Feeding Preterm Babies for Lifelong Health

(1)

Early Life Nutrition:

Feeding Preterm Babies for Lifelong Health

Jane Harding Jane Alsweiler

Frank Bloomfield Anna Tottman

Barbara Cormack

Tanith Alexander

(2)

(3)

Feeding Preterm Babies for Lifelong Health

• Why worry?

• Parenteral nutrition

• Enteral nutrition

• Sex effects

(4)

Faltering post-natal growth

T Cole Arch Dis Child 2011;A4 96(Suppl 1):A1–A100

(5)

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

(6)

Neurodevelopmental outcome

and postnatal weight gain in ELBW babies

0 10 20 30 40 50 60

12 16 18 21

%

Weight gain g/kg.d

Neurodevelopmental impairment, % Cerebral palsy, %

N = 490

Ehrenkranz RA et al , Pediatrics 2006, 117 (4)

(7)

Early Nutrition Predicts Brain Growth and Maturation

Schneider et al, PAS, 2017

(8)

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

(9)

P value for linearity=0.42.

Gestational age (weeks)

Log of insulin AUC

30 35 40

-0.4-0.20.00.20.4

Dalziel et al, Int J Epidemiol 36: 907, 2007

Effect of Gestational Age on Insulin

Response to Glucose Load at 30 Years

(10)

Body Composition At Term of Babies Born Preterm

Johnson et al, Pediatrics 130: e640, 2012

% Total Body Fat

Fat Mass

Fat Free Mass

+3%

+50g

-460g

(11)

Preterm Birth is Associated with Altered Fat Distribution in Adults and their Children

Mathai et al, PLOS One, 2013

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)**

(12)

Preterm Birth is Associated with Altered Fat Distribution in Adults and their Children

Mathai et al, PLOS One, 2013

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/m² 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)**

(13)

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

A potential trade-off between

neurodevelopmental and metabolic outcomes

(14)

Maternal Milk Fortification for Two Weeks in Preterm Lambs Alters Adult Body Composition

Spirosky et al, J Physiol, in press.

(15)

Daily Mean Blood Glucose Concentration on Insulin

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0

2 4 6 8 10

12 ^Tight

Control

Day of randomisation Blood Glucose

Concentration (mmol/L)

HINT: Hyperglycaemia and Insulin in Neonates Trial

Alsweiler, et al. (2012). Pediatrics, 129(4), 639-647.

(16)

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.

(17)

PIANO study: Protein, Insulin And

Neonatal Outcomes

(18)

Tight Control of Neonatal Hyperglycaemia Alters Body Proportions at 7 Years

-0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8

Height Sitting

Height Leg Length

Tight Control Usual Control

*

Standard

Deviations **

**

Tottman et al, J Pediatr 193: 68, 2018

(19)

Feeding Preterm Babies for Lifelong Health

• Why worry?

• Parenteral nutrition

• Enteral nutrition

• Sex effects

(20)

Protein Intake Falls Immediately After Birth

protein intake g/Kg.d

in utero week 1 week 2

Birth

Cormack and Bloomfield

(21)

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 alClin Nutr 2010

Agostoni et al Pediatr Res 2010

(22)

Bell EF, Acarregui MJ. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD000503. DOI: 10.1002/14651858.CD000503.pub3.

PDA

NEC

Restricted versus liberal water intake for preventing

morbidity and mortality in preterm infants

(23)

Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants

Bell EF, Acarregui MJ. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD000503. DOI: 10.1002/14651858.CD000503.pub3.

BPD

IVH

(24)

(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

Percentage of NICUs meeting preterm IVN

guidelines in Germany, France, Italy and the UK

Koletzko B, J Pediatr Gastroenterol Nutr 2005;41(Suppl 2):S1–87.

Lapillonne et al BMJ Open 2013, 3:e003478

(25)

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

Reasons for inadequate nutrition in early life

Cormack & Bloomfield, Nutrition Today 2015;50(5):230Y239

(26)

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

(27)

• 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

ProVIDe RCT - does an additional 1 g protein/day over the first 5 days improve survival free of neurodisability?

protein intake g/Kg.d

in utero week 1 week 2

Birth Bloomfield et al BMC Paediatrics 2015 (protocol)

(28)

Feeding Preterm Babies for Lifelong Health

• Why worry?

• Parenteral nutrition

• Enteral nutrition

• Sex effects

(29)

Advantages of Breastmilk

•  necrotising enterocolitis

•  sepsis

•  immune function

•  oxygen requirement

•  growth (improved with fortifier)

•  developmental outcome

•  metabolic outcome

(30)

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.

(31)

Multi‐nutrient fortification of human milk for preterm infants Weight gain

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

1.81 g/kg.d

2.82 g/kg.d

1.86 g/kg.d

(32)

Multi‐nutrient fortification of human milk for preterm infants Length gain

8 MAY 2016 DOI: 10.1002/14651858.CD000343.pub3

0.12 cm/wk

0.21 cm/wk

0.18 cm/wk

(33)

Multi‐nutrient fortification of human milk for preterm infants Size at 12 to 18 months

Weight

Length

Head

Circumference

8 MAY 2016 DOI: 10.1002/14651858.CD000343.pub3

(34)

Blencowe et al Pediatr Res 2013; 74(S1): 17-34

Preterm birth-associated neurodevelopmental

impairment estimates for 2010

(35)

• 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

Survey of nutrition of moderate-late preterm babies in New Zealand and Australia

Alexander T & Bloomfield FH

(36)

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?

(37)

32-33 ⁺⁶ ; stable on admission, whilst waiting for first breastmilk what is the first form of nutritional support?

infant formula

parenteral

nutrition

(38)

If 10% dextrose, how many days would you be willing to wait for breastmilk supply to match

prescribed fluid intake before providing additional

nutrition?

(39)

(40)

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

(41)

Feeding Preterm Babies for Lifelong Health

• Why worry?

• Parenteral nutrition

• Enteral nutrition

• Sex effects

(42)

Supplementation of newborn lambs

affects insulin secretion post-weaning in a sex-specific manner

Jaquiery et al, Pediatr Res 861-869, 2016

glucose 0.5 g/Kg

(43)

Nutritional Supplements May Benefit Boys and Not Girls

Preterm Babies Neonatal

Preterm Babies Post-discharge

Term SGA Babies Post-

discharge

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

(44)

9 months

Development 18 months Mental Index 18 Months

Height 20

22 24 26 28 30 32 34 36

control enriched control enriched

Boys Girls

Enriched Diet Increases Growth But Impairs Development in IUGR Girls

70 75 80 85 90 95 100 105 110

9 Months Height Height

(cm)

Development Quotient

Fewtrell, et al. (2001). Am J Clin Nutr, 74(4), 516-523.

Morley, et al. (2004). Pediatrics, 113(3), 515-521.

(45)

*P<0.05; **P<0.01

Intelligence Quotients at 7-8 years in Preterm

Girls and Boys Fed Standard vs Preterm Formula

Lucas A, el at. BMJ1998;317:1481.

Preterm Standard

Girls Boys

Preterm Standard

(46)

Australia and New Zealand

Energy and Nutrient Requirements Differ by Age and Sex

Age group and gender Energy Protein Dietary fats

Carbohy -drates

Dietary fibre

Total water

Infants 0-6 m 7-12 m Children 1-3 y

4-8 y Adolescents 9-13 y

14-18 y Adults >18 y

Nutrient Reference Values for Australia and New Zealand (National Health and Medical Research Council 2006)

(47)

Human Milk for Boys Contains More Lipids and Energy

Thakkar et al, American Journal of Human Biology 25: 770, 2013

Boys

Girls

(48)

Girls and Boys Grow Differently on Different Infant Diets

Cheng et al, Am J Clin Nutr 2015 DOI:10.3945/ajcn.115.115493

Breast Fed Formula Fed

Breast Fed

Formula Fed

(49)

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