judged hemolytic and 36 non-hemolytic. High ETCOc differentiated the hemolytic group (p < 0.001). First-day ETCOc correlated with bilirubin and with reticulocyte count (r = 0.896 and 0.878) and sensitivity and specificity for predicting hyperbilirubinemia were excellent (83% and 95%). CONCLUSIONS: ETCO measurement in the first 48 hours after birth predicts hemolytic hyperbilirubinemia.

Diameter of ductus arteriosus on postnatal Day 7 is associated with late pulmonary hypertension in extremely preterm infants.

OBJECTIVES: A clinically feasible biomarker for pulmonary hypertension (PH) prediction is still lacking. Thus, we aim to assess the association between ductus arteriosus (DA) diameter and PH in extremely preterm infants. STUDY DESIGN: A retrospective case-control study was performed to compare the diameter of DA in infants with and without late PH. Propensity scores were calculated to match the gestational age in two groups with a match ratio of 1:2. The diameter of DA was measured by echocardiography on postnatal Days 3 and 7. RESULTS: A total of 91 infants were included in the study. The diagnosis of late PH was made in 32 infants between postnatal life of 28-159 days. Univariable analysis showed that late PH was associated with birth weight, invasive mechanical ventilation, hemodynamically significant PDA (hsPDA), duration of PDA exposure, the rate of surgical ligation, and diameter of DA on postnatal Days 3 and 7. After adjusting for these selected factors, the diameter of DA measured on postnatal Day 7 was independently associated with the risk of late PH (odds ratios: 5.511, 95% confidence interval: 1.552-19.562, p = .008). Receiver operator curve analysis indicated that 1.95 mm in DA diameter on postnatal Day 7 was the cutoff value for late PH with an area under the curve of 0.697. CONCLUSIONS: Our findings suggest that DA diameter (larger than or equal to 1.95 mm) on postnatal Day 7 might serve as a predictor for late PH in extremely preterm infants.

The Predictive Value of Lung Ultrasound Score on Hemodynamically Significant Patent Ductus Arteriosus among Neonates ≤25 Weeks.

Lung ultrasound (LU) is increasingly used to diagnose and monitor neonatal pulmonary disorders; however, its role in hemodynamically significant patent ductus arteriosus (hsPDA) has not been elucidated. This prospective study investigated the predictive value of the LU score (LUS) for hsPDA in preterm infants with gestational age (GA) ≤ 25 weeks. Preterm infants with GA ≤ 25 weeks were enrolled in this study. LU was conducted on the fourth day of life (DOL). Six lung regions in every lung were scanned, with each region rated as 0-4 points. The performance of the LUS in predicting hsPDA among infants aged ≤25 weeks was analyzed by plotting the receiver operating characteristic (ROC) curve. A total of 81 infants were included in this study. GA, birth weight (BW), gender, Apgar score, delivery mode, antenatal steroids, meconium-stained amniotic fluid, premature rapture of membrane, and early-onset sepsis were not significantly different, but infants in the hsPDA group had increased LUS (38.2 ± 2.8 vs. 30.3 ± 4.3, p < 0.001) compared with non-hsPDA group. The area under the ROC curve (AUC) value of the LUS on the fourth DOL was 0.94 (95% CI: 0.93-0.99) in predicting hsPDA. The LUS threshold at 33 achieved 89% sensitivity and 83% specificity, with the positive and negative predictive values (PPV and NPV) being 87 and 86%, respectively. The LUS can predict hsPDA in extremely preterm infants at an early stage.

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.

Mixed Feedings and Necrotizing Enterocolitis: The Proportion of Human Milk Matters.

Objectives: Impact of the proportion of human milk (HM) in mixed feeding on necrotizing enterocolitis (NEC) remains unknown. This study explores the influence of different proportions of HM on the risk of NEC. Materials and Methods: A retrospective cohort study was performed in infants with very low birth weight (VLBW). A spline smoothing curve was used to evaluate the dose-dependent association between HM and the risk of NEC. Univariate and multivariate analyses were performed to detect the association between the proportion of HM and NEC. Results: Twenty-four infants developed NEC, with 4 (1.9%) in the high HM group, 18 (28.1%) in the low HM group, and 2 (8.0%) in the exclusive formula group (p < 0.001). After adjusting for the relevant confounders, low HM (proportion of HM ≤54%) (OR 33.526, 95% confidential interval [CI] 7.183-156.475, p < 0.001) and exclusive formula feeding (OR 8.493, 95% CI 1.107-65.187, p = 0.040) significantly increased the incidence of NEC, compared with the high HM feeding (proportion of HM >54%). Similarly, low HM was independently associated with an increased risk of feeding intolerance compared with high HM feeding (OR 4.383, 95% CI 2.243-8.564, p < 0.001). Conclusion: A low ratio of HM (≤54%) significantly increased the risk of intestinal complications in VLBW infants. Mixed feeding should relate to the proportion of HM in premature infants.

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.

Enteral Feeding/Total Fluid Intake Ratio Is Associated With Risk of Bronchopulmonary Dysplasia in Extremely Preterm Infants.

Background: Nutrition is an essential factor in preventing and managing bronchopulmonary dysplasia (BPD), a multifactorial chronic respiratory disease in premature infants. This study examined the association between nutritional intakes during the first 2 weeks of life and BPD in extremely preterm infants. Methods: A retrospective single-center cohort study was performed in infants born <28 weeks' gestational age or with a birth weight <1,000 g. Intake of energy and ratio of enteral feeding/ total fluid intake during the first 2 weeks of life and association with outcome of BPD were examined. Results: 134 infants were included in our study, and 43 infants (32.1%) developed BPD. During the first 2 weeks of life, the average of total caloric intake and the ratio of enteral feeding/ total fluid intake were significantly lower in the BPD group (total caloric intake:91.90 vs. 95.72 kcal/kg/d, p < 0.05, ratio of enteral feeding/total fluid intake: 0.14 vs. 0.18, p < 0.05), while the average of total fluid intake, caloric and protein intake from parenteral nutrition did not differ between the groups. The ratio of enteral feeding/ total fluid intake during the second week were significantly lower in the BPD group (0.21 vs. 0.28, p < 0.05), while this ratio during the first week did not differ between the groups. An increase of 10% in the ratio of enteral feeding/ total fluid intake during the second week of life significantly reduced the risk of BPD (OR 0.444, 95% CI: 0.270-0.731). Conclusions: A higher ratio of enteral feeding/ total fluid intake was associated with a lower risk for BPD. Early and rapidly progressive enteral nutrition should be encouraged in extremely preterm infants in the absence of feeding intolerance.

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.

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.

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.

[Influence of premature rupture of membranes on the early prognosis of extremely premature infants].

OBJECTIVE: To study the influence of premature rupture of membranes (PROM) on the early prognosis of extremely premature infants, and to provide a basis for the management of extremely premature infants and prenatal consultation. METHODS: A total of 179 extremely premature singleton infants who were born from 2017 to 2019 were enrolled. According to the presence or absence of PROM, they were divided into two groups: PROM group (n=69) and non-PROM group (n=110). A statistical analysis was performed for maternal data and early prognostic indicators. RESULTS: Compared with the non-PROM group, the PROM group had significantly higher incidence rates of earlyonset sepsis and necrotizing enterocolitis (NEC) (P < 0.05) and significantly lower rate of use of pulmonary surfactant and incidence rate of hemodynamically significant patent ductus arteriosus (P < 0.05). The multivariate logistic regression analysis showed that chorioamnionitis was an independent risk factor for early-onset sepsis and NEC (OR=11.062 and 9.437 respectively, P < 0.05), and PROM was an independent protective factor against the use of pulmonary surfactant (OR=0.363, P < 0.05). CONCLUSIONS: PROM increases the incidence rates of early-onset sepsis and NEC in extremely premature infants and does not increase the incidence rates of other adverse outcomes. For pregnant women with PROM at the risk of extremely preterm delivery, prevention of miscarriage and chorioamnionitis is recommended to prolong gestational weeks, reduce the incidence rate of infection, and thus improve the outcome of extremely premature infants.

[Clinical value of droplet digital PCR in rapid diagnosis of invasive fungal infection in neonates].

OBJECTIVE: To evaluate the clinical value of droplet digital PCR (ddPCR) in rapid and accurate diagnosis of invasive fungal infection (IFI) in neonates. METHODS: The highly conserved sequence of fungi 18S RNA was selected as the target sequence, and primers were designed to establish a ddPCR fungal detection system. Blood samples were collected from 83 neonates with high-risk factors for IFI and/or related clinical symptoms in the neonatal intensive care unit (NICU) of a hospital in Shenzhen, China. Blood culture and ddPCR were used for fungal detection. RESULTS: The ddPCR fungal detection system had a specificity of 100% and a sensitivity of 3.2 copies/µL, and had a good reproducibility. Among the 22 blood samples from neonates with a confirmed or clinical diagnosis of IFI, 19 were detected positive by ddPCR. Among the 61 blood samples from neonates who were suspected of IFI or had no IFI, 2 were detected positive by ddPCR. CONCLUSIONS: The ddPCR technique can be used for the detection of neonatal IFI and is a promising tool for the screening and even diagnosis of neonatal IFI.

Randomized, controlled trial comparing laryngeal mask versus endotracheal intubation during neonatal resuscitation---a secondary publication.

BACKGROUND: This study aimed to study the feasibility, efficacy and safety of using laryngeal mask (LM) ventilation compared with endotracheal intubation (ETI) during neonatal resuscitation. METHODS: Neonates with a heart rate below 60 beats per minute despite 30 s of face mask ventilation were assigned quasi-randomly (odd/even birth date) to LM (n = 36) or ETI (n = 32) ventilation. Differences in first attempt insertion success, insertion time, Apgar score, resuscitation outcome, and adverse effects were compared. RESULTS: There were no significant differences in first attempt at successful insertion (LM, 94.4 % vs. ETI, 90.6 %), insertion time (LM, 7.58 ± 1.16 s vs. ETI, 7.89 ± 1.52 s), Apgar score at 1 and 5 min, response time, ventilation time, successful resuscitation (LM, 86.1 % vs. ETI,  96.9 %), and adverse events (LM, n =3 vs. ETI, n =4) between groups. CONCLUSIONS: Laryngeal mask ventilation is an effective alternative to endotracheal intubation during resuscitation of depressed newborns who do not respond to face-mask ventilation. During an emergency, laryngeal mask ventilation may be a preferred technique for medical staff who are unable to acquire or maintain endotracheal intubation skills. TRIAL REGISTRATION: Current Controlled Trials ChiCTR-IOQ-15006488. Registered on 2 June 2015.

A prospective evaluation of the efficacy of the laryngeal mask airway during neonatal resuscitation.

OBJECTIVE: To study the feasibility, efficacy and safety of using the laryngeal mask airway (LMA) in neonatal resuscitation. METHODS: In total, 369 neonates (gestational age ≥ 34 weeks, expected birth weight ≥2.0 kg) requiring positive pressure ventilation at birth were quasi-randomised to resuscitation by LMA (205 neonates) or bag-mask ventilation (164 neonates). RESULTS: (1) Successful resuscitation rate was higher with the LMA compared with bag-mask ventilation (P<0.001) and the total ventilation time was shorter with the LMA than with bag-mask ventilation (P<0.001). Seven of nine neonates with an Apgar score of 2 or 3 at 1 min after birth were successfully resuscitated in the LMA group, while in the BMV group all six neonates with an Apgar score of 2 or 3 at 1 min required tracheal intubation and ventilation. In neonates with an Apgar score of 4 or 5 at 1 min after birth, successful resuscitation rate with the LMA was higher than with bag-mask ventilation (P<0.01). (2) Successful insertion rate of the LMA at the first attempt was 98.5% and the insertion time was 7.8 s ± 2.2 s. There were few adverse events (vomiting and aspiration) in the LMA group. CONCLUSION: The LMA is safe, effective and easy to implement for the resuscitation of neonates with a gestational age of 34 or, more weeks.