Nutritional interventions to promote brain dev and catch up growth

1. Nutritional Interventions to Promote
Brain Development & Catch Up Growth in
Preterm & LBW Infants
Rinawati Rohsiswatmo

5. The Goal of Growth in
Preterm Infants
• From return to birth weight through discharge, the goal
of enteral nutritional management should include
requirements for catch-up growth and should be set for
weight gain >18 g/kg/ day and HC >0.9 cm/week
• This growth rate was associated with better
neurodevelopmental and growth outcomes
• If the growth rate falters  focus on protein content
and the protein/energy ratio (P/E ratio)
William WH Jr. Optimizing Nutrition of The Preterm Infant. Zhongguo Dang Dai Er Ke Za Zhi. 2017 Jan 25;19(1):1–21.
Su BH. Optimizing Nutrition in Preterm infants. Pediatrics & Neonatology. 2014 Feb 1;55(1):5-13.
The goal of nutrition of the preterm infant is to meet the growth rate of the healthy fetus
of the same gestational age and to produce the same body composition of the healthy
fetus in terms of organ growth, tissue components, cell number and structure

6. A Structural MRI Study of Human Brain Development from Birth to 2 Years. J Neurosci. November 19, 2008 • 28(47):12176 –12182.
Early Childhood Brain Development. Todd Twogood, MD, FAAP
(TBV)
Brain Development is Most Rapid in
The First 1000 Days of Life
Intrauterine Growth in The Last Trimester TBV at 2 years is ~ 83% of adult volume
50cm
800 g 30 cm 75g
5600 mg
BW
3500 g
375 g
Body calcium
BL BrainWeight
28000 mg
25 40 25 40 25 40
25 40

7. The Importance of Nutrition for
Brain Development
• In preterm infant, the brain is the most metabolically demanding organ and
consumes the largest amount of energy and nutrients for its function and
programmed growth and maturation
• The number of cell replication cycles in the CNS is decreased in malnutrition 
thereby reducing total brain DNA and leading to reduction in the connections
between neurons
• Alterations in dietary precursors  may affect neurotransmitter levels
The resulting CNS impairment, caused by these nutrient deficiencies, involves motor and cognitive
development and social abilities
Skinner AM, Narchi H. Preterm nutrition and neurodevelopmental outcomes. World J Methodol. 2021 Nov 20;11(6):278-293.

8. The Importance of Nutrition for
Brain Development
• Inadequate nutrition during the critical periods of brain development alters the
growth trajectory of the brain and can have permanent negative consequences
• The most critical period of brain growth and development for humans
corresponds to the 3rd trimester of pregnancy andVLBW infants
• Infants born early in the 3rd trimester miss the placental transfer of nutrients which would
create stores for use in the postnatal period
Better linear growth and early gains in fat-free body mass have been found to be associated with improved
neurodevelopment inVLBW preterm infants
Arslanoglu S, Boquien CY, King C, Lamireau D, Tonetto P, Barnett D, et al. Fortification of Human Milk for Preterm Infants: Update and Recommendations of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification.
Front Pediatr. 2019;7:76.

9. • 49 preterm neonates  3 serial MRI scans
• Nutritional intake from age 1-14 days was monitored & clinical factors were collected
• Greater energy and lipid intake predicted increased total brain and basal nuclei volumes over the course of
neonatal care to term-equivalent age
• The association of ventilation duration with smaller brain volumes was attenuated by higher energy intake. Brain
growth predicted psychomotor outcome at 18 months’ corrected age
• Conclusions: In preterm neonates, greater energy and enteral feeding during the first 2 weeks of life predicted
more robust brain growth and accelerated white matter maturation
• The long-lasting effect of early nutrition on neurodevelopment may be mediated by enhanced brain growth
• Optimizing nutrition in preterm neonates may represent a potential avenue to mitigate the adverse brain health
consequences of critical illness
Schneider J, Fischer Fumeaux CJ, Duerden EG, Guo T, Foong J, Graz MB, Hagmann P, et al. Nutrient Intake in the First Two Weeks of Life and Brain Growth in Preterm Neonates. Pediatrics. 2018 Mar;141(3):e20172169.

10. Component of Premature Human-Milk
Component
(unit/kg/day)
Premature Human-Milk Mature
Human-
Milk
Nutritional
Needs
FirstWeek
Second
Week
Third Week
Energy (kcal)
Volume (mL)
Protein (g)
Natrium
(mEq)
Calcium (mg)
Phosphorus (mg)
120
180
3,9
4
53
25
120
180
3,4
2,7
46
27
120
180
2,8
1,8
42
23
120
190
2,4
2
47
26
120
150
3,5
3,5
160-200
80-100
Schanler RJ. Clin Perinatol 1995;22:207-22

11. Human Milk Fortification
• Unfortified HM doesn't provide sufficient amounts of nutrients to tiny preterm infants when fed at
usual feeding volumes
• To prevent EUGR which is associated with poor neurocognitive outcome and to avoid specific
nutrient deficiencies, nutrient fortification of HM is necessary
Arslanoglu S, Boquien CY, King C, Lamireau D, Tonetto P, Barnett D, et al. Fortification of Human Milk for Preterm Infants: Update and Recommendations of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification.
Front Pediatr. 2019;7:76.
WHO recommendations for care of the preterm or low birth weight infant. Geneva: World Health Organization; 2022.

12. Human Milk Fortification
• HMF (Human Milk Fortifier) may be used only when the infant
reaches a feed of 100 mL/kg/day
• One sachet (1 g) of HMF may be used for 20 or 25 mL of expressed or donor
pasteurized human milk, depending on the product guideline
• The calorie requirement of a preterm infant is usually met with the addition
of HMF, which provides about 4 g/kg/day of protein and 3.5–4 g/kg/day of fats
Kumar RK, Singhal A, Vaidya U, Banerjee S, Anwar F, Rao S. Optimizing Nutrition in Preterm Low Birth Weight Infants—Consensus Summary. Front Nutr 2017;4
Thoene MK, Anderson-Berry AL. A review of Best Evidenced-based Enteral and Parenteral Nutrition Support Practices for Preterm Infants Born <1,500 Grams. Pediatric Medicine. 2018 Oct 23];1(0).

13. Formula Composition (per 100 mL)
Standard
Formula
Standard
Preterm
Formula
Amino Acid
Formula
HMF
(per 4 sachet)
Energy (kcal) 67 81 67 14
Protein (g) 1.45 2.3 1.8 1.1
Calcium (mg) 35 99 65.6 90 (42)*
Phosphorus (mg) 29 54 47.1 50 (23)*
Magnesium (mg) 5.2 8.0 7.0 1
Vitamin D (ug) 1.0 2 1.2 3.75
Zinc (mg) 0.5 1.6 0.73 0.72
*Premature human milk (3rd week)

14. Types of Human Milk Fortifier (HMF)
Multi-Nutrient Fortifiers
• Contain protein, energy, minerals, trace elements, vitamins, and electrolytes
Single-Nutrient Supplements
• Contain protein, lipids, or carbohydrates
Arslanoglu S, Boquien CY, King C, Lamireau D, Tonetto P, Barnett D, et al. Fortification of Human Milk for Preterm Infants: Update and Recommendations of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification. Front
Pediatr. 2019 Mar 22;7:76.
There are a number of products available for fortifying human milk for preterm babies which differ by the
origin of milk used (bovine, human or donkey), and by nutrient composition (multi-nutrient fortifiers or
supplements of protein, lipids, carbohydrates).

15. The Fortification Methods
Arslanoglu S, Boquien CY, King C, Lamireau D, Tonetto P, Barnett D, et al. Fortification of Human Milk for Preterm Infants: Update and Recommendations of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification. Front
Pediatr. 2019 Mar 22;7:76.
Standard (STD) Fortification
• A fixed amount of fortifier is added to a fixed volume of HM according to the manufacturers’
instructions
• Fortification method currently in use in most of the neonatal units
Individualized HM Fortification Methods
• Adjustable (ADJ) Fortification
• Protein adequacy is monitored by BUN twice weekly, cut-off levels of BUN are 10-16 mg/dl*
• If the level is < 10 mg/dl extra protein is added to the STD fortification
• Targeted Fortification
• Macronutrient concentrations in HM are analyzed and based on the results milk is supplemented with extra
protein and/or fat

16. • 18 small trials totalling 1456 preterm infants  multi‐nutrient fortified human breast milk vs
unfortified breast milk
• Multi‐nutrient fortification of human milk increases in‐hospital rate of weight gain, body length or
head circumference among preterm infants
• The data do not suggest other benefits or harms and provide low‐certainty evidence suggesting
effects of multi‐nutrient fortification on the risk of necrotizing enterocolitis (NEC) in preterm
infants
• Authors’ conclusion: feeding preterm infants with multi-nutrient fortified human breast milk
compared with unfortified human breast milk is associated with modest increases in in-hospital
growth rates. Evidence is insufficient to show whether multi-nutrient fortification has any effect on
long term growth or neurodevelopment
Brown JV, Lin L, Embleton ND, Harding JE, McGuire W. Multi-nutrient fortification of human milk for preterm infants. Cochrane Database Syst Rev. 2020 Jun 3;6(6):CD000343.

17. Controlled, multicenter, double-blind study, a
sample of preterm infants ≤32 weeks or ≤1500g
were randomized to receive nHMF (n=77) or
cHMF (n=76) for a minimum of 21 days
Weight gain rate between study days 1 and 21
(g/kg/day)
18.3
16.8
16
16.5
17
17.5
18
18.5
nHMF cHMF
The difference:
1.5 g/kg/day
nHMF: new powdered HM fortifier
cHMF: control HM fortifier
A new human milk fortifier containing partially hydrolyzed
protein, fat, and carbohydrate provides a higher protein : energy
ratio  improves weight gain and reduces postnatal growth
restriction compared to the current fortifier
Rigo J, Hascoët JM, Billeaud C, Picaud JC, Mosca F, Rubio A, et al. Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial. J Pediatr Gastroenterol Nutr. 2017 Oct;65(4):e83-e93.

18. HMF Composition
HMF - A
(per sachet 1 g) +
Breastmilk
HMF - B
(Per Sachet 0.71 g) +
Breastmilk
HMF - C
(Per 1 g)
Energy 4.35 kcal 3.5 kcal Not mentioned
Protein 0.36 g 0.28 g 0.27 g
Omega 3 4.17 mg Not mentioned Not mentioned
Omega 6 9.58 mg Not mentioned Not mentioned
DHA 1.57 mg Not mentioned Not mentioned
ARA 0.12 mg Not mentioned Not mentioned
Iron 0.44 mg 0.36 mg 0.0972 mg
Nutritional value information on the labels of some HMF.

19. New Powdered Human Milk Fortifier
FSI1=fortification strength increase day 1; W40CA=week 40 corrected age; z scores calculated using Fenton preterm growth chart
*P=0.013 vs cHMF (by analysis of covariance, adjusting for value at D1, sex, and center); †P=0.007 vs day 1 (by t test); **P=0.003 vs cHMF (by analysis of covariance, adjusting for value at D1, sex, and center)
Mean±SD weight-for-age
• Weight for-age z score (at D21) was significantly higher in nHMF compared to cHMF (0.12 [95% CI: 0.03, 0.22])
• Head circumference-for-age z scores (atW40CA)were significantly higher in nHMF compared to cHMF
(0.41 [95% CI: 0.14, 0.68])
Mean±SD head circumference-for-age
nHMF = new powdered HM fortifier
cHMF = control HM fortifier
Rigo J, Hascoët JM, Billeaud C, Picaud JC, Mosca F, Rubio A, et al. Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial. J Pediatr Gastroenterol Nutr. 2017 Oct;65(4):e83-e93.

20. Fortification of Feeding
• If maternal or donor human milk is not utilized or sufficient to meet
required feeding volumes  formula feedings can be initiated
• It is important to monitor the growth velocity of the infant, along
with monitoring for osteopenia of prematurity
Kumar RK, Singhal A, Vaidya U, Banerjee S, Anwar F, Rao S. Optimizing Nutrition in Preterm Low Birth Weight Infants—Consensus Summary. Front Nutr 2017;4
Thoene MK, Anderson-Berry AL. A review of Best Evidenced-based Enteral and Parenteral Nutrition Support Practices for Preterm Infants Born <1,500 Grams. Pediatric Medicine. 2018 Oct 23];1(0).

21. Preterm Formula Composition
ESPGHAN 2010
Recommendation
Unit Preterm
Formula A
Preterm
Formula B
Preterm
Formula C
Preterm
Formula D
Energy 110 – 135 kcal/kg/day Kcal/100 ml 83 80 83 74
Protein Body weight 1 -1.8 kg =
3.2 – 3.6 g/100 kcal
g/100 kcal 3.4 3.3 3.4 2.5
Omega 6 /
LA
350 – 1400 mg/100 kcal mg/100 kcal 889.7 740 698 601.2
Omega 3 /
ALA
> 50 mg/100 kcal mg/100 kcal 65.1 74 56 64.5
DHA 11 – 27 mg/100 kcal mg/100 kcal 19.8 17 20 8.25
AA 16 – 39 mg/100 kcal mg/100 kcal 20.8 34 21 18.8
Iron 1.8 – 2.7 mg/100 kcal mg/100 kcal 2.2 1.8 1.8 1.4
Osmolarity mOsm/L 317 320 374.5 N/A
Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and
Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010 Jan;50(1):85-91.
Nutritional value information on the labels of some premature formula.

22. Anthropometry
Anthropometry
Parameter
Should be Measure Until
Weight 24 month
Length 42 month
Head circumference 18 month
INTERGROWTH-21st. International Fetal and Newborn Growth Standards for the 21st Century: Anthropometry handbook. The International Fetal and Newborn Growth Consortium; 2012.

23. Optimal Growth for Preterm Neonates in CMH

25. 0 = does not apply; + to +++ reflects relative importance; +/− = of dubious value. w = weeks; m = months; y = years;
CVS = cardiovascular system; UR = unreliable. *prior to school entry; †1-2 years after starting school; ‡growth 12–14 years
includes normal pubertal development; §overweight/obesity an ongoing issue; ¶ongoing life learning; ^relevant to early
presentation of autism spectrum disorder. Shaded areas represent a suggested minimal checklist for busy clinicians.
High Risk Children Follow Up
Doyle LW, Anderson PJ, Battin M, Bowen JR, Brown N, Callanan C, et al.
Long term follow up of high risk children: who, why and how? BMC Pediatr. 2014 Dec;14(1):279.
High-risk children who are
destined to have higher than
expected rates of health or
developmental problems
 need more structured &
specialised follow-up
programs

26. 0 = does not apply; + to +++ reflects relative importance; +/− = of dubious value. w = weeks; m = months; y = years; CVS =
cardiovascular system; UR = unreliable. *prior to school entry; †1-2 years after starting school; ‡growth 12–14 years includes
normal pubertal development; §overweight/obesity an ongoing issue; ¶ongoing life learning; ^relevant to early presentation
of autism spectrum disorder. Shaded areas represent a suggested minimal checklist for busy clinicians.
Doyle LW, Anderson PJ, Battin M, Bowen JR, Brown N, Callanan C, et al.
Long term follow up of high risk children: who, why and how? BMC Pediatr. 2014 Dec;14(1):279.
High Risk Children Follow Up (cont)

27. Take Home Message
Optimization of the nutritional care for the preterm infants has a key role in
improving neurodevelopmental outcomes and has become a priority.
Fortification of human milk is necessary to prevent EUGR which is associated
with poor neurocognitive outcome and to avoid specific nutrient deficiencies.

28. ThankYou!

29. Bone Mineral Disease
 Urinary calcium and phosphate excretion have also been indicated as biomarkers of
postnatal skeletal mineralization
 Since Phosphate isn’t bound to albumin like calcium, urinary phosphate excretion is
preferable than urinary calcium for the screening of MBD
• Tubular Reabsorption of Phosphate (TRP)  measure the fraction of filtered
phosphate that is reabsorbed and is a calculated from the ratio of phosphorus and
creatinine in serum and urine
• Hypophosphatemia causes reduced PTH release which increasesTRP
Renal TRP (Tubular Reabsorption of Phosphate) more than 95% suggest that there might
be insufficient supplementation of either calcium or phosphate
TRP = [1-(urinary phosphorus/urinary creatinine × serum creatinine/serum phosphorus)] × 100
Rehman MU, Narchi H. Metabolic Bone Disease in The Preterm Infant: Current State and Future Directions. World J Methodol. 2015;5(3):115-121.
Faienza MF, D’Amato E, Natale MP, Grano M, Chiarito M, Brunetti G, et al. Metabolic Bone Disease of Prematurity: Diagnosis and Management. Front Pediatr. 2019 Apr 12;7.

30. TRP Calculator
http://www.scymed.com/en/smnxps/pshpd274.htm

31. Choices of Enteral Feeding in RSCM