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Nutritional Management of Premature
               Infants

        Ekhard E. Ziegler, M.D.

      Fomon Infant Nutrition Unit
       Department of Pediatrics
         University of Iowa
Acknowledgement
Dr. Ziegler receives grant support form
Abbott, Mead Johnson and Nestlé

Dr. Ziegler gives talks, for which he
     sometimes receives payment, on
     behalf of Abbott, MeadJohnson and
     Nestlé
Phases of nutritional support

Phase 1: - Parenteral nutrition
         - Gut priming
Phase 2: Transition feeding: Enteral
           phased in, parenteral phased
out
Phase 3: Enteral (late)
Phase 4: Post-discharge
Early nutrition period
Gut priming

Dealing with an immature and unused gut

Objective: Maturation of immature gut
The immature gut
•   Diminished cell mass, enzyme activity
•   Increased permeability
•   Disordered, immature motility
•   Susceptibility to NEC
•   Absent or abnormal microbiota
A Walker J Pediat 2010; 156: S3-7
Small intestinal motility
                               Term infant




From: C.L.Berseth, J Pediatr 1990;117:777
Small intestinal motility
                         Premature infant (32 weeks)




From: C.L.Berseth, J Pediatr 1990;117:777
From: Cormack & Bloomfield, J Paed Child Health 2006;42:458-63
Gastric residuals
•   Are normal in the first 2 weeks of life
•   Are sometimes green or yellow
•   Consist mostly of gastric secretions
•   Do not indicate "intolerance"
•   Indicate immature motility
•   Do not indicate NEC, or impending NEC,
       unless there are other signs of NEC
Clinical manifestations of GI
         tract immaturity
1. Gastric emptying slow and erratic and
   strongly dependent on body position
2. Duodenal reflux common (bilious residuals)
3. Susceptibility to NEC
4. Intestinal transit time long
5. Bowel movements irregular
Gut priming

Q: Start when?
A: On day of birth or next day
Q: Why early?
A: Delay only postpones maturation and
    induces atrophy
Q: Doesn't early start increase risk of NEC?
A: No, it does not increase risk of NEC, it
    actually decreases it and that of sepsis
Gut priming

Q: Priming with what?
A: Human milk
Q: Why?
A: Human milk primes the gut more efficiently
    and more safely than anything else
Gut priming
Q: Priming with how much?
A: Very small volumes, 1-2 cc every 8 hrs

Q: Start to advance?
A: When residuals begin to decrease
Why is human milk so important
       for gut priming?

 • Strong trophic effects
 • Strong anti-infectious effects
 • Protects against sepsis, NEC and death
Human milk and GI priming
           Relevant properties
•    Trophic effects
•    Anti-infective effects
•    Ant-inflammatory effects
•    (Prebiotic effects)
•    (Anti-NEC effect)
Human milk
          Trophic factors
EGF (epidermal growth factor)
TGFα
Insulin
IGF-1
Lactoferrin
Heat-stable factor(s)
Trefoil factors
Human milk in the VLBW infant
             Trophic effects

•   Stimulates cell proliferation
•   Decreases permeability
•   Enhances motility maturation
•   Protects from NEC
Clinical correlates of trophic
     effects of human milk
1. Fewer and smaller residuals
2. Rapid feeding advancement, full feeds
     sooner
3. Absence of abdominal distention episodes
4. Rapid gastric emptying
5. Low susceptibility to NEC
Human milk
        Anti-infectious components
•   Cells (macrophages, T and B cells)
•   Secretory IgA
•   Lactoferrin
•   Lysozyme
•   Bactericidal substances
•   Fatty acids
•   Oligosaccharides      anti-adhesive
•   Mucins                 effects
Human milk oligosaccharides (2)
                    Effects
• Anti-infectious: Inhibit pathogen binding
• Anti-inflammatory
• Prebiotic: Foster colonization by fucose-
     utlizing bacteria
Human milk & the premature infant
                     Sepsis
El-Mohandes et al., 1997
Hylander et al., 1998
Furman et al., 2003
Schanler et al., 2005         not for donor milk
                 Sepsis + NEC
Schanler et al., 1999
Meinzen-Derr et al., 2008
Human milk protects ELBW infants
      against NEC or death

The likelihood of NEC or death was
 decreased by a factor of 0.87 for each 100
 ml/kg increase in human milk intake during
 the first 14 days

Meinzen-Derr et al. for the NICHD Neonatal Research Network
From: J Meinzen-Derr et al., J Perinatol 2009;29:57-62
The huge advantages of human
 milk for the premature infant
1. Protects against sepsis, NEC and
     death
2. Leads to higher IQ later in life
3. Primes the gut better than anything
     else
The disadvantages of human milk
    for the premature infant
1. Nutritionally inadequate
2. There is not always enough of it, not
     all mothers pump
3. The nutrient composition is not known
Securing human milk
Because of its important protective effects, we
must make every effort to secure human milk:
1. Educate mothers before delivery, explain
     how expressed milk is stored and used
2. Support and encourage mothers after
     delivery
3. Obtain donor milk if the mother's milk
     supply is insufficient
Feeding advancement in VLBW infants
                 Guidelines
1. Start feeds on day 1 or 2
2. Start with low volume, e.g., 2 cc/8hrs
3. Monitor gastric residuals
4. Increase feeds slowly in frequency and/or
   size as residuals subside
5. Do not hold feedings because of occasional
   large residuals
6. Pay attention to passage of meconium
Transition feeding
              Issues
How fast to advance
When to start fortification
When to stop TPN
Advancement of feedings

1. Kennedy & Tyson 2009 Cochrane
       3 studies; 10 – 20 cc/kg/d vs 30 – 35 cc/kg/d
       No effect on NEC, reached full feeds sooner
2. Morgan et al. 2011 Cochrane
       4 studies; 15-20 cc/kg/d vs 30 – 35 cc/kg/d
       No effect on NEC or mortality; full feeds
                    sooner (2-5 days)
3. At least 2 newer studies, same findings
Early feeding advancement
     Härtel et al., J Ped Gast Nutr 2009;48:464-470


                         Slow         p       Rapid
Late-onset sepsis        20.4%       0.002    14.0%
Central line             48.6%      <0.001    31.1%
Antibiotics              92.4%      <0.001    77.7%
Ronnestad, A. et al. Pediatrics 2005;115:e269-e276
         Copyright ©2005 American Academy of Pediatrics
When to start fortification

1.  At Iowa we start when the feeding
   volume reaches 25 ml/day (= 1 packet
   of powder fortifier)
2. Most commonly started at 100
   ml/kg/day. Why so late?
Fortification of human milk
                     Initiation
1. Most commonly at 80 or 100 cc/kg/day
      enteral feeding volume
2. At Iowa: At feeding volume of 25 cc/kg/d
   Advantages: - Probably decreases need for
   PN
                  - Baby still has gastric
   residuals
Transition feeding

Q: When to stop parenteral nutrition?
A: When enteral feeds are >90% of full
Late enteral feeding

Enteral feedings are sole source of
             nutrients
Late enteral feeding
Objective: Deliver adequate amounts of
         nutrients for normal* growth
Main problem: Fortification of human
         milk

* normal = like fetus +- catch-up
Late enteral feeding

          The key issue:
How to consistently provide adequate
          protein intakes
Human milk fortification
              Why fortification?
Human milk provides about 1/3 of the protein and
 only a fraction of most other nutrients needed by
 the premature infant
Meeting the need for protein with human milk alone
 would require feed volumes of >300 ml/kg/d and
 provide 3x the amount of energy needed, and
 would still not meet the needs for most other
 nutrients
Human milk fortification
                  Objective
Increase concentration of protein and minerals
  so that we can meet the requirements for
  protein and minerals without feeding huge
  amounts of calories
Data of Lemons et al., Ped. Res. 16:113 (1982)
Fortified Human Milk
                          Protein (g/100 mL)
  Human milk, 2 weeks             1.5
  Fortifier                       1.0
  Total                           2.5
Protein/energy = 3.1 g/100 kcal
Protein intake = 3.4 g/kg/d (at 110 kcal/kg/d)
Fortification of Mother’s Milk
                          Protein (g/100 mL)
  Mother’s milk, 4 weeks          1.1
  Powder fortifier                1.0
  Total                           2.1
Protein/energy = 2.6 g/100 kcal
Protein intake = 3.1 g/kg/d (at 120 kcal/kg/d)
Fortification of Mother’s Milk
                          Protein (g/100 mL)
  Mother’s milk, 4 weeks          1.1
  Powder fortifier                1.0
  Extra fortifier                 0.5
  Total                           2.6
Protein/energy = 3.25 g/100 kcal
Protein intake = 3.9 g/kg/d (at 120 kcal/kg/d)
Human milk fortifiers
(amounts of nutrients added to each100 ml human milk)

                Powder A Powder B Liquid
Calories (kcal)   14        14     14
Protein (g)       1.0       1.1    1.8
Na (meq)          0.65      0.5    0.5
Ca (mg)           117       90     90
Iron (mg)         0.35      1.4    1.4
Plus all other minerals, trace minerals and vitamins in
    adequate amounts
Alternative to fortification

Alternate feeding of mother's milk
 with feeding of formula (HiPro)
Formulas for premature infants
Caloric density: Standard 80 kcal/dl (some also
      available at 90 kcal/dl and 100 kcal/dl)
Protein: 3.0 or 3.3g/100 kcal
Lipid: 40% MCT oil; DHA, ARA
Carbohydrate: 40% lactose, 60% glucose polymers
Minerals (per 100 kcal): Ca 165, P 83
Iron: 14 mg/L (or 4 mg/L)
Formulas for preterm infants
          protein content (g/100 kcal)

Body weight Requir.      Formula     Formula
    (g)                   Standard   Hi-protein
  500-700        3.8        3.0      3.3 3.5
  700-900        3.7        3.0      3.3 3.5
 900-1200        3.4        3.0      3.3 3.5
1200-1500        3.1        3.0      3.3
1500-1800        2.8        3.0
1800-2200        2.6        3.0
2200-2800        2.5        2.8
2800-3500        2.3        2.8
3500+            1.8        2.2
What can you do to ensure
  adequate nutrition?

Monitor protein intakes
Monitor growth: Plot infant weight
   on chart (or use target weight
   gains), make sure growth runs
   parallel to fetal percentiles, or
   crosses them upwards
Fenton chart
Human milk fortification
Adding calories alone to mother's milk
 lowers the protein/energy ratio to <1.6
               g/100 kcal
               Therefore
     Fat (canola oil, MCT oil) or
              carbohydrate
must never be added to mother's milk
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
    undermineralized bones
Hence the infant needs more protein and
    more minerals than plain mother's milk
    or term formula can provide
Selected Nutrient Levels of Formulas
                (per 100 kcal)
               Premature   Post-     Term
               formula     discharge formula
                           formula
Kcal/dl        80          74        67
Protein        3.0-3.5     2.8       2.1
Vitamin A      1250        460       300
Vitamin B6     250         100       60
Ca             180         105       78
Fe             1.8         1.8       1.8
Post-discharge nutritional
 management of the VLBW infant
                      Summary
• Formula-fed infants: Special post-discharge
  formulas (provide adequate protein, Ca, P; Fe)
• Breast-fed infants: Fortification
  (supplementation) indicated, but not practiced
  regularly, difficult to perform; special attention
  to Fe supplementation
Good nutrition does not save
            lives
      It saves brains

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Nutritional Management of Premature Infants

  • 1. Nutritional Management of Premature Infants Ekhard E. Ziegler, M.D. Fomon Infant Nutrition Unit Department of Pediatrics University of Iowa
  • 2. Acknowledgement Dr. Ziegler receives grant support form Abbott, Mead Johnson and Nestlé Dr. Ziegler gives talks, for which he sometimes receives payment, on behalf of Abbott, MeadJohnson and Nestlé
  • 3. Phases of nutritional support Phase 1: - Parenteral nutrition - Gut priming Phase 2: Transition feeding: Enteral phased in, parenteral phased out Phase 3: Enteral (late) Phase 4: Post-discharge
  • 5. Gut priming Dealing with an immature and unused gut Objective: Maturation of immature gut
  • 6. The immature gut • Diminished cell mass, enzyme activity • Increased permeability • Disordered, immature motility • Susceptibility to NEC • Absent or abnormal microbiota
  • 7. A Walker J Pediat 2010; 156: S3-7
  • 8. Small intestinal motility Term infant From: C.L.Berseth, J Pediatr 1990;117:777
  • 9. Small intestinal motility Premature infant (32 weeks) From: C.L.Berseth, J Pediatr 1990;117:777
  • 10. From: Cormack & Bloomfield, J Paed Child Health 2006;42:458-63
  • 11. Gastric residuals • Are normal in the first 2 weeks of life • Are sometimes green or yellow • Consist mostly of gastric secretions • Do not indicate "intolerance" • Indicate immature motility • Do not indicate NEC, or impending NEC, unless there are other signs of NEC
  • 12. Clinical manifestations of GI tract immaturity 1. Gastric emptying slow and erratic and strongly dependent on body position 2. Duodenal reflux common (bilious residuals) 3. Susceptibility to NEC 4. Intestinal transit time long 5. Bowel movements irregular
  • 13. Gut priming Q: Start when? A: On day of birth or next day Q: Why early? A: Delay only postpones maturation and induces atrophy Q: Doesn't early start increase risk of NEC? A: No, it does not increase risk of NEC, it actually decreases it and that of sepsis
  • 14. Gut priming Q: Priming with what? A: Human milk Q: Why? A: Human milk primes the gut more efficiently and more safely than anything else
  • 15. Gut priming Q: Priming with how much? A: Very small volumes, 1-2 cc every 8 hrs Q: Start to advance? A: When residuals begin to decrease
  • 16. Why is human milk so important for gut priming? • Strong trophic effects • Strong anti-infectious effects • Protects against sepsis, NEC and death
  • 17. Human milk and GI priming Relevant properties • Trophic effects • Anti-infective effects • Ant-inflammatory effects • (Prebiotic effects) • (Anti-NEC effect)
  • 18. Human milk Trophic factors EGF (epidermal growth factor) TGFα Insulin IGF-1 Lactoferrin Heat-stable factor(s) Trefoil factors
  • 19. Human milk in the VLBW infant Trophic effects • Stimulates cell proliferation • Decreases permeability • Enhances motility maturation • Protects from NEC
  • 20. Clinical correlates of trophic effects of human milk 1. Fewer and smaller residuals 2. Rapid feeding advancement, full feeds sooner 3. Absence of abdominal distention episodes 4. Rapid gastric emptying 5. Low susceptibility to NEC
  • 21. Human milk Anti-infectious components • Cells (macrophages, T and B cells) • Secretory IgA • Lactoferrin • Lysozyme • Bactericidal substances • Fatty acids • Oligosaccharides anti-adhesive • Mucins effects
  • 22. Human milk oligosaccharides (2) Effects • Anti-infectious: Inhibit pathogen binding • Anti-inflammatory • Prebiotic: Foster colonization by fucose- utlizing bacteria
  • 23. Human milk & the premature infant Sepsis El-Mohandes et al., 1997 Hylander et al., 1998 Furman et al., 2003 Schanler et al., 2005 not for donor milk Sepsis + NEC Schanler et al., 1999 Meinzen-Derr et al., 2008
  • 24. Human milk protects ELBW infants against NEC or death The likelihood of NEC or death was decreased by a factor of 0.87 for each 100 ml/kg increase in human milk intake during the first 14 days Meinzen-Derr et al. for the NICHD Neonatal Research Network
  • 25. From: J Meinzen-Derr et al., J Perinatol 2009;29:57-62
  • 26. The huge advantages of human milk for the premature infant 1. Protects against sepsis, NEC and death 2. Leads to higher IQ later in life 3. Primes the gut better than anything else
  • 27. The disadvantages of human milk for the premature infant 1. Nutritionally inadequate 2. There is not always enough of it, not all mothers pump 3. The nutrient composition is not known
  • 28. Securing human milk Because of its important protective effects, we must make every effort to secure human milk: 1. Educate mothers before delivery, explain how expressed milk is stored and used 2. Support and encourage mothers after delivery 3. Obtain donor milk if the mother's milk supply is insufficient
  • 29. Feeding advancement in VLBW infants Guidelines 1. Start feeds on day 1 or 2 2. Start with low volume, e.g., 2 cc/8hrs 3. Monitor gastric residuals 4. Increase feeds slowly in frequency and/or size as residuals subside 5. Do not hold feedings because of occasional large residuals 6. Pay attention to passage of meconium
  • 30.
  • 31. Transition feeding Issues How fast to advance When to start fortification When to stop TPN
  • 32. Advancement of feedings 1. Kennedy & Tyson 2009 Cochrane 3 studies; 10 – 20 cc/kg/d vs 30 – 35 cc/kg/d No effect on NEC, reached full feeds sooner 2. Morgan et al. 2011 Cochrane 4 studies; 15-20 cc/kg/d vs 30 – 35 cc/kg/d No effect on NEC or mortality; full feeds sooner (2-5 days) 3. At least 2 newer studies, same findings
  • 33. Early feeding advancement Härtel et al., J Ped Gast Nutr 2009;48:464-470 Slow p Rapid Late-onset sepsis 20.4% 0.002 14.0% Central line 48.6% <0.001 31.1% Antibiotics 92.4% <0.001 77.7%
  • 34. Ronnestad, A. et al. Pediatrics 2005;115:e269-e276 Copyright ©2005 American Academy of Pediatrics
  • 35. When to start fortification 1. At Iowa we start when the feeding volume reaches 25 ml/day (= 1 packet of powder fortifier) 2. Most commonly started at 100 ml/kg/day. Why so late?
  • 36. Fortification of human milk Initiation 1. Most commonly at 80 or 100 cc/kg/day enteral feeding volume 2. At Iowa: At feeding volume of 25 cc/kg/d Advantages: - Probably decreases need for PN - Baby still has gastric residuals
  • 37. Transition feeding Q: When to stop parenteral nutrition? A: When enteral feeds are >90% of full
  • 38. Late enteral feeding Enteral feedings are sole source of nutrients
  • 39. Late enteral feeding Objective: Deliver adequate amounts of nutrients for normal* growth Main problem: Fortification of human milk * normal = like fetus +- catch-up
  • 40. Late enteral feeding The key issue: How to consistently provide adequate protein intakes
  • 41. Human milk fortification Why fortification? Human milk provides about 1/3 of the protein and only a fraction of most other nutrients needed by the premature infant Meeting the need for protein with human milk alone would require feed volumes of >300 ml/kg/d and provide 3x the amount of energy needed, and would still not meet the needs for most other nutrients
  • 42. Human milk fortification Objective Increase concentration of protein and minerals so that we can meet the requirements for protein and minerals without feeding huge amounts of calories
  • 43.
  • 44. Data of Lemons et al., Ped. Res. 16:113 (1982)
  • 45. Fortified Human Milk Protein (g/100 mL) Human milk, 2 weeks 1.5 Fortifier 1.0 Total 2.5 Protein/energy = 3.1 g/100 kcal Protein intake = 3.4 g/kg/d (at 110 kcal/kg/d)
  • 46. Fortification of Mother’s Milk Protein (g/100 mL) Mother’s milk, 4 weeks 1.1 Powder fortifier 1.0 Total 2.1 Protein/energy = 2.6 g/100 kcal Protein intake = 3.1 g/kg/d (at 120 kcal/kg/d)
  • 47. Fortification of Mother’s Milk Protein (g/100 mL) Mother’s milk, 4 weeks 1.1 Powder fortifier 1.0 Extra fortifier 0.5 Total 2.6 Protein/energy = 3.25 g/100 kcal Protein intake = 3.9 g/kg/d (at 120 kcal/kg/d)
  • 48. Human milk fortifiers (amounts of nutrients added to each100 ml human milk) Powder A Powder B Liquid Calories (kcal) 14 14 14 Protein (g) 1.0 1.1 1.8 Na (meq) 0.65 0.5 0.5 Ca (mg) 117 90 90 Iron (mg) 0.35 1.4 1.4 Plus all other minerals, trace minerals and vitamins in adequate amounts
  • 49. Alternative to fortification Alternate feeding of mother's milk with feeding of formula (HiPro)
  • 50. Formulas for premature infants Caloric density: Standard 80 kcal/dl (some also available at 90 kcal/dl and 100 kcal/dl) Protein: 3.0 or 3.3g/100 kcal Lipid: 40% MCT oil; DHA, ARA Carbohydrate: 40% lactose, 60% glucose polymers Minerals (per 100 kcal): Ca 165, P 83 Iron: 14 mg/L (or 4 mg/L)
  • 51. Formulas for preterm infants protein content (g/100 kcal) Body weight Requir. Formula Formula (g) Standard Hi-protein 500-700 3.8 3.0 3.3 3.5 700-900 3.7 3.0 3.3 3.5 900-1200 3.4 3.0 3.3 3.5 1200-1500 3.1 3.0 3.3 1500-1800 2.8 3.0 1800-2200 2.6 3.0 2200-2800 2.5 2.8 2800-3500 2.3 2.8 3500+ 1.8 2.2
  • 52. What can you do to ensure adequate nutrition? Monitor protein intakes Monitor growth: Plot infant weight on chart (or use target weight gains), make sure growth runs parallel to fetal percentiles, or crosses them upwards
  • 54. Human milk fortification Adding calories alone to mother's milk lowers the protein/energy ratio to <1.6 g/100 kcal Therefore Fat (canola oil, MCT oil) or carbohydrate must never be added to mother's milk
  • 55. 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 undermineralized bones Hence the infant needs more protein and more minerals than plain mother's milk or term formula can provide
  • 56. Selected Nutrient Levels of Formulas (per 100 kcal) Premature Post- Term formula discharge formula formula Kcal/dl 80 74 67 Protein 3.0-3.5 2.8 2.1 Vitamin A 1250 460 300 Vitamin B6 250 100 60 Ca 180 105 78 Fe 1.8 1.8 1.8
  • 57. Post-discharge nutritional management of the VLBW infant Summary • Formula-fed infants: Special post-discharge formulas (provide adequate protein, Ca, P; Fe) • Breast-fed infants: Fortification (supplementation) indicated, but not practiced regularly, difficult to perform; special attention to Fe supplementation
  • 58. Good nutrition does not save lives It saves brains