1. Innovations in Human Milk: Putting Evidence to Practice
Amy B. Hair, MD
Assistant Professor of Pediatrics
Program Director of Neonatal Nutrition
Program Director of NICU Intestinal Rehab Team
Section of Neonatology
Department of Pediatrics
Texas Children’s Hospital

2. Disclosures I receive research support from:
Prolacta Bioscience® for the Human Milk Cream Length of Stay Multicenter Study (Study PI)
I receive speaker honoraria from Prolacta Bioscience®

3. Overview Benefits of human milk for preterm infants
Role of donor human milk-derived fortifier for extremely preterm infants
Innovations: An exclusive human milk-based diet
Studies in progress and future directions
Implementation of an exclusive human milk-based diet

4. AAP Statement 2012 “Breastfeeding and the Use of Human Milk”
“All preterm infants should receive human milk.”
Human milk should be fortified, with protein, minerals, and vitamins to ensure optimal nutrient intake for infants weighing <1500 grams at birth
Pasteurized donor human milk (DHM), appropriately fortified, should be used if mother’s own milk is unavailable or its use is contraindicated
Significant short and long-term beneficial effects of feeding preterm infants human milk
American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012; 129(3): e827-e841.

5. Benefits of Human Milk ↓ Respiratory tract infections and otitis media
↓ Sudden infant death syndrome and mortality
↓ GI infections
↓ Risk of celiac disease and IBD
↓ Asthma, atopic dermatitis and eczema
↓ Incidence of NEC
Associated with a decrease in obesity and diabetes
Beneficial influence on neurodevelopmental outcomes
Possible reduction in severity of retinopathy of prematurity
American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012; 129(3): e827-e841.

6. Necrotizing Enterocolitis
NEC is a devastating illness that affects 5.4 to 7.4% of VLBW infants/year (Vermont Oxford Network)
Despite years of ongoing research, the exact pathophysiology of necrotizing enterocolitis is still not known
Multifactorial
Mucosal injury leading to an exaggerated immune response, which then results in bacterial translocation, systemic infection, and inflammation

7. Necrotizing Enterocolitis
Problems of the Neonate. (2007).

8. Pasteurized Donor Human Milk
Human Milk Banking Association of North America
Medolac / Mothers Milk Cooperative
Prolacta Bioscience
Hospital Based Milk Banks

9. Texas Children’s Hospital Mothers’ Milk Bank
Opened in August 2011
(832) 824-MILK

10. Exclusive Human Milk-Based Diet
The use of an exclusive human milk-based diet in infants ≤ 1250 grams birth weight is associated with a lower rate of necrotizing enterocolitis (NEC)1,2 and decreased parenteral nutrition days2
An exclusive human milk diet is associated with lower mortality and morbidity compared to a cow milk based protein diet3
Study 1- Decreases NEC by 60% and the rate of NEC needing surgical intervention by 90%
Study 2- decreases surgical NEC and TPN days
parenteral nutrition days 36 (29,77) vs 27 (14,39) p=0.04
NEC surgery 4 (17%) vs. 0 p=0.036
NEC 5 (21%) vs 1 (3%), p=0.08
1Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): , Cristafalo et al: Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants. J Pediatr 163 (6): , Abrams et al: Greater mortality and morbidity in extremely preterm infants fed a diet containing cow milk protein products. Breastfeeding Medicine 9 (6): 281-5, 2014.

11. An Exclusive Human Milk-Based Diet and NEC¹
Medical NEC by 60%
Surgical NEC by 90%
NNT to prevent 1 case of NEC is 10
NNT to prevent 1 case of surgical NEC is 8
¹Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): , 2010.

12. Exclusive Human Milk-Based Diet
Sullivan et al1 showed that there is no difference in growth between infants fed an exclusively human milk-based diet and infants fed human milk plus bovine milk-based products
However, concerns remain related to risks of slow growth in these infants
1Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): , Cristafalo et al. A Randomized Trial of Exclusive Human Milk Versus Preterm Formula Diets in Extremely Premature Infants. J Pediatr 163 (6): , 2013.

13. Human Milk Feeding Supports Adequate Growth
Exclusive Human Milk-Based Diet
Early and rapid advancement of fortification1
104 infants, consecutively followed, BW ≤ 1250 g, received diet until 34 weeks PMA
Weight gain 24.8 ± 5.4 g/kg/day, length 0.99 ± cm/week, HC 0.72 ± 0.14 cm/week
Compared to human milk-fed cohorts (Sullivan et al2)
Infants had greater growth in weight and length
43% of infants had postnatal growth failure
Diet until 34 weeks PMA
Fortification advanced to 8 kcal/oz or 140 kcal/kg/day and 4.4 g/kg/d of protein (mature human milk and feeds of 150 ml/kg/day) up to kcal/kg/d and 5.25 g/kg/d protein
3 cases of NEC and 1 case of surgical NEC
1Hair et al: Human Milk Feeding Supports Adequate Growth in Infants ≤ 1250 grams birth weight. BMC Res Notes 2013; 6: Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): , 2010.

14. Sullivan et al. J Pediatrics. 20102
Hair et al Study1
Human Milk
+ HMF 60
(n=104)
Sullivan et al. J Pediatrics
p-value
+ HMF 40
(n=71)
+ HMF 100
(n=67)
Bovine
(n=69)
Days to full feeds*
18.2 ± 10.6
24.4 ± 12.7
26.5 ± 18.0
25.0 ± 13.5
<0.001
TPN days†
13 (10,19)
20 (11,33)
20 (13,34)
22 (13,34)
Feeds initiated (DOL)*
3.3 ± 2.9
5.6 ± 6.6
4.3 ± 3.9
4.7 ± 4.8
0.56
Fortification of feeds (DOL)*
13.0 ± 8.3
14.1 ± 9.0
21.0 ± 14.9
18.4 ± 9.2
Kruskal-Wallis test for means
Kaplan-Meier estimation/ method for medians and (25th,75th %tile)
No censoring assumed in Baylor data
Full feeds
*Mean ± SD, †Median (25th, 75th percentile).
DOL = day of life; TPN = total parenteral nutrition.
1Hair et al: Human Milk Feeding Supports Adequate Growth in Infants ≤ 1250 grams birth weight. BMC Res Notes 2013; 6: Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): , 2010.

15. Caloric Variation of Human Milk
Study of 415 sequential samples from 273 unique donors
Analyzed for fat, protein, carbohydrate
Mean energy content of milk was 19 kcal/oz
25% of the samples were < 17 kcal/oz
65% were < 20 kcal/oz
Fat content was the most variable
3.2 g/dL
Wojcik KY, Rechtman DJ, Lee ML et al. Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc 109: , 2009.

16. Human Milk Cream
We have the ability to measure the caloric density and macronutrients of human milk
IR analyzer
Requires < 5 mL of milk
A novel donor human milk-derived cream supplement is now available
Human Milk Cream or Human Milk Fat is derived from the processing of donor human milk
Caloric content is 2.5 kcal/mL
Prolact-CR

17. Randomized Trial of Human Milk Cream as a Supplement to Standard Fortification of an Exclusive Human Milk- Based Diet in Infants g BW

18. Objective
To evaluate whether premature infants who received an exclusive human milk-based diet and a human milk-derived cream supplement (cream) would have weight gain (g/kg/day) at least as good as infants receiving a standard feeding regimen (control)

19. Infants 750 to 1250 grams BW receiving exclusive human milk-based diet
(Standard Feeding Regimen)
Analysis of Mother’s Milk or Donor Milk every 24 hrs
CONTROL GROUP
Analysis of Mother’s Milk or Donor Milk every 24 hrs
INTERVENTION GROUP
Caloric Content of
Milk ≥ 20 kcal/oz
Caloric Content of
Milk < 20 kcal/oz
Data recorded for Nutrition and Growth until 36 weeks PMA
Data recorded for Nutrition and Growth until 36 weeks PMA
Addition of Cream Supplement to increase caloric content of milk
to 20 kcal/oz
Data recorded for Nutrition and Growth until 36 weeks PMA

20. Addition of Cream to Human Milk
Caloric Content of Mother’s Own Milk or Donor HM*
Kcal/oz Kcal/100 mL
Volume
of HM
Volume of Cream to
Add to HM
19-20
98 mL
2 mL
96 mL
4 mL
94 mL
6 mL
93 mL
7 mL

21. Comparison of Growth Velocities
Control group
(n=39)
Cream group
p-value
Weight velocity (g/kg/day)
12.4 ± 3.9*
14.0 ± 2.5
0.03
Length velocity (cm/week)
0.83 ± 0.41
1.03 ± 0.33
0.02
Head circumference (cm/week)
0.84 ± 0.22
0.90 ± 0.19
0.21
Weight velocity from time infant regained BW (g/kg/day)
13.7 ± 4.0
15.7 ± 2.5
Two sample t-test
*Mean ± SD

22. Milk Energy Content (kcal/oz)
Houston Site
San Antonio Site
Mother’s Milk
20 ± 5.6
17.6 ± 5.6*
Donor Milk
20.6 ± 1.5
19 ± 2.1*
*p<0.001
Analyzer overestimated by 1.2 kcal/oz for both groups
21.2/18.8
21.8/20.2
Average of 1.2 kcal/oz higher for unity analyzer than lab methods, confidence interval kcal/oz

23. Clinical Outcomes Control group (n=39) Cream Necrotizing
enterocolitis (%)
Sepsis (%)
7.7
10.3
Death (%)
p=1.0, Fisher’s exact test

24. Conclusions
Premature infants who received HM- derived cream supplement to an exclusive HM-based diet had superior weight and length velocity compared to infants who did not receive the supplement

25. Human Milk Cream Follow-up Study
Comparing infants who received cream supplement to control group (standard feeding regimen with exclusive human milk-based diet)
Currently evaluating as many of the 78 original study infants in follow-up at both study centers
18-24 months corrected gestational age
Anthropometrics, Bayley III Neurodevelopmental Exams, triceps skin fold and DXA scans

26. Effects of Cream Supplement on Length of Stay and Bronchopulmonary Dysplasia
The Human Milk Cream Study showed a trend towards a 2-week decreased length of stay for babies who received cream supplement, especially babies who had BPD
Randomized Controlled Trial comparing the use of a cream supplement routinely to infants’ exclusive human milk-based diet compared to standard regimen
Secondary outcomes include BPD, ROP, mortality, growth, NEC

27. Necrotizing Enterocolitis and Beyond: Improving Outcomes with Human Milk
1587 infants < 1250 gram birth weight
4 centers in Texas, Florida, Illinois and California

28. NEC Rates BOV (n=768) HUM (n=819) p-value All NEC % (n) 16.7 (128)
BOV
(n=768)
HUM
(n=819)
p-value
All NEC % (n)
16.7 (128)
6.9 (53)
<
Medical NEC % (n)
6.1 (47)
2.1 (16)
Surgical NEC % (n)
10.6 (81)
4.8 (37)

29. Secondary Outcomes Among All Infants
BOV
n=768
HUM
n=819
p-value
Late onset infection (%)
30.3
19.0
<
Mortality (%)
17.2
13.6
0.04
Weight gain (g/d)
19.5 ± 8.4
20.3 ± 8.6
0.08
IVH: Grade III or IV (%)
16.8
14.5
0.22
Ventilator days
32.2 ± 44.9
29.3 ± 44.2
0.003
Threshold ROP (%)
9.0
5.2
Patent Ductus Arteriosus (%)
64.7
55.1
0.0001
Bronchopulmonary Dysplasia (%)
56.3
47.7
0.0015
Antenatal steroids (%)
75.2
80.5
0.01
Mean ± SD
IVH = intraventricular hemorrhage; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity

30. Conclusions
The use of an exclusive HM-based diet is associated with significant benefits for extremely premature infants < 1250 gram BW
Decreased medical and surgical NEC
Decreased late onset sepsis
Decreased mortality
Decreased bronchopulmonary dysplasia and ventilator days
Decreased retinopathy of prematurity

31. Multicenter Follow-up Study
Combine multicenter data of infants at 2 and 5 years of age
Exclusive human milk-based diet
Bovine milk-based diet
Compare outcomes
Bayley III scores
Growth

32. Objective: Determine the Effect of Syringe Orientation on Fat Retention
Hypothesis: Fat retention will be greatest with the syringe facing “up”, and lowest with syringe “down”
Discuss At TCH, syringes are “flat” in NICU.
“down”
“flat”
“up”

33. Determine the Effect of Syringe Orientation on Fat Retention
Fat Content vs. Infusion Time with Varying Syringe Positions
Fat Retention (%) with Varying Syringe Positions

34. “Pump It Up”
Make sure syringe tip is positioned “up” when giving feeds to all babies
Avoid using extension tubing when feasible
You can help our NICU babies grow by making sure they receive all the nutrients they can from syringe feedings

35. Studies in Progress
Use of an all human milk-based diet in infants with single ventricle congenital heart disease
Multicenter Study
Large Cardiac Centers
Dr. Cynthia Blanco and Dr. Jose Perez are lead PIs
Comparing an all human milk-based diet to bovine fortifiers
Canada and Europe

36. Studies in Progress
Long-term cost analysis of an all human milk- based diet

37. Future Directions
Use of an exclusive human milk-based diet in other high risk infant populations
Congenital Heart Disease
Fluid restricted infants
Abdominal Wall Defects
Human Milk Oligosaccharides (HMOs)
Lacto-engineering

38. Implementation
Evaluate your highest risk population for NEC and feeding intolerance
Gather data regarding NEC rates, TPN days, and feeding intolerance so you have a baseline
Implement Donor Human Milk and DHM Fortifier
Evaluate your results using balancing measures
If cost is an issue consider collecting data including length of stay as a surrogate marker
Often budgets for nutrition are limited

39. Decreased cost and improved feeding tolerance with Exclusive HM diet
293 infants studied
23-34 weeks and BW g
Retrospective study with 3 groups:
Exclusive HM- mother’s milk + donor milk + donor milk derived fortifier
Mother’s milk + bovine fortifier
Mother’s milk + bovine fortifier + formula
Non-industry funded study
Assad et al. Journal of Perinatology 2015

40. Decreased cost and improved feeding tolerance with Exclusive HM diet
Exclusive Human Milk group
Less feeding intolerance
Less number of days to full feeds
Less NEC
Similar growth between all groups
Total hospitalization costs were lower by up to $106,968 per infant in those fed Exclusive Human milk compared to other groups
NEC 10% to 1.1%
Assad et al. Journal of Perinatology 2015

41. Costs- Exclusive HM Diet
Costs of NEC and cost-effectiveness of exclusively human milk-based diet compared to bovine based diet in extremely premature infants
NEC $74,004 and NEC requiring surgery $198,040
Costs over the hospitalization for a preterm infant
100% human milk diet infants had decreased length of stay= cost savings of $8,167
Using mother’s milk with different fortifier
What is the cost of a good outcome?
Infants with surgical NEC have increased risk of re-hospitalization and poor neurodevelopment, extra $$, quality of life
Ganapathy V, Hay JW, Kim JH. Costs of Necrotizing enterocolitis and cost-effectiveness of exclusively human milk based products in feeding extremely premature infants. Breastfeed Med. 7(1):29-37, 2012.

42. Implementation Increase maternal milk supply for premature infants
Pumps at the bedside
Education about benefits of mother’s own milk
Lactation Support
Use of Pasteurized Donor Human Milk
Milk Bank
Availability
Drop off site for donated human milk
Potential variability in energy density of donor human milk depending on milk bank

43. Implementation
Standardized Feeding Protocol

44. Feeding Guidelines ≤ 1250 g BW
Day of Feed
Human Milk [EBM or Donor]
kcal/oz
Feeding Volume
(mL/kg/d)
TPN
Lipids
Total Fluids = Enteral + TPN + IL (mL/kg/d) 1 20
15-20
90-100
5-10
120 2
95-105
10-15
130 3 15
150 4 40 95 5
24 (add donor milk-derived fortifier +4) 60 75
EBM = expressed breast milk; IL = intravenous lipid; TPN = total parenteral nutrition.
Baylor College of Medicine, Section of Neonatology, Department of Pediatrics. Guidelines for Acute Care of the Neonate. 23rd Ed

45. Feeding Guidelines ≤ 1250 g BW
Day of Feed
Human Milk [EBM or Donor]
kcal/oz
Feeding Volume
(mL/kg/d)
TPN
Lipids
Total Fluids = Enteral + TPN + IL (mL/kg/d) 6
24 (donor milk-derived fortifier +4) 80
55-70
15 or Off Lipids
150 7
26 (add donor milk- derived fortifier +6)
100 50 8
26 (donor milk-derived fortifier +6)
120
Off TPN
120 Off TPN or IV fluids 9
140 10
28 (donor milk-derived fortifier +6)+ cream (2 kcal/oz)
160
160 Full enteral feeds
Baylor College of Medicine, Section of Neonatology, Department of Pediatrics. Guidelines for Acute Care of the Neonate. 23rd Ed

46. Positive Outcomes to Follow
Rates of Necrotizing Enterocolitis
Central line days, Parenteral Nutrition Days
CLABSI infection
Growth- weight, length, head circumference
Postnatal growth failure
Feeding tolerance- number of times feeds are stopped and restarted
Costs $$, Decreased Length of Stay
Number of infants not transferred to higher level of care

47. Implementation Extra Costs Implementation
Administrative
Staffing
Milk Bank Techs, Nurses, Preparing Milk
Donor Milk and DHM Fortifier Storage (Freezer)
Implementation
Education of Staff
Implement Consent / Assent of Parents
Risk of Milk Errors
Possible Delay of Enteral Feeding
Awaiting Mother’s own milk or Donor Human Milk Consent

48. We Should Strive for the Best Possible Long Term Outcomes
Liam- 26 weeks, 800 grams

49. Questions?