Optimized growth and reduced morbidity in preterm infants : focus on nutrition and saturation targets

Preterm birth alters the conditions during an important period of growth and organ maturation. Extremely preterm infants have a high risk of developing morbidity. Retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) originate in a disturbed retinal and pulmonary development. Associations between nutrition and risk of ROP and BPD have been demonstrated in some previous studies. Practical guidelines published 2005 included recommendations of higher early macronutrient intakes after preterm birth, compared to previous guidelines. One well known risk factor for ROP is oxygen exposure. As a result of five coordinated randomized trials, European saturation target guidelines were revised 2013. The objective of this thesis is to study neonatal practices potentially associated with the risk of developing ROP and BPD. In addition, this thesis examines the adherence to implemented new recommendations of nutritional intakes and saturation targets. The overall aim is to increase the quality of care, in order to improve outcome in the high-risk population of extremely preterm infants. Paper I examined growth patterns in a large cohort of infants born in gestational age (GA) 23 0/7 to 30 6/7 weeks. Longitudinal data were used to investigate differences in growth patterns. The results demonstrated reduced postnatal weight gain in infants who developed ROP and BPD compared to infants without these diseases. The growth patterns differed depending on gestational age and postnatal age. Paper II used detailed nutritional data from infants born between 2004 and 2011 at GA <27 weeks to study whether early energy and protein intakes were associated with initial growth and risk for ROP and BPD. The results showed that higher intakes of energy and protein were associated with improved weight development the first week of life. Increased energy intake during postnatal days 7 to 27 was associated with a reduced risk of ROP among infants with fewer than ten days of mechanical ventilation. Increased energy and protein intake during postnatal days 7 to 27 was associated with a reduced risk of BPD among infants born during 2008 to 2011. Paper III showed that nutritional intakes have increased continuously during 2004 to 2011 in Stockholm. This coincided with implementation of a bundle of interventions aiming at improved nutrition. During 2004 to 2009 the majority infants had lower protein intakes the first postnatal days than the then prevailing guidelines recommended. Paper IV studied peripheral oxygen saturation in infants born at GA 23 0/7 to 30 6/7 with two different saturation targets and alarm limits. Higher saturation target and tighter alarm limits were associated with an increased proportion of time within the target range and a reduced oxygen saturation variability. Mean oxygen saturation and the proportion of time with hyperoxia were increased with the higher target range. In conclusion, this thesis highlights the importance of neonatal practices. Increased early nutritional intakes are associated with reduced initial growth restriction and morbidity. Poor postnatal weight gain is a marker for disease. Improved nutritional regimen and enhanced focus on postnatal growth may improve outcomes for extremely preterm infants. It is important to monitor adherence to guidelines as there is room for further improvement in quality of care. LIST OF SCIENTIFIC PAPERS I. Cohort study of growth patterns by gestational age in preterm infants developing morbidity Klevebro S, Lundgren P, Hammar U, Smith L E, Bottai M, Domellöf M, Löfqvist C, Hallberg B, Hellström A BMJ Open. 2016;6(11):e012872. II. Early energy and protein intakes and associations with growth, BPD and ROP in extremely preterm infants Klevebro S, Westin V, Stoltz Sjöström E, Norman M, Domellöf M, Edstedt Bonamy A-K, Hallberg B Submitted Manuscript III. Improved nutrition for extremely preterm infants – A population based observational study Westin V, Klevebro S, Domellöf M, Vanpée M, Hallberg B, Stoltz Sjöström E Clinical Nutrition ESPEN. 2018;23:245-251. IV. Altered oxygen saturation targets, alarm limits and peripheral oxygen saturation Klevebro S, Hammar U, Holmström G, Bottai M, Hellström A, Hallberg B Submitted Manuscript CONTENTS 1 BACKGROUND . 1 1.1 PREMATURITY . 1 1.1.1 Incidence and Definitions . 1 1.1.2 Mortality . 1 1.2 DEVELOPMENT OF NEONATAL CARE . 2 1.2. 1 Advances in neonatal care . 2 1.2. 2 Implementation of knowledge . 3 1.3 NUTRITION . 4 1.3.1 Energy . 5 1.3.2 Amino acids and protein . 5 1.3.3 Protein to energy ratio . 6 1.3. 4 Carbohydrates and lipids . 6 1.3. 5 Other important factors for growth . 6 1.3. 6 Enteral nutrition . 7 1.4 GROWTH . 7 1.4. 1 Intrauterine growth . 7 1.4. 2 Growth charts . 7 1.4. 3 Growth rate . 9 1.4. 4 Intrauterine growth restriction . 9 1.5 ORGAN DEVELOPMENT AND MORBIDITY . 10 1.5. 1 Retinal development and Retinopathy of prematurity . 10 1.5. 2 Pulmonary development and Bronchopulmonary dysplasia . 12 1.5. 3 Other morbidities . 12 1.6 NUTRITION & GROWTH, ASSOCIATIONS WITH ROP & BPD . 13 1.6. 1 Growth and ROP . 13 1.6. 2 Growth and BPD . 13 1.6. 3 Nutrition and Growth . 14 1.6. 4 Nutrition and ROP . 16 1.6. 5 Nutrition and BPD . 16 1.7 OXYGEN AND SATURATION TARGETS . 17 1.7. 1 Oxygen . 17 1.7. 2 Monitoring of oxygenation . 18 1.7. 3 Saturation target . 18 1.7. 4 Adherence to target . 20 1.8 CONCEPTS OF EPIDEMIOLOGY . 20 1.8. 1 Causality . 20 1.8. 2 Study design . 20 1.8. 3 Bias and confounding . 21 1.8. 4 Interaction . 21 1.8. 5 Directed acyclic graphs . 22 1.8. 6 Statistical concepts . 22 2 AIMS . 24 3 RESEARCH APPROACH . 25 3.1 DATA COLLECTION . 25 3.1.1 Paper I . 25 3.1.2 Paper II & III . 26 3.1.3 Paper IV . 29 3.2 STATISTICAL METHODS . 30 3.2. 1 Paper I . 30 3.2. 2 Paper II . 30 3.2. 3 Paper III . 31 3.2. 4 Paper IV . 31 3.3 METHODOLOGICAL CONSIDERATIONS .