Macronutrients and Development. Dr Julian Eason Chair NICU Corniche Hospital, Abu Dhabi

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1 Macronutrients and Development Dr Julian Eason Chair NICU Corniche Hospital, Abu Dhabi

2 Corniche Hospital 64 Bed NICU 8000 deliveries Tertiary referral for Fetal medicine and High Risk Maternity 1000 NICU admissions/year Vermont-Oxford since 1998, 250 infants <1500g 12 Consultants and 27 Specialists UK Model of care 145 nurses and increasing Stand alone Maternity Hospital Paediatric facility Sheik Khalifa Medical City 3 miles away

3 Statement Children who are not adequately nourished are at risk for failing to reach their developmental potential in cognitive, motor, and socio-emotional abilities. These abilities are strongly linked to academic achievement and economic productivity.

4 Recommended nutrient intakes ESPGHAN 2010 Preterm Per kg/day Per 100kcal Fluid mls/kg/day Energy, kcal Protein, g (<1kg) Protein, g (1-1.8kg) Carbohydrate, g Lipid, g (MCT<40%) Vitamin A, ug Vitamin D, IU Calcium, mg Phosphorus, mg Iron, mg Sodium, mg

5 Effects from Defficiency 1. environment aspects 2. timing of deprivation 3. degree of defficiency 4. possibility of recovery

6 What are Macronutrients? Carbohydrates Fat Protein

7 Carbohydrate 11.5g/kg/day = 8mg/kg/min Calculations based upon: Endogenous production and Utilisation Response to Glucose administration Brain utilisation Basal and total energy expenditure Type of carbohydrate eg Sucrose, Lactose etc

8 Glucose and the Brain Relation between body weight and Brain in Children CHO as nutrient in the Infant and Child. Kalhan SC et al. European Journal of Clinical Nutrition (1999) 53 Supp 1 S94-S100

9 Minimum CHO Requirements CHO requirements Minimum to meet needs of brain and other glucose dependent organs Minimising cost of protein for gluconeogenesis and nitrogen loss Preventing ketosis

10 NHBI Neonatal Hypoglycaemic Brain Injury Cornblath et al. J Pediatr 1959 Described 8 cases of symptomatic neonatal hypoglycaemia Boluyt N et al. Neurodevelopment after neonatal hypoglycemia: a systematic review and design of an optimal future study. Pediatrics 2006 No clinical research of high quality on the exact relationship between neonatal blood glucose levels and neurological outcome had presented convincing evidence.

11 Current beliefs are mmol/l Epidemiological data used based on populations for normal levels No prospective RCT has yet to confirm the long term sequelae of hypoglycaemia But The neonatal brain develops rapidly. Persistent or recurrent hypoglycaemia may lead to long-term visual disturbance, hearing impairment, cognitive abnormalities, secondary epilepsy, and other disorders in the central nervous system.

12 What do we know? Early feeding is crucial for the prevention of NHBI Neonatal hypoglycaemia may cause irreversible neurological sequelae. Early Hum Dev 2005 Persistent and recurrent hypoglycaemia can severely impair brain growth and its function. Research 2006 and 2008 Most cases of neonatal hypoglycaemia can be asymptomatic or only have nonspecific clinical symptoms. Blood glucose testing conducted within postnatal 72 h is useful for the prevention and treatment of NHBI. Sinclair et al. Interventions for prevention of neonatal hyperglycaemia in very low birth weight infants. Cochrane Database Syst Rev 2011

13 Occipital Lobe Injury

14 MRI Classically posterior regions of Brain affected Patterns of Cerebral Injury and Neurodevelopmental Outcomes After Symptomatic Neonatal Hypoglycemia Pediatrics July 2008, VOLUME 122 / ISSUE 1 Basal Ganglia, Cortex, MCA and even IVH but PLIC damage 65% impaired at 18 months

15 Fats The omega-3 fatty acid alpha-linolenic acid (ALA) and the omega-6 fatty acid linoleic acid (LA) are essential fatty acids (EFAs) as they can not be produced by the human body. Omega-3 and omega-6 fatty acids, particularly docosahexaenoic acid (DHA), are known to play an essential role in the development of the brain and retina.

16 LC-PUFA s Macronutrients

17 DHA and ARA LCPUFA are important for neuronal membrane integrity and function, and as well as vision may protect in BPD and NEC LCPUFAs, especially DHA, are involved in cell signalling, regulation of gene expression and neuronal growth Accretion is rapid in last trimester to support rapid growth and brain development Premature infants are deficient and remain so due to ineffective conversion, low stores and low supplies

18 Evidence Studies in animals show that lack of the long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) during periods of rapid brain growth may lead to impaired neurodevelopment Trials of the effect of DHA-fortified formula in babies have produced conflicting but useful results.

19 Omega-3 and Omega-6 LCPUFA synthesis from precursor essential fatty acids Flaxseed Canola Walnuts Soy Vegetable oils Nuts Seeds Meat Eggs Oily Fish

20 Early Studies 1992 Lucas demonstrates breast fed infants have higher IQ than formula fed. 8.3 point advantage. Lancet 1992; 339(8788): (Although these results could be explained by differences between groups in parenting skills or genetic potential (even after adjustment for social and educational factors), our data point to a beneficial effect of human milk on neurodevelopment) Fleith s review of studies in 2005 says fewer than half of all studies have found beneficial effects of LCPUFA on visual, mental, or psychomotor functions. Crit Rev Sci Nutr 2005;45 (3)

21 Breast-feeding and cognitive development: a meta-analysis. Anderson JW, Johnstone BM, Remley DT. Am J Clin Nutr 1999;70: Most studies have found that breastfeeding is associated with better cognition, but few adjusted for the confounding effect of maternal education and socio-economic status i.e. The educated breast feed so of course they score higher

22 Meta-analysis Mean difference in cognitive function between breast and formula fed infants 20 studies initially with 11 controlled Unadjusted benefit 5.32 (CI ) increase in cognitive points Adjusted benefit 3.16 ( ) increase Low birth weight infants showed a larger difference than normal birth weight 5.18 v 2.66 suggesting greater benefit in less mature infants Differences observed from 6 months to 15 years

23 LC PUFA and Perinatal development Koletzco et al. Acta Pediatrica 2001 Apr 90 (4) Investigators summarised the relevant randomised trials to date 1. Support Breast Feeding 2. Infant formula needs 0.2% DHA and 0.3% AA 3. Preterm infants very deficient so 0.3% DHA and 0.4% AA 4. Prudent for pregnant and lactating women to have source of DHA and AA in diet 5. Continue to investigate benefits

24 Randomized, double-blind trial of long-chain polyunsaturated fatty acid supplementation with fish oil and borage oil in preterm infants. Fewtrell MS, Abbott RA, Kennedy K, et al. J Pediatr 2004;144: preterm infants LCPUFA-fortified formula was associated with higher scores on the Mental Development Index of the Bayley Scales at 18 months, only in boys overall there were no differences in neurodevelopment between the formula groups

25 Growth and development of preterm infants fed infant formulae containing docosahexaenoic acid andarachidonic acid. Clandinin MT, Van Aerde JE, Merkel KL, et al. J Pediatr 2005;146: preterm infants LCPUFA-fortified formula was linked with significantly higher Bayley Scales scores at 18 months.

26 Effects of maternal docosahexaenoic acid intake on visual function and neurodevelopment in breastfed term infants. Jensen CL, Voigt RG, Prager TC, et al. Am J Clin Nutr 2005;82: Trial examined the effect of supplementing breastfeeding women with DHA Children of supplemented women scored significantly higher than those of a control group on the Psychomotor Development Index of the Bayley Scales at age 30 months No difference in score on the Mental Development Index

27 Cognitive function in 18-month-old term infants of the DIAMOND study: a randomized, controlled clinical trial with multiple dietary levels of docosahexaenoic acid. Drover et al. Early Hum Dev 2011; 87(3): Double masked, randomised, controlled prospective trial 181 infants 1-9 days randomly assigned to 1 of 4 formulae: Control (0%DHA), 0.32% DHA, 0.64% DHA, 0.96% DHA All contained 0.64% ARA 12 months assignment 141 infants completed 131 children assessed at 18 months of age

28 Results No diet group differences on MDI, PDI or Behaviour Rating Scale (BSID 11) But when scores combined comparing supplemented to controls then significant MDI difference found v 98.4 p=0.02 Conclude need 0.32% DHA conc to make a difference

29 LCPUFA supplementation in infants born at term Simmer K et al. Cochrane Library Dec 2011 Jasani B et al. Cochrane Library Dec 2017 Conclusions Majority of the RCTS have not shown beneficial effects of LCPUFA supplementation on the neurodevelopmental outcomes of term infants. The beneficial effects on visual acuity have not been consistently demonstrated. Routine supplementation of term infant milk formula with LCPUFA can not be recommended. Longchain polyunsaturated fatty acid supplementation in preterm infants Moon et al. Cochrane Library Dec 2016

30 Beyond Building better brains: bridging the docohexanoic acid (DHA) gap of prematurity Harris et al. J Perinat (2015) 35, 1-7 Selected conclusions: Pregnant and lactating women should take 200mg/day DHA via diet or supplement Formula should contain between 0.2 and 0.5% as DHA and ARA More DHA provision is required for preterm infants but exact dose not known

31 Protein Amine NH3 Carboxylic COOH Side Chain

32 Amino Acids 4 Non essential Alanine, Aspartic Acid, Glutamic Acid, Cysteine 7 Conditional Arginine, Asparagine, Glutamine, Glycine, Proline, Serine, Tyrosine 9 Essential Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine

33 Proteins what do they do? Growth cells and tissues Immunity Antibodies Enzymes biocatalyst Energy Chemical messengers neuro-transmitters, hormones Transport haemoglobin, transferrin

34 The brain grows 260% during the 3rd trimester and another 175% during the 1 st year of life Adult

35 Newborn v 24 weeks

36 Current situation Nutritional strategies for very preterm compromise protein intake. Protein under-nutrition is overcompensated by high rates of carbohydrate and lipid intakes

37 Protein Our primary goal is Protein accretion: Protein gain is best indicator of real growth. Greatest rate of protein gain occurs prior to birth. The amount of protein intake early in life correlates with improved developmental outcome.

38 Protein The preterm infants should receive enough protein for growth and must rely on carbohydrate and lipid to promote energy production. Preterm infants are not fed as much protein as they would have received in utero. Therefore, it is not surprising, that they end up growth restricted at term gestation.

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40 Could the premature infant's nutrient needs be met by feeding more human milk? No One has to feed >300 ml/kg/day If that were possible (it is not), it would provide about 200 kcal /kg/day and would still not provide all nutrients in adequate amounts

41 Why Human Milk Fortification? Because nutrients are present in amounts that are inadequate to meet the premature baby s needs. Amount/ Per 4 sachets in 100mls Breast Milk Similac S26 prenan HMF HMF HMF Energy (kcal) Protein (g) Choline (mg) Fat (g) DHA (mg) (0.32%) (.15%) Carbohydrate (g) Calcium (mg) Phosphorous(mg) Vitamin A (IU) Vitamin D (IU)(1ug=40) Vitamin E (mg) Iron (mg) Folic Acid (mcg) Sodium (mg) Potassium (mg) Nucleotide (mg) Yes FOS:GOS Yes Osmolality (mosm/kg H 2 O) mls/kg Breast = 1.6g Fort 1,2 = 3.1g Fort 3 = 4g

42 Going home When the premature infant leaves the hospital, his/her protein needs are still much higher than those of the term infant. Also, the infant has almost always undermineralised bones. (Phosphate should have been added to every breast-fed infants milk until at least 34 weeks gestation). Hence the infant needs more protein and more minerals than plain mother s milk or term formula can provide for a period of time.

43 Randomised trial of early diet in preterm babies and later IQ Lucas et al BMJ Vol 317 Nov infants <1850g Tested at years Formula only Preterm (2.0g protein/100ml) or Term (1.5g protein/100ml) Breast fed Supplement Preterm or Term 4 weeks intervention Significant inc in IQ increase in preterm formula use CP more present in standard formula

44 g/day Protein Intake Hilbig A et al., JPGN 2006; 43(4): Fantino M et al. Arch Pediatr (4) Comparison of mean total protein consumption by infants and RDA RDA Tot Protein consumption Months

45 Protein requirements in first 6 months 12 kg 10 3g to 1 1 to 2 2 to 3 3 to 4 4 to 5 5 to 6 months 2g 1g 0g Av male body weight kg Protein requirements g/kg

46 Evolution of protein content of breast milk and intake in first 6 months 900 ml/day Breast milk intake ml/day to 1 1 to 2 2 to 3 3 to 4 4 yo 5 5 to 6 months 8g Protein content in breast milk g/l

47 Do recommended protein intakes improve neurodevelopment in extremely preterm babies? Arch Dis Child Fet & Neo May babies before and 42 babies after policy changes on protein intake <1000g within 24 hours birth TPN 3.8 4g/kg/day Formula 2-2.5g/100mls No sensory, visual or gross motor differences Bayley 3 at 18 months no difference Improved early growth No adequately powered RCT done on new protein recommendations and neurodevelopment

48 Most emphsasis on high calories Per 100 mls Breast Milk Breast Milk + Fortifier Term Post Discharge Preterm Energy (kcal) Protein (g) Whey (%) Casein (%) Fat (g) Carbohydrate (g) Calcium (mg) Phosphorous(mg) Iron (mg) Sodium (mg) Potassium (mg) Nucleotide (mg) Yes Yes Osmolality (mosm/kg H 2 O)

49 Thank you Research continues to help fine tune appropriate recommendations for nutritional requirements in vulnerable infants

50 Iron Deficiency Anaemia 2 Billion anaemic people (30% of global population) in the world are anaemic ID affects more people than any other condition in the world It remains silent despite more severe consequences than some other common conditions Haemoglobin, Ferritin, Enzymes

51 Population at Risk of Deficiency Global UNICEF

52 Preschool and pregnancy Iron defficiency UNICEF 2005 Pre-school Pregnancy Mild 5-19% Moderate 20-39% Severe >40% Lebanon 20-30% 2008 study

53 Prevelance of iron deficiency anaemia Region 0-5 years 5-12 years South Asia 56% 50% Africa 56% 49% Latin Am 26% 26% Gulf Region 40% 36% Developed 12% 7% World 43% 37%

54 Newborn Iron Stores 75 mg/kg of iron at birth Dependent on haemoglobin concentration at birth (majority of iron in circulating RBCs) Minimally dependent on maternal iron status Depleted by 3 months in low birth weight infants without supplementation Depleted by age 5-6 months in term infants Delayed cord clamping (by 2 minutes) leads to higher ferritin and iron stores at 6 months of age

55 Cows Milk and Iron Defficiency Poor source of iron Poor absorption (5-10%) Reduces consumption of other foods, especially with overconsumption Can cause microscopic GI bleeding

56 Recent evidence from human and animal studies regarding iron status and infant development. J Nutr Feb;137(2):524S-530S. Infants are at risk for iron deficiency as breast milk or formula is replaced by semisolid foods during weaning A lack of sufficient iron intake may significantly delay the development of the central nervous system because of alterations in morphology, neurochemistry, and bioenergics. Depending on the stage of development at the time of iron deficiency, there may be an opportunity to reverse adverse effects, but the success of repletion efforts may be time dependent.

57 Conclusions Data in monkeys show significant effects on neurodevelopment with dietary iron deficiency. Findings in human infants are consistent with altered myelination and changes in monoamine functioning. Rodent studies show that effects of iron deficiency during gestation and lactation persist despite restoration of iron status at weaning. These cross-species studies indicate a vulnerable period in early development that may result in long-lasting damage

58 Why iron deficiency is important in infant development. Beard JL. J Nutr Dec;138(12): Depending on the stage of development at the time of iron deficiency, there may be an opportunity to reverse adverse effects, but the success of repletion efforts appear to be time dependent. Publications in the past several years describe the emerging picture of the consequences of iron deficiency in both human and animal studies. The data in human infants are consistent with altered myelination of white matter, changes in monoamine metabolism in striatum, and functioning of the hippocampus. These studies indicate that gestation and early lactation are likely critical periods when iron deficiency will result in long-lasting damage.

59 Iron supplements reduce impaired neurodevelopment in LBW babies Berglund et al. Pediatrics 2012 RCT 285 marginally LBW infants (<2,500 g) Placebo or either 1 mg/kg or 2 mg/kg of ferrous succinate per day 6 weeks to 6 months. A 3.5-year follow-up, psychometric test to determine verbal, performance, and full-scale IQ. Parents completed a checklist questionnaire for behavioural and emotional problems.

60 Results No significant differences in cognitive scores among the 3 groups of LBW infants compared with controls. Infants who received the 1 mg/kg and 2 mg/kg iron supplements were significantly less likely (2.9% and 2.7%, respectively) to score above the subclinical cutoff for behaviour problems than infants given placebo (12.7%). The rates for LBW infants given supplements were similar to the rate for babies of normal birth weight (3.2%).

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62 Conclusion Early iron supplementation of marginally LBW infants does not affect cognitive functions at 3.5 years of age but significantly reduces the prevalence of behavioural problems. The study suggests a causal relation between infant iron deficiency and later behavioral problems.

63 Enteral iron supplementation in preterm and low birth weight infants. Mills R, Davies M. Cochrane Database of Systematic Reviews 2012; Issue 3. To evaluate the effect of prophylactic enteral iron supplementation on growth and neurodevelopmental outcomes in preterm and low birth weight infants. 26 studies, 2672 infants 21 studies comparing iron with controls did not look at neurodevelopment 1 of 13 looking at growth found a week correlation 1 study looking at high and low dose iron found no neurodevelopmental difference No haematological difference between 2 or 3 mg/kg/day

64 Prevention? Delayed cord clamping Breastfeeding for the first 6 months of life Iron fortified formula/cereals Iron supplementation for preterm infants Iron supplementation for breastfeeding infants at 4 months of age Avoid cows milk before 1 year of age? longer Limit cows milk intake to 500mls/day after 12 months of age

65 Conclusion It remains unclear whether iron supplementation in preterm and low birth weight infants has long term benefits in terms of neurodevelopmental outcome and growth. Infants who receive iron supplementation have a slightly higher haemoglobin level, improved iron stores and a lower risk of developing iron deficiency anaemia when compared with those who are unsupplemented

66 Does correcting a deficiency correct the underling developmental problem? 1. Always 2. Never 3. Sometimes 4. If given at the correct time

67 Accretion of LC PUFA s is greatest in which trimester supporting brain growth and development? 1. First Trimester 2. Second Trimester 3. Third Trimester 4. Second and Third Trimester

68 Which are a natural source of precursors for LC PUFA s? Meat and eggs Fish Seeds and nuts Cereals

69 Early onset iron deficiency has knock-on effects into adult life? Is rare Is easily corrected Has no clinical consequences Can be associated with behaviour

70 The prevalence of Iron deficiency worldwide is? 1. >30% 2. >40% 3. >50% 4. >60%