BOOK
Bronchopulmonary Dysplasia: An Update, An Issue of Clinics in Perinatology, E-Book
(2016)
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Book Details
Abstract
Bronchopulmonary dysplasia (BPD) as a chronic lung disease affecting preterm infants has been recognized for more than 45 years. However, little progress has been made in the prevention and treatment of the disease. BPD continues to be a major morbidity affecting preterm infants. Studies in pre-adolescent children demonstrate that the abnormal lung function from BPD persists well into childhood. Infants with BPD also have an increased risk for adverse neurodevelopmental outcome. Thus BPD imposes a significant burden of adverse health outcomes in preterm infants.
The major risk factors for BPD are prematurity, mechanical ventilation, exposure to noxious insults such as oxygen, infections. New research data both in basic science and clinical studies have shed light on the pathogenesis, and possible new treatment or management strategies for the future. In the proposed issue of the Clinics in Perinatology, we would like to comprehensively cover BPD both from a basic science and clinical perspective. Our attempt is to balance new information along with classic topics. The proposed authors for the issue are recognized experts in the topic area/s. We hope that the issue will be of interest to a broad array of readership.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | Cover | ||
| Bronchopulmonary Dysplasia: An Update\r | i | ||
| Copyright\r | ii | ||
| Contributors | iii | ||
| CONSULTING EDITOR | iii | ||
| EDITORS | iii | ||
| AUTHORS | iii | ||
| Contents | vii | ||
| Foreword: Why the Bronchopulmonary Dysplasia Improvement Curve Lags Behind\x0B | vii | ||
| Preface: Bronchopulmonary Dysplasia—The Search for Answers Continues\r | vii | ||
| Update on Molecular Biology of Lung Development—Transcriptomics\r | vii | ||
| Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity\r | vii | ||
| Role of Ureaplasma Respiratory Tract Colonization in Bronchopulmonary Dysplasia Pathogenesis: Current Concepts and Update\r | vii | ||
| Biomarkers, Early Diagnosis, and Clinical Predictors of Bronchopulmonary Dysplasia\r | viii | ||
| Evidence-Based Pharmacologic Therapies for Prevention of Bronchopulmonary Dysplasia: Application of the Grading of Recommen ... | viii | ||
| Mechanical Ventilation and Bronchopulmonary Dysplasia\r | viii | ||
| Impact of Nutrition on Bronchopulmonary Dysplasia\r | viii | ||
| Oxygen Saturation Targeting and Bronchopulmonary Dysplasia\r | ix | ||
| Hypoxic Episodes in Bronchopulmonary Dysplasia\r | ix | ||
| Pulmonary Hypertension and Vascular Abnormalities in Bronchopulmonary Dysplasia\r | ix | ||
| Airway Disease and Management in Bronchopulmonary Dysplasia\r | ix | ||
| Newer Imaging Techniques for Bronchopulmonary Dysplasia\r | x | ||
| Bronchopulmonary Dysplasia and Chronic Lung Disease: Stem Cell Therapy\r | x | ||
| The Natural History of Bronchopulmonary Dysplasia: The Case for Primary Prevention\r | x | ||
| PROGRAM OBJECTIVE | xi | ||
| TARGET AUDIENCE | xi | ||
| LEARNING OBJECTIVES | xi | ||
| ACCREDITATION | xi | ||
| DISCLOSURE OF CONFLICTS OF INTEREST | xi | ||
| UNAPPROVED/OFF-LABEL USE DISCLOSURE | xi | ||
| TO ENROLL | xii | ||
| METHOD OF PARTICIPATION | xii | ||
| CME INQUIRIES/SPECIAL NEEDS | xii | ||
| CLINICS IN PERINATOLOGY\r | xiii | ||
| FORTHCOMING ISSUES | xiii | ||
| March 2016 | xiii | ||
| June 2016 | xiii | ||
| September 2016 | xiii | ||
| RECENT ISSUES | xiii | ||
| September 2015 | xiii | ||
| June 2015 | xiii | ||
| March 2015 | xiii | ||
| Foreword: Why the Bronchopulmonary Dysplasia Improvement Curve Lags Behind \r | xv | ||
| REFERENCES | xvii | ||
| Preface: Bronchopulmonary Dysplasia—The Search for Answers Continues \r | xix | ||
| Update on Molecular Biology of Lung Development—Transcriptomics | 685 | ||
| Key points | 685 | ||
| INTRODUCTION | 685 | ||
| DISCUSSION | 686 | ||
| Introduction to Lung Development | 686 | ||
| Molecular Stages of Development | 687 | ||
| Ontogeny of Lung Epithelial Cells | 688 | ||
| Regulation of Diversity of Lung Mesenchyme | 689 | ||
| A Molecular Basis for Dysanapsis? | 690 | ||
| Integrated Genomics Analysis of Development | 690 | ||
| A Molecular Atlas for Lung Development | 691 | ||
| Transcriptomics of Bronchopulmonary Dysplasia | 691 | ||
| REFERENCES | 692 | ||
| Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity | 697 | ||
| Key points | 697 | ||
| INTRODUCTION | 697 | ||
| INFLAMMATION AS A MECHANISM FOR RESPIRATORY MORBIDITY | 699 | ||
| PRENATAL INDUCTION OF INFLAMMATION AND RESPIRATORY MORBIDITY | 699 | ||
| Chorioamnionitis | 699 | ||
| Other Prenatal Proinflammatory Exposures | 701 | ||
| POSTNATAL INDUCTION OF INFLAMMATION AND RESPIRATORY MORBIDITY | 701 | ||
| Oxygen and Mechanical Ventilation | 701 | ||
| Bacterial Infection and Sepsis | 701 | ||
| Viral Infections | 701 | ||
| Neonatal Cytomegalovirus | 702 | ||
| Respiratory Syncytial Virus and Other Common Viruses | 703 | ||
| SUSCEPTIBILITY FACTORS FOR ENHANCED INFLAMMATION | 704 | ||
| Genetics | 704 | ||
| Alterations in Immune Responses Due to Developmental Window of Preterm Delivery | 704 | ||
| Evidence for Lymphocytic Abnormalities in Premature Infants with Lung Disease | 705 | ||
| Age at First Infection | 706 | ||
| Altered Establishment of Colonizing Microbiota | 708 | ||
| REFERENCES | 709 | ||
| Role of Ureaplasma Respiratory Tract Colonization in Bronchopulmonary Dysplasia Pathogenesis | 719 | ||
| Key points | 719 | ||
| INTRODUCTION | 719 | ||
| UREAPLASMA SPECIES | 720 | ||
| Ureaplasma Species Virulence Factors | 721 | ||
| Host Response to Ureaplasma Infection | 721 | ||
| Ureaplasma Species as Perinatal Pathogens Causing Preterm Birth | 722 | ||
| EPIDEMIOLOGIC EVIDENCE FOR ROLE OF UREAPLASMA SPECIES IN BRONCHOPULMONARY DYSPLASIA PATHOGENESIS | 722 | ||
| Characteristics of Infants with Ureaplasma Respiratory Tract Colonization | 722 | ||
| Association of Ureaplasma Respiratory Tract Colonization and Bronchopulmonary Dysplasia | 723 | ||
| Ureaplasma Species and Lung Inflammation in the Developing Lung: Animal Studies | 725 | ||
| DIAGNOSTIC METHODS | 726 | ||
| Culture Methods | 726 | ||
| Colorimetric Assays | 727 | ||
| Molecular Diagnostic Methods | 727 | ||
| THERAPEUTIC CONSIDERATIONS | 727 | ||
| Macrolide Antibiotics | 727 | ||
| Efficacy Studies | 727 | ||
| Pharmacokinetics Studies | 732 | ||
| BEST PRACTICES: CURRENT RECOMMENDATIONS AND THE FUTURE | 732 | ||
| REFERENCES | 732 | ||
| Biomarkers, Early Diagnosis, and Clinical Predictors of Bronchopulmonary Dysplasia | 739 | ||
| Key points | 739 | ||
| INTRODUCTION | 739 | ||
| WHY DO WE NEED BIOMARKERS OR PREDICTORS? | 740 | ||
| BIOMARKERS | 741 | ||
| Clinical Predictors as Biomarkers of Bronchopulmonary Dysplasia | 741 | ||
| Imaging Biomarkers of Bronchopulmonary Dysplasia | 742 | ||
| Chest radiographs | 742 | ||
| Chest computed tomography scans | 743 | ||
| Chest MRI | 743 | ||
| Echocardiogram for the diagnosis of pulmonary hypertension in bronchopulmonary dysplasia | 744 | ||
| Lung Function Biomarkers | 744 | ||
| Biofluid Biomarkers | 744 | ||
| Blood | 744 | ||
| Inflammatory markers | 745 | ||
| Angiogenic growth factors | 745 | ||
| Epithelial and fibrotic markers | 745 | ||
| Markers of pulmonary hypertension in bronchopulmonary dysplasia | 745 | ||
| Tracheal aspirate or bronchoalveolar lavage | 746 | ||
| Inflammatory, fibrotic and epithelial markers | 746 | ||
| Oxidant injury markers | 746 | ||
| Angiogenic growth factors | 747 | ||
| Other factors | 747 | ||
| Urine | 747 | ||
| Exhaled Breath Condensates as Biomarkers | 747 | ||
| Genomic Biomarkers | 747 | ||
| Differences in the genome | 748 | ||
| Differences in gene expression | 748 | ||
| Respiratory Microbiome as a Biomarker of Bronchopulmonary Dysplasia | 748 | ||
| THE FUTURE OF BRONCHOPULMONARY DYSPLASIA DIAGNOSTICS AND BIOMARKERS | 749 | ||
| REFERENCES | 749 | ||
| Evidence-Based Pharmacologic Therapies for Prevention of Bronchopulmonary Dysplasia | 755 | ||
| Key points | 755 | ||
| INTRODUCTION | 755 | ||
| Grading of Recommendations Assessment, Development, and Evaluation Framework | 756 | ||
| METHODS | 756 | ||
| Search Strategy | 756 | ||
| Study Selection | 757 | ||
| Clinical Trials Registry Search | 757 | ||
| SUMMARY OF THE EVIDENCE FOR INDIVIDUAL THERAPIES | 757 | ||
| Azithromycin | 757 | ||
| Systematic search results | 758 | ||
| Risk-to-benefit comparison | 758 | ||
| Overall quality of the evidence | 758 | ||
| Recommendation | 758 | ||
| Caffeine | 758 | ||
| Systematic search results | 761 | ||
| Azithromycin | 761 | ||
| Caffeine | 761 | ||
| Dexamethasone | 761 | ||
| Vitamin A | 761 | ||
| Risk-to-benefit comparison | 764 | ||
| Timing of caffeine initiation | 764 | ||
| Quality of the evidence | 764 | ||
| Recommendation | 764 | ||
| Dexamethasone | 765 | ||
| Systematic search results | 765 | ||
| Risk-to-benefit comparison | 765 | ||
| Quality of the evidence | 769 | ||
| Recommendation | 772 | ||
| Vitamin A | 772 | ||
| Systematic search results | 772 | ||
| Risk-to-benefit comparison | 772 | ||
| Quality of the evidence | 773 | ||
| Recommendation | 774 | ||
| CLINICAL TRIALS REGISTRY SEARCH RESULTS | 774 | ||
| SUMMARY | 774 | ||
| REFERENCES | 774 | ||
| Mechanical Ventilation and Bronchopulmonary Dysplasia | 781 | ||
| Key points | 781 | ||
| INTRODUCTION | 781 | ||
| WHAT IS VENTILATOR-ASSOCIATED LUNG INJURY? | 783 | ||
| MITIGATING VENTILATOR-ASSOCIATED LUNG INJURY | 784 | ||
| IMPORTANCE OF THE GOLDEN FIRST HOUR | 784 | ||
| POSITIVE END-EXPIRATORY PRESSURE IN THE DELIVERY ROOM | 785 | ||
| SUSTAINED INFLATION | 785 | ||
| HYPEROXIC INJURY | 785 | ||
| NONINVASIVE RESPIRATORY SUPPORT | 786 | ||
| LESS INVASIVE SURFACTANT ADMINISTRATION | 787 | ||
| LUNG-PROTECTIVE STRATEGIES OF MECHANICAL VENTILATION | 787 | ||
| Volume-targeted Ventilation | 787 | ||
| Importance of the Open Lung Strategy | 789 | ||
| High-frequency Ventilation | 789 | ||
| PUTTING IT ALL TOGETHER | 791 | ||
| SUMMARY | 792 | ||
| REFERENCES | 792 | ||
| Impact of Nutrition on Bronchopulmonary Dysplasia | 797 | ||
| Key points | 797 | ||
| INTRODUCTION | 797 | ||
| INTRAUTERINE GROWTH AND PULMONARY OUTCOMES | 798 | ||
| POSTNATAL GROWTH AND CLINICAL OUTCOMES | 798 | ||
| GROWTH OUTCOMES OF INFANTS WITH BRONCHOPULMONARY DYSPLASIA | 799 | ||
| CAUSE OF POOR GROWTH IN INFANTS WITH BRONCHOPULMONARY DYSPLASIA | 799 | ||
| NUTRITIONAL INTERVENTIONS TO PREVENT BRONCHOPULMONARY DYSPLASIA | 799 | ||
| IMPACT OF TREATMENT FOR BRONCHOPULMONARY DYSPLASIA ON NUTRITIONAL STATUS | 800 | ||
| NUTRITIONAL STRATEGIES TO OPTIMIZE GROWTH | 800 | ||
| POSTDISCHARGE MANAGEMENT OF INFANTS WITH BRONCHOPULMONARY DYSPLASIA | 801 | ||
| RESEARCH OPPORTUNITIES IN THE ROLE OF NUTRITION AND LUNG DISEASE | 801 | ||
| REFERENCES | 803 | ||
| Oxygen Saturation Targeting and Bronchopulmonary Dysplasia | 807 | ||
| Key points | 807 | ||
| INTRODUCTION | 807 | ||
| OXYGEN MONITORING | 808 | ||
| OXYGEN TOXICITY | 809 | ||
| HISTORY OF OXYGEN MONITORING IN PRETERM INFANTS | 811 | ||
| TRIALS OF OXYGEN SATURATION TARGETING AND BRONCHOPULMONARY DYSPLASIA | 812 | ||
| THE NEONATAL OXYGENATION PROSPECTIVE META-ANALYSIS TRIALS OF OXYGEN SATURATION TARGETING | 813 | ||
| THE NEONATAL OXYGENATION PROSPECTIVE META-ANALYSIS TRIALS AND BRONCHOPULMONARY DYSPLASIA | 815 | ||
| WHAT CAN BE CONCLUDED FROM THE EVIDENCE PUBLISHED TO DATE? | 817 | ||
| OTHER ISSUES THAT ARISE | 818 | ||
| REFERENCES | 819 | ||
| Hypoxic Episodes in Bronchopulmonary Dysplasia | 825 | ||
| Key points | 825 | ||
| INTRODUCTION | 825 | ||
| ROLE OF IMMATURE RESPIRATORY CONTROL IN BRONCHOPULMONARY DYSPLASIA | 826 | ||
| Data from Animal Models | 826 | ||
| Data from Human Infants | 828 | ||
| CONSEQUENCES OF INTERMITTENT HYPOXIC EPISODES | 829 | ||
| ROLE OF THE IMMATURE AIRWAY | 831 | ||
| ROLE OF PULMONARY VASOCONSTRICTION | 833 | ||
| SUMMARY | 834 | ||
| REFERENCES | 834 | ||
| Pulmonary Hypertension and Vascular Abnormalities in Bronchopulmonary Dysplasia | 839 | ||
| Key points | 839 | ||
| INTRODUCTION | 840 | ||
| PATHOGENESIS OF PULMONARY VASCULAR DISEASE IN BRONCHOPULMONARY DYSPLASIA | 841 | ||
| DIAGNOSIS AND EPIDEMIOLOGY OF PULMONARY VASCULAR DISEASE IN PRETERM INFANTS | 842 | ||
| RISK FACTORS FOR PERIPHERAL VASCULAR DISEASE AND PULMONARY HYPERTENSION IN PRETERM INFANTS | 845 | ||
| OTHER PULMONARY VASCULAR AND CARDIAC ABNORMALITIES ASSOCIATED WITH BRONCHOPULMONARY DYSPLASIA | 846 | ||
| TREATMENT OF PULMONARY HYPERTENSION IN BRONCHOPULMONARY DYSPLASIA | 847 | ||
| SUMMARY | 850 | ||
| REFERENCES | 850 | ||
| Airway Disease and Management in Bronchopulmonary Dysplasia | 857 | ||
| Key points | 857 | ||
| INTRODUCTION | 857 | ||
| RESPIRATORY SUPPORT OF CHILDREN WITH BRONCHOPULMONARY DYSPLASIA | 858 | ||
| WEANING FROM NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE | 858 | ||
| HEATED HUMIDIFIED HIGH-FLOW NASAL CANNULA THERAPY IN CHILDREN | 859 | ||
| High-flow Nasal Cannula for Primary Respiratory Support | 859 | ||
| High-flow Nasal Cannula in Extremely Preterm Infants After Extubation | 859 | ||
| POSITIVE PRESSURE VENTILATION FOR TREATMENT OF APNEA OF PREMATURITY | 860 | ||
| OUTCOMES OF CHILDREN WITH SEVERE BRONCHOPULMONARY DYSPLASIA WHO ARE VENTILATOR DEPENDENT AT HOME | 860 | ||
| Predischarge Planning Includes the Following | 861 | ||
| Postdischarge Management | 861 | ||
| Prevention of Acute Superimposed on Chronic Respiratory Failure | 861 | ||
| Prevention of Gradual Respiratory Decompensation | 861 | ||
| AIRWAY MANAGEMENT OF CHILDREN WITH BRONCHOPULMONARY DYSPLASIA | 862 | ||
| SUBGLOTTIC STENOSIS | 863 | ||
| TRACHEOMALACIA AND TRACHEOBRONCHOMALACIA | 865 | ||
| INDICATIONS FOR TRACHEOTOMY PLACEMENT | 865 | ||
| TRACHEOTOMY TECHNIQUES AND GUIDELINES IN NEONATES | 866 | ||
| TRACHEOTOMY IN THE SETTING OF CHRONIC VENTILATOR DEPENDENCY | 867 | ||
| TIMING OF TRACHEOTOMY AND OUTCOMES IN PRETERM INFANTS | 868 | ||
| REFERENCES | 868 | ||
| Newer Imaging Techniques for Bronchopulmonary Dysplasia | 871 | ||
| Key points | 871 | ||
| INTRODUCTION | 871 | ||
| CHEST RADIOGRAPH | 872 | ||
| COMPUTERIZED TOMOGRAPHY | 873 | ||
| NUCLEAR MEDICINE | 876 | ||
| MRI | 876 | ||
| Conventional 1H MRI | 877 | ||
| Hyperpolarized-Gas MRI | 880 | ||
| SUMMARY | 882 | ||
| REFERENCES | 882 | ||
| Bronchopulmonary Dysplasia and Chronic Lung Disease | 889 | ||
| Key points | 889 | ||
| INTRODUCTION | 890 | ||
| MESENCHYMAL STROMAL CELLS | 890 | ||
| DISRUPTION OF MESENCHYMAL STROMAL CELL HOMEOSTASIS IN THE EVENTS THAT LEAD TO BRONCHOPULMONARY DYSPLASIA | 890 | ||
| PRECLINICAL EVIDENCE OF MESENCHYMAL STROMAL CELL EFFECTS ON ARRESTED LUNG DEVELOPMENT | 890 | ||
| Bronchopulmonary Dysplasia is an Arrest in Lung Development | 890 | ||
| Animal Models of Arrested Lung Development: the Hyperoxia-Induced Lung Injury | 890 | ||
| Treatment with Mesenchymal Stromal Cells Ameliorates Hyperoxia-Induced Arrest in Lung Growth | 891 | ||
| Prophylactic treatment | 891 | ||
| Rescue treatment | 892 | ||
| PRECLINICAL EVIDENCE OF MESENCHYMAL STROMAL CELL EFFECTS ON DISRUPTED VASCULAR DEVELOPMENT | 892 | ||
| Hypoplastic Vascular Bed in Human Bronchopulmonary Dysplasia | 892 | ||
| Hyperoxia Induces Pulmonary Vascular Disruption and Pulmonary Hypertension | 892 | ||
| Mesenchymal Stromal Cells Treatment Mitigates Hyperoxia-Related Pulmonary Hypertension | 895 | ||
| Prophylactic treatment | 895 | ||
| Rescue treatment | 895 | ||
| PRECLINICAL EVIDENCE OF MESENCHYMAL STROMAL CELL EFFECTS ON INFLAMMATION, OXIDATIVE STRESS, AND FIBROSIS | 895 | ||
| Mechanisms of Cellular Damage in Bronchopulmonary Dysplasia | 895 | ||
| Hyperoxia Induces Lung Inflammation, Fibrosis and Oxidative Stress | 895 | ||
| Mesenchymal Stromal Cells Reduce Hyperoxia-Induced Inflammation, Fibrosis, and Oxidative Stress | 896 | ||
| Prophylactic treatment | 896 | ||
| Rescue treatment | 896 | ||
| LONG-TERM CONSIDERATIONS FROM PRECLINICAL STUDIES | 896 | ||
| Life-Long Consequences of Bronchopulmonary Dysplasia | 896 | ||
| Animals Exposed to Hyperoxia in the Neonatal Period Show Long-Term Features of Bronchopulmonary Dysplasia | 896 | ||
| Beneficial Effects of Mesenchymal Stromal Cells Persist in Adult Rats | 896 | ||
| Mesenchymal Stromal Cells Display Long-Term Safety in the Hyperoxia-Induced Lung Injury | 896 | ||
| CONCLUSIONS FROM PRECLINICAL DATA | 897 | ||
| MECHANISM OF ACTION OF MESENCHYMAL STROMAL CELLS | 897 | ||
| Homing to Site of Injury and Regeneration | 897 | ||
| Paracrine Effect | 899 | ||
| Immunomodulatory Properties | 900 | ||
| CLINICAL TRANSLATION | 900 | ||
| EFFICACY OF MESENCHYMAL STROMAL CELL TREATMENT | 900 | ||
| Factors Affecting Efficacy of Stem Cell Treatment: Considerations | 901 | ||
| Timing | 901 | ||
| Rescue administration or treatment of established bronchopulmonary dysplasia | 901 | ||
| Prophylactic or early administration | 901 | ||
| Treatment of evolving bronchopulmonary dysplasia | 901 | ||
| Route of administration | 901 | ||
| Systemic administration | 901 | ||
| Endotracheal administration | 901 | ||
| Dose | 904 | ||
| Source | 904 | ||
| Adult sources: bone marrow and adipose tissue | 904 | ||
| Perinatal sources | 904 | ||
| Practical aspects of mesenchymal stromal cell manufacturing | 904 | ||
| Passage number | 904 | ||
| Culture conditions | 905 | ||
| Type of transplantation | 905 | ||
| Autologous | 905 | ||
| Allogeneic | 905 | ||
| SAFETY OF MESENCHYMAL STROMAL CELL TREATMENT | 905 | ||
| SUMMARY | 906 | ||
| REFERENCES | 906 | ||
| The Natural History of Bronchopulmonary Dysplasia | 911 | ||
| Key points | 911 | ||
| INTRODUCTION | 911 | ||
| NATURAL HISTORY OF PULMONARY FUNCTION TESTING MEASUREMENTS | 912 | ||
| Neonatal Studies | 913 | ||
| Infants | 913 | ||
| Children and Adolescents | 921 | ||
| Adults | 921 | ||
| NATURAL HISTORY OF RESPIRATORY SYMPTOMS IN PATIENTS WITH BRONCHOPULMONARY DYSPLASIA: CLINICAL PULMONARY OUTCOMES | 922 | ||
| Infants | 922 | ||
| Children | 922 | ||
| Adolescents and Young Adults | 923 | ||
| EVOLUTION OF RADIOGRAPHIC/HIGH-RESOLUTION COMPUTED TOMOGRAPHY CHANGES | 923 | ||
| EVOLUTION OF EXERCISE TOLERANCE THROUGH ADULTHOOD | 924 | ||
| NEED FOR PRIMARY PREVENTION OF BRONCHOPULMONARY DYSPLASIA | 924 | ||
| The Challenge of Defining a Healthy Lung in the Premature Infant | 924 | ||
| Causal Pathways of Bronchopulmonary Dysplasia | 925 | ||
| FUTURE GOALS AND RESEARCH PRIORITIES FOR BRONCHOPULMONARY DYSPLASIA PREVENTION | 925 | ||
| REFERENCES | 927 | ||
| Index | 933 |