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
abhair@texaschildrens.org
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®
Pediatrics
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
Pediatrics
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.
Pediatrics
Benefits of Human Milk
•↓ Respiratory tract infections and
otitis media
• Associated with a decrease in
obesity and diabetes
•↓ Sudden infant death syndrome
and mortality
• Beneficial influence on
neurodevelopmental outcomes
•↓ GI infections
• Possible reduction in severity of
retinopathy of prematurity
•↓ Risk of celiac disease and IBD
•↓ Asthma, atopic dermatitis and
eczema
•↓ Incidence of NEC
American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the use of human milk.
Pediatrics. 2012; 129(3): e827-e841.
Pediatrics
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
Pediatrics
Necrotizing Enterocolitis
Problems of the Neonate. (2007). http://web.squ.edu.om/med-Lib/med/net/ETALC9/html/clients/who/hcfc_images/necrotising%20enterocolitis%201.jpg
Pediatrics
Pasteurized Donor Human Milk
• Human Milk Banking Association of
North America
• Medolac / Mothers Milk Cooperative
• Prolacta Bioscience
• Hospital Based Milk Banks
Pediatrics
Texas Children’s Hospital
Mothers’ Milk Bank
Opened in August 2011
www.texaschildrens.org/milk
(832) 824-MILK
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
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): 562-567, 2010. 2Cristafalo et al: Randomized Trial of Exclusive Human Milk versus
Preterm Formula Diets in Extremely Premature Infants. J Pediatr 163 (6): 1592-1595, 2013.3Abrams 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.
Pediatrics
An Exclusive Human Milk-Based Diet and NEC¹
18.0%
16.0%
14.0%
12.0%
10.0%
8.0%
6.0%
4.0%
2.0%
0.0%
NEC
NEC
Surgery
 Medical NEC by 60%
 Surgical NEC by 90%
HM100
(n=67)
HM40
(n=71)
BOV
(n=69)
All HM
(n=138)
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): 562-567, 2010.
Pediatrics
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): 562-567, 2010. 2Cristafalo et al. A Randomized Trial of Exclusive Human Milk
Versus Preterm Formula Diets in Extremely Premature Infants. J Pediatr 163 (6): 1592-1595, 2013.
Pediatrics
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 ± 0.23
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
1Hair
et al: Human Milk Feeding Supports Adequate Growth in Infants ≤ 1250 grams birth weight. BMC Res Notes 2013; 6: 459.
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): 562-567, 2010.
2Sullivan
Pediatrics
Hair et al
Study1
Human Milk
+ HMF 60
(n=104)
Days to full feeds*
Sullivan et al. J Pediatrics. 20102
Human Milk
+ HMF 40
(n=71)
Human Milk
+ HMF 100
(n=67)
Bovine
(n=69)
p-value
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)
<0.001
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
*Mean
± SD, †Median (25th, 75th percentile).
1Hair
DOL = day of life; TPN = total parenteral nutrition.
et al: Human Milk Feeding Supports Adequate Growth in Infants ≤ 1250 grams birth weight. BMC Res Notes 2013; 6: 459.
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): 562-567, 2010.
2Sullivan
Pediatrics
<0.001
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 109:137-140, 2009.
Pediatrics
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
Pediatrics
Randomized Trial of Human
Milk Cream as a
Supplement to Standard
Fortification of an
Exclusive Human MilkBased Diet in Infants 7501250 g BW
Pediatrics
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)
Pediatrics
Infants 750 to 1250 grams BW receiving exclusive human milkbased diet
(Standard Feeding Regimen)
Analysis of Mother’s Milk or
Donor Milk every 24 hrs
CONTROL GROUP
Data recorded for Nutrition
and Growth until 36 weeks
PMA
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
Addition of Cream
Supplement to increase
caloric content of milk
to 20 kcal/oz
Data recorded for Nutrition
and Growth until 36 weeks
PMA
Pediatrics
Addition of Cream to Human Milk
Caloric Content of Mother’s
Own Milk or Donor HM*
Pediatrics
Volume
of HM
Volume of
Cream to
Add to HM
Kcal/oz
Kcal/100 mL
19-20
64-67.9
98 mL
2 mL
18-18.9
61-63.9
96 mL
4 mL
17-17.9
57-60.9
94 mL
6 mL
16-16.9
54-56.9
93 mL
7 mL
Comparison of Growth Velocities
Control group
(n=39)
Cream group
(n=39)
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
13.7 ± 4.0
15.7 ± 2.5
0.02
Weight velocity from time
infant regained BW
(g/kg/day)
*Mean ± SD
Pediatrics
Milk Energy Content (kcal/oz)
Mother’s Milk
Donor Milk
*p<0.001
Pediatrics
Houston Site
San Antonio
Site
20 ± 5.6
17.6 ± 5.6*
20.6 ± 1.5
19 ± 2.1*
Clinical Outcomes
Control
group
(n=39)
0
Cream
group
(n=39)
0
Sepsis (%)
7.7
10.3
Death (%)
0
0
Necrotizing
enterocolitis (%)
Pediatrics
Conclusions
• Premature infants who received HMderived cream supplement to an exclusive
HM-based diet had superior weight and
length velocity compared to infants who
did not receive the supplement
Pediatrics
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
Pediatrics
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
Pediatrics
Necrotizing Enterocolitis and
Beyond: Improving Outcomes with
Human Milk
• 1587 infants < 1250 gram birth weight
• 4 centers in Texas, Florida, Illinois
and California
Pediatrics
NEC Rates
BOV
(n=768)
HUM
(n=819)
p-value
16.7 (128)
6.9 (53)
<0.00001
Medical NEC % (n)
6.1 (47)
2.1 (16)
0.00005
Surgical NEC % (n)
10.6 (81)
4.8 (37)
0.00002
All NEC % (n)
Pediatrics
Secondary Outcomes Among All
Infants
BOV
n=768
HUM
n=819
p-value
Late onset infection (%)
30.3
19.0
<0.00001
Mortality (%)
17.2
13.6
0.04
19.5 ± 8.4
20.3 ± 8.6
0.08
16.8
14.5
0.22
32.2 ± 44.9
29.3 ± 44.2
0.003
Threshold ROP (%)
9.0
5.2
0.003
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
Weight gain (g/d)
IVH: Grade III or IV (%)
Ventilator days
Mean ± SD
IVH = intraventricular hemorrhage; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity
Pediatrics
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
Pediatrics
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
Pediatrics
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”
“down”
Pediatrics
“flat”
“up”
Determine the Effect of Syringe
Orientation on Fat Retention
Fat Retention (%) with Varying
Syringe Positions
Fat Content vs. Infusion Time
with Varying Syringe Positions
100%
90%
Fat Retention
80%
70%
60%
50%
40%
30%
20%
10%
0%
Pediatrics
94.8%
78.6%
60.9%
Syringe
"up"
“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
Pediatrics
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
Pediatrics
Studies in Progress
• Long-term cost analysis of an all human milkbased diet
Pediatrics
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
Pediatrics
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
Pediatrics
Decreased cost and improved feeding
tolerance with Exclusive HM diet
• 293 infants studied
‐ 23-34 weeks and BW 490-1700 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
Pediatrics
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
Assad et al. Journal of Perinatology 2015
Pediatrics
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
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.
Pediatrics
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
Pediatrics
Implementation
• Standardized Feeding Protocol
Pediatrics
Feeding Guidelines ≤ 1250 g BW
Day of
Feed
Human Milk
[EBM or
Donor]
kcal/oz
Feeding
Volume
(mL/kg/d)
TPN
(mL/kg/d)
Lipids
(mL/kg/d)
Total Fluids =
Enteral +
TPN + IL
(mL/kg/d)
1
20
15-20
90-100
5-10
120
2
20
15-20
95-105
10-15
130
3
20
15-20
115-120
15
150
4
20
40
95
15
150
5
24 (add donor
milk-derived
fortifier +4)
60
75
15
150
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. 2015-2016.
Pediatrics
Feeding Guidelines ≤ 1250 g BW
Day of
Feed
6
7
8
9
10
Human Milk
[EBM or Donor]
kcal/oz
24 (donor milk-derived
fortifier +4)
26 (add donor milkderived fortifier +6)
26 (donor milk-derived
fortifier +6)
26 (donor milk-derived
fortifier +6)
28 (donor milk-derived
fortifier +6)+ cream
(2 kcal/oz)
Feeding
Volume
(mL/kg/d)
TPN
(mL/kg/d)
Lipids
(mL/kg/d)
Total Fluids =
Enteral + TPN + IL
(mL/kg/d)
80
55-70
15 or
Off Lipids
150
100
50
0
150
120
Off TPN
0
120
Off TPN or IV fluids
140
0
0
140
160
0
0
160
Full enteral feeds
Baylor College of Medicine, Section of Neonatology, Department of Pediatrics. Guidelines for Acute Care of
the Neonate. 23rd Ed. 2015-2016.
Pediatrics
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
Pediatrics
Implementation
• Extra Costs
‐ 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
Pediatrics
We Should Strive for the Best Possible Long
Term Outcomes
Pediatrics
Questions?
Pediatrics