Early Life Nutrition: Feeding Preterm Babies for Lifelong Health Jane Alsweiler Frank Bloomfield Anna Tottman Barbara Cormack Tanith Alexander Jane Harding
Feeding Preterm Babies for Lifelong Health Why worry? Parenteral nutrition Enteral nutrition Sex effects
Faltering post-natal growth T Cole Arch Dis Child 2011;A4 96(Suppl 1):A1 A100
Nutrition and brain growth Total brain tissue volume increases by 22 ml each week (3 D MRI) Very rapid development - greater vulnerability to damage from less than optimal nutrition
Neurodevelopmental outcome and postnatal weight gain in ELBW babies 60 50 N = 490 Neurodevelopmental impairment, % Cerebral palsy, % % 40 30 20 10 0 12 16 18 21 Weight gain g/kg.d Ehrenkranz RA et al, Pediatrics 2006, 117 (4)
Schneider et al, PAS, 2017 Early Nutrition Predicts Brain Growth and Maturation
Moderate-late preterm birth also is associated with increased risk of NCDs All Swedish births 1973-9 n = 636,552 25-37 years old Hypertensive or diabetic prescription in year of study Crump et al Am J Epidemiol 2011; 173:797-803 Crump et al Diabetes Care 2011; 34: 1109-1113
Effect of Gestational Age on Insulin Response to Glucose Load at 30 Years Log of insulin AUC -0.4-0.2 0.0 0.2 0.4 30 35 40 Dalziel et al, Int J Epidemiol 36: 907, 2007 Gestational age (weeks) P value for linearity=0.42.
ody Composition At Term of Babies Born Preterm % Total Body Fat +3% Fat Mass Fat Free Mass +50g Johnson et al, Pediatrics 130: e640, 2012-460g
Preterm Birth is Associated with Altered Fat Distribution in Adults and their Children Born Preterm (n = 31) Adults Born at Term (n = 21) Preterm Parent (n = 37) Children Parent Born at Term (n = 24) Age (years) 35.7 ± 1.3 35.7 ± 0.9 7.9 ± 1.6 8.2 ± 1.7 Gestation (wks) 33.3 ± 2.2 39.7 ± 1.2**** 39.7 ± 0.8 40.2 ± 0.7* BMI (kg/m 2 or SDS) 30.5 (28.3-32.9) Body fat (%) 35.4 (32.0-38.8) Truncal fat (%) 38.3 (34.1-42.5) Adroid:Gynoid fat 1.09 (1.01-1.16) 28.3 (25.8-31.0) 29.4 (25.2-33.6)** 30.1 (25.0-35.3)** 0.93 (0.83-1.02)** 0.26 (-0.22-0.75) 19.3 (16.3-18.4) 15.8 (13.6-18.4) 0.71 (0.63-0.81) 0.38 (-0.13-0.90) 17.2 (14.3-20.7) 12.3 (10.1-15.1)* 0.60 (0.52-0.68)** Mathai et al, PLOS One, 2013
Preterm Birth is Associated with Altered Fat Distribution in Adults and their Children Adults Children Born Preterm (n = 31) Born at Term (n = 21) Preterm Parent (n = 37) Parent Born at Term (n = 24) Age (years) 35.7 ± 1.3 35.7 ± 0.9 7.9 ± 1.6 8.2 ± 1.7 Gestation (wks) 33.3 ± 2.2 39.7 ± 1.2**** 39.7 ± 0.8 40.2 ± 0.7* BMI (kg/m 2 or SDS) 30.5 (28.3-32.9) 28.3 (25.8-31.0) 0.26 (-0.22-0.75) 0.38 (-0.13-0.90) Body fat (%) 35.4 (32.0-38.8) 29.4 (25.2-33.6)** 19.3 (16.3-18.4) 17.2 (14.3-20.7) Truncal fat (%) 38.3 (34.1-42.5) 30.1 (25.0-35.3)** 15.8 (13.6-18.4) 12.3 (10.1-15.1)* Adroid:Gynoid fat 1.09 (1.01-1.16) 0.93 (0.83-1.02)** 0.71 (0.63-0.81) 0.60 (0.52-0.68)** Mathai et al, PLOS One, 2013
potential trade-off between eurodevelopmental and metabolic outcomes Metabolism Development 20% decreased risk of IQ <85 27% increased risk of overweight / obesity per z-score weight change from birth to 4 months Belfort J Pediatr 163, 1564, 2013
Maternal Milk Fortification for Two Weeks in Preterm Lambs Alters Adult Body Composition Spirosky et al, J Physiol, in press.
HINT: Hyperglycaemia and Insulin in Neonates Trial Daily Mean Blood Glucose Concentration on Insulin 12 10 Tight Control 8 Blood Glucose Concentration (mmol/l) 6 4 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Day of randomisation Alsweiler, et al. (2012). Pediatrics, 129(4), 639-647.
HINT: Hyperglycaemia and Insulin in Neonates Trial Tight glycaemic control group had: Reduced linear growth Increased weight gain Doubled incident of hypoglycaemia Alsweiler, et al. (2012). Pediatrics, 129(4), 639-647.
PIANO study: Protein, Insulin And Neonatal Outcomes
Tight Control of Neonatal Hyperglycaemia Alters Body Proportions at 7 Years 0.8 0.6 0.4 * Tight Control Usual Control 0.2 0 Standard Deviations ** -0.2-0.4-0.6 ** -0.8 Height Sitting Height Tottman et al, J Pediatr 193: 68, 2018 Leg Length
Feeding Preterm Babies for Lifelong Health Why worry? Parenteral nutrition Enteral nutrition Sex effects
Protein Intake Falls Immediately After Birth protein intake g/kg.d in utero week 1 week 2 Cormack and Bloomfield Birth
Protein intake >1.5 g/kg.d is required to avoid accumulating a nitrogen deficit, let alone support growth van den Akker Curr Opin Clin Nutr Metab Care 2010; 13:327-335 Corpeleijn et al Clin Nutr 2010 Agostoni et al Pediatr Res 2010
Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants PDA NEC Bell EF, Acarregui MJ. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD000503. DOI: 10.1002/14651858.CD000503.pub3.
Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants BPD IVH Bell EF, Acarregui MJ. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD000503. DOI: 10.1002/14651858.CD000503.pub3.
Percentage of NICUs meeting preterm IVN guidelines in Germany, France, Italy and the UK (n=161) Day of birth, 1.5g/Kg.d Target dose 3 4 g/kg.d Initiation day 3 Initiation dose 1 g/kg.d Target dose 3 4 g/kg.d 110 to 120 kcal/kg.d Koletzko B, J Pediatr Gastroenterol Nutr 2005;41(Suppl 2):S1 87. 2013 by British Medical Journal Publishing Group Lapillonne et al BMJ Open 2013, 3:e003478
Reasons for inadequate nutrition in early life 1.Delayed start of nutrition (no protein or fat) 2.Graded increases (parenteral and enteral) 3.Dilute intravenous and enteral solutions 4.Fluid restriction 5.Nutritional fluids prescribed replaced by other solutions Cormack & Bloomfield, Nutrition Today 2015;50(5):230Y239
Nutritional strategy - intravenous nutrition Start parenteral nutrition as soon as vascular access lipid 1-2 g/kg.d amino acids 2-3 g/kg.d increasing to 4-4.5 by day 5 Use concentrated starter solutions amino acids 68 g/l (central access) or 42 g/l (peripheral venous access) 15% dextrose (central access) Consider how administered nutrition might not match prescribed nutrition e.g. parenteral nutrition stopped for drug infusions
ProVIDe RCT - does an additional 1 g protein/day over the first 5 days improve survival free of neurodisability? P: Babies with birthweight < 1000 g, UAC in situ I: Extra 1 g per day of protein for 5 days C: Compared with standard hospital PN O: Survival free from neurodisability age 2 years sample size is 430 babies currently at 97% recruitment no safety concerns to date protein intake g/kg.d in utero week 1 week 2 Birth Bloomfield et al BMC Paediatrics 2015 (protocol)
Feeding Preterm Babies for Lifelong Health Why worry? Parenteral nutrition Enteral nutrition Sex effects
Advantages of Breastmilk necrotising enterocolitis sepsis immune function oxygen requirement growth (improved with fortifier) developmental outcome metabolic outcome
Multi-nutrient fortification of human milk for preterm infants. 14 trials, 1071 infants Trials generally small and weak methodologically Low-quality evidence that multi-nutrient fortification of breast milk increases in-hospital rates of growth Very limited data available for growth and developmental outcomes beyond infancy, and these show no effects of fortification No other potential benefits or harms Brown JVE, Embleton ND, Harding JE, McGuire W. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD000343. DOI: 10.1002/14651858.CD000343.pub3.
Multi nutrient fortification of human milk for preterm infants Weight gain 1.81 g/kg.d 2.82 g/kg.d 1.86 g/kg.d Cochrane Database of Systematic Reviews 8 MAY 2016 DOI: 10.1002/14651858.CD000343.pub3 http://onlinelibrary.wiley.com/doi/10.1002/14651858.cd000343.pub3/full#cd000343-fig-0003
Multi nutrient fortification of human milk for preterm infants Length gain 0.12 cm/wk 0.21 cm/wk 0.18 cm/wk Cochrane Database of Systematic Reviews 8 MAY 2016 DOI: 10.1002/14651858.CD000343.pub3 http://onlinelibrary.wiley.com/doi/10.1002/14651858.cd000343.pub3/full#cd000343-fig-0004
Multi nutrient fortification of human milk for preterm infants Size at 12 to 18 months Weight Length Head Circumference Cochrane Database of Systematic Reviews 8 MAY 2016 DOI: 10.1002/14651858.CD000343.pub3 http://onlinelibrary.wiley.com/doi/10.1002/14651858.cd000343.pub3/full#cd000343-fig-00104
Preterm birth-associated neurodevelopmental impairment estimates for 2010 Blencowe et al Pediatr Res 2013; 74(S1): 17-34
Survey of nutrition of moderate-late preterm babies in New Zealand and Australia Neonatologists and general paediatricians on-line survey circulated through ANZNN 83 responses Investigating nutritional support provided to MLPT babies whilst waiting for full enteral feeds with breastmilk Alexander T & Bloomfield FH
32-33 +6 ; stable on admission, whilst waiting for first breastmilk what is the first form of nutritional support? If 10% dextrose, how many days would you be willing to wait for breastmilk supply to match prescribed fluid intake before providing additional nutrition? What would that additional nutrition be?
32-33 +6 ; stable on admission, whilst waiting for first breastmilk what is the first form of nutritional support? infant formula parenteral nutrition
If 10% dextrose, how many days would you be willing to wait for breastmilk supply to match prescribed fluid intake before providing additional nutrition?
Parenteral nutrition Milk supplement Taste/Smell + + + - - - 3 independent variable or factors Babies randomised to receive or not receive each of the three factors D10% vs Amino acid solution (P100) milk supplementation vs wait for mother s own milk Taste/smell vs standard protocol Sample size: 528 babies; 66 per condition, 264 per comparison group Alexander T & Bloomfield FH
Feeding Preterm Babies for Lifelong Health Why worry? Parenteral nutrition Enteral nutrition Sex effects
Supplementation of newborn lambs affects insulin secretion post-weaning in a sex-specific manner glucose 0.5 g/kg Jaquiery et al, Pediatr Res 861-869, 2016
Nutritional Supplements May Benefit Boys and Not Girls Preterm Babies Neonatal Preterm Babies Post-discharge Term SGA Babies Postdischarge Preterm Lambs Neonatal Multinutrients Term lambs Neonatal High Protein Male Female Male Female Male Female Male Female Male Female Early growth /= = = = /= Juvenile size /= = = = /= = = = Adult size = = /= = Adiposity =/ = = Glucose = tolerance Insulin sensitivity /= Blood pressure = = /= Autonomic Function Intelligence/ non-disabled = = = =/ = =/ Abstracted from publications by Berry, Cooke, Fewtrell, Jaquiery, Lucas, Makrides, Morley, Singhal
Enriched Diet Increases Growth But Impairs Development in IUGR Girls Height (cm) 36 34 32 30 28 26 24 22 110 105 100 95 90 85 80 75 Development Quotient 20 9 Months Height 18 Months Height 9 months Development Fewtrell, et al. (2001). Am J Clin Nutr, 74(4), 516-523. Morley, et al. (2004). Pediatrics, 113(3), 515-521. 18 months Mental Index 70 control enriched control enriched Boys Girls
Intelligence Quotients at 7-8 years in Preterm Girls and Boys Fed Standard vs Preterm Formula *P<0.05; **P<0.01 Girls Preterm Standard Boys Preterm Standard Lucas A, el at. BMJ 1998;317:1481.
Energy and Nutrient Requirements Differ by Age and Sex Australia and New Zealand Age group and gender Energy Protein Dietary fats Carbohy -drates Dietary fibre Total water Infants Children Adolescents Adults 0-6 m 7-12 m 1-3 y 4-8 y 9-13 y 14-18 y >18 y Nutrient Reference Values for Australia and New Zealand (National Health and Medical Research Council 2006)
Human Milk for Boys Contains More Lipids and Energy Boys Girls Thakkar et al, American Journal of Human Biology 25: 770, 2013
Girls and Boys Grow Differently on Different Infant Diets Formula Fed Breast Fed Formula Fed Breast Fed Cheng et al, Am J Clin Nutr 2015 DOI:10.3945/ajcn.115.115493
Population: Infants born preterm or small ( 2.5 kg or 10th centile) Inclusion Criteria: Trials where the intervention was intended to increase the intake of one or more macronutrients with the aim of improving growth or development Outcomes: Results so far: 1. Cognitive impairment 2. Metabolic risk 88 potentially eligible studies 32 have published post-discharge data 10 data not available 39 still searching 11 likely to be included, 8 more possible >450 e-mails to date
Feeding Preterm Babies for Lifelong Why worry? o o Health Related to developmental outcome May be a trade-off for metabolic outcomes Parenteral nutrition o Start protein and fat early while restricting fluid Enteral nutrition o o Multinutrient supplements in small babies?how to feed late preterm babies Sex effects o o Boys and girls respond differently Need longterm outcomes separately by sex