Use Of An Entirely Human Milk-based Diet In Very Low Birth Weight

Transcription

Use Of An Entirely Human Milk-based
Diet In Very Low Birth Weight Infants:
Review Of Current Evidence And
Future Directions
Steven A. Abrams, MD
Professor of Pediatrics
Baylor College of Medicine
[email protected]
Disclosure
I have disclosed the following relevant financial
relationships:

Mead Johnson, Inc. – Grant Holder
Outline

Human milk (HM): safe and effective enteral nutrition in
very low birth weight (VLBW) neonates

Early research related to human milk and sepsis/NEC

Role of human milk-based fortifier in allowing for adequate
growth in VLBW neonates

Current controlled trials of necrotizing enterocolitis (NEC)
and other outcomes using an all human milk-based diet

Recent combined analysis of human milk trials

Future directions including research into other populations

Conclusions
Human Milk Use And Outcomes Of
ELBW Infants At 30 Months Of Age


At 30 months, human milk was associated with increased
Bayley MDI scores, BRS, and fewer re-hospitalizations
For every 10 mL/kg of HM in the NICU, at 30 months:
 MDI increased by 0.59 points, PDI by 0.56 points
 Re-hospitalization decreased by 5%
Vohr B R, et al., 2007
Human Milk And Intellectual
Performance In Premature
Infants At 8Y
Significant factors affecting IQ:
Social Class
- 3.5/class
Mechanical Ventilation - 2.6/week
Mother’s Education
+ 2.0/group
Female Gender
+ 4.2
Receipt of Human Milk + 8.3 IQ points
IQ: Weschler Scale, WISC-R Lucas, Lancet 1992;339:261
Donor Human Milk And NEC: Early Data
Several
meta-analyses support decreased risk of NEC
with donor HM.
Studies
are older, mixed population, not always fortified.
Morales and Schanler: Semin Perinatol 31:83-88 © 2007
‘Survival’ Curves For NEC Or Death* By
Amount Of Human Milk (Ml/Kg/D)
1.00
100 ml
0.95
Survival
Estimate
50 ml
0.90
20 ml
10 ml
0.85
0 ml
*For NEC or Death after 14 days,
adjusted for birth weight, race, PDA treatment, ventilation, and site
Meinzen-Derr, et al NICHD Neonatal NetworkJ Perinatol 2009
0.80
0
10
20
30
40
50
60
70
Postnatal age (d)
80
90 100 110 120
Nutrients Limited In Human Milk
For Very Preterm Infants

Protein: Need extra to continue to resolve deficit
and to support catch-up growth. Key component
in length growth.

Minerals: Calcium, phosphorus, iron and zinc

Vitamins: Especially vitamin D


Unless mother is receiving mega-dose (6400 IU/d)
vitamin D supplementation, there is negligible vitamin
D in human milk.
Energy Density: Primarily limited by feeding
volume, also caloric density
Protein Requirements From Enteral
Nutrition In Very Preterm Infants

Factorial approach Growth – 2.0 g/d

Losses – 0.9 g/d

Unabsorbed – 0.5 g/d

Total: 3.4 g/d

For 800 g infant – about 4 g/kg/d
European (ESPGHAN) Recommendations
Agostoni et al. JPGN, 2010; 50:85-91
AAP Policy 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
American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the
use of human milk. Pediatrics. 129(3): e827-e841; 2012.
Growth And Donor Human Milk


Small descriptive studies suggest that the nutrient
content of DHM is lower in fat, calories, protein, sodium,
and calcium as compared to formula

Premature infants have increased nutritional requirements

All infants with a birth weight ≤1250 g are at risk for poor growth
and metabolic abnormalities
One meta-analysis showed that DHM is associated with
slower growth in the early postnatal period
Boyd et al: Donor breast milk versus infant formula for preterm infants: systematic
review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 92: F169-F175; 2007.
Growth Parameters

Targeted growth for preterm infants is based upon
estimated intrauterine growth from historical cohort
studies1,2
Weight
15.0 g/kg/day
Length
1.0 cm/week
Head circumference
0.7 cm/week
1. Lucas A ,et al: Multicentre trial on feeding low birth weight infants: effects of diet on
early growth. Arch Dis Childhood. 59: 722-730; 1984. 2. Lubchenco LO, et al: Intrauterine
growth in length and head circumference as estimated from live births at gestational
ages from 26 to 42 weeks. Pediatrics. 37(3): 403-408; 1966.
Postnatal Growth Failure

NICHD Neonatal Research Network (1995-1996)


4438 infants 501-1500 g BW
 22%
weight <10th percentile at birth
 97%
had growth failure at 36 weeks corrected age
Infants weighing 501-1000 g BW
 17%
weight <10th percentile at birth
 99%
had growth failure at 36 weeks corrected age
Lemons JA, Bauer CR, Oh W, et al: Very low birth weight outcomes of the National
Institute of Child Health and Human Development Neonatal Research Network, January
1995 through December 1996. Pediatrics. 107 (1): e1; 2001.
Why Is This Important?

495 Infants 501-1000 g birth weight (BW) were divided
into quartiles of in-hospital growth velocity rates and
evaluated at 18-22 months corrected gestational age

As the rate of weight gain increased from
12.0 to 21.2 g/kg/day (quartile 1 to 4), head circumference
increased from 0.77 to 1.07 cm/wk

Incidence decreased significantly for:

Cerebral palsy, Low Bayley II Mental Development Index
Psychomotor Development Index, neurodevelopmental
impairment, re-hospitalization
Ehrenkranz RA, et al: Growth in the neonatal intensive care unit influences
neurodevelopmental and growth outcomes of extremely low birth weight infants.
Pediatrics. 117(4): 1253-1261; 2006.
Approaches To Human Milk Fortification To
Meet Nutrient And Growth Requirements

Commercial cow milk protein based fortifiers (liquid or
powder)


Addition of powdered preterm/transitional formula


Widely used, exposes infant to non HM protein. We use this for
larger preterms
Risk of contamination of non-sterilized powder. We rarely
recommend this especially before 44 weeks postmenstrual age
(PMA).
Several daily feeds of formula, others non-fortified HM

Limited added nutrients, best at discharge phase
Additional Approaches

Supplementation with non-cow milk based products


Supplementation with fat, protein, carbohydrates
individually


Currently available, relatively little data
Also may be non-sterile, difficult to use and does not provide
minerals. We do not currently recommend this.
Human milk protein-based fortifier

No exposure to either non-sterile products or cow milk protein.
Our current approach for infants <1250 g BW and
some 1250-1500 g BW

Concern about growth of infants receiving only donor milk
An All HM Diet: Methods Of Our Evaluation

Single center, prospective observational cohort study of
preterm infants weighing ≤1250 g BW fed an all human
milk protein-based diet

Inclusion criteria


Infants admitted within first 48 hours of birth

Full enteral feedings achieved within 4 weeks
Exclusion criteria

Infants with major congenital anomalies

Death
Hair AB, et al: Human milk feeding supports adequate growth in infants ≤ 1250
grams birth weight. BMC Research Notes. 6: 459; 2013.
Our Evaluation: Hypothesis
We hypothesized that a feeding
protocol providing an exclusive human
milk-based diet would meet growth
standards in infants ≤1250 g BW and
lead to decreased extrauterine growth
restriction
Feeding Guidelines ≤ 1250g 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.
www.neonate.net
Baylor College of Medicine, Section of Neonatology, Department of Pediatrics.
Guidelines for Acute Care of the Neonate. 21st Ed. 2013-2014.
Feeding Guidelines ≤1250 g BW
Day of
Feed
6
7
8
9
10
11
Human Milk
[EBM or Donor]
kcal/oz
24 (donor milk-derived
fortifier +4)
fortifier +4)
26 (add donor milkderived fortifier +6)
fortifier +6)
fortifier +6)
fortifier +6)
Feeding
TPN
Lipids
Total Fluids =
Volume (mL/kg/d) (mL/kg/d) Enteral + TPN +
(mL/kg/d)
IL (mL/kg/d)
80
55-70
15 or
Off Lipids
150
100
50
0
150
100
50
0
150
120
Off TPN
0
120
Off TPN or IV fluids
140
0
0
140
150
0
0
150
Full enteral feeds
Baylor College of Medicine, Section of Neonatology, Department of Pediatrics.
Guidelines for Acute Care of the Neonate. 21st Ed. 2013-2014.
Table 1: Patient Demographics
n=104
Birth weight (g)
Gestational age (wk)
Male, n (%)
Race, n (%)
White
Black
Hispanic
Other
Birth length (cm)
Birth HC (cm)
APGAR 5 minute
Inborn, n (%)
Antenatal Steroids, n (%)
913 ± 182*
27.6 ± 2.0*
49 (47)
28 (27)
40 (38)
24 (23)
12 (12)
34.4 ± 2.6*
24.2 ± 1.8*
7 ± 2*
59 (57)
77 (74)
± SD
Hair AB, et al: Human milk feeding supports adequate growth in infants ≤ 1250 grams
birth weight. BMC Research Notes. 6: 459; 2013.
*Mean
Growth Velocities From Birth To
Discharge
*Mean ± SD
*
Hair AB, et al: Human milk feeding supports adequate growth in infants ≤1250 grams
Growth Outcomes
n=104
Weight gain (g/kg/d)
Length (cm/wk)
Head circumference (cm/wk)
Days to regain birth weight
Days to full feeds
Days to fortification of feeds
Volume feeds were fortified (mL/kg/d)
Parenteral nutrition days
Transition to bovine products (wk)
SGA at birth, n (%)
SGA at discharge or 40 weeks PMA, n (%)
24.8 ± 5.4*
0.99 ± 0.23*
0.72 ± 0.14*
8.4 ± 4.0*
14 (12,19)†
10 (8,14)†
80 (60,90)†
13 (10,19)†
36 ± 1.5*
22 (21)
45 (43)
*Mean ± SD, †Median (25th, 75th percentile)
Secondary Outcomes
n=104
Medical NEC
3 (2.8)*
Surgical NEC
1 (1.0)*
Spontaneous intestinal perforation
2 (1.9)*
Late onset sepsis
14 (13)*
Patent ductus arteriosus
49 (47)*
No IVH
78 (75)*
Intraventricular hemorrhage: Grade III or IV
Bronchopulmonary dysplasia
Weight at discharge (g)
Length of stay (d)
5 (5)*
46 (44)*
2795 (2247,3155)†
82 (68,106)†
*n (%), †Median (25th, 75th percentile)
Hair AB, et al: Human milk feeding supports adequate growth in infants ≤ 1250 grams
Postnatal Growth Failure

43% of all infants had a weight <10th percentile at
discharge or 40 weeks PMA

21% of infants were small for gestational age (SGA) at
birth


100% of these infants had a weight <10th percentile at
discharge or 40 weeks PMA
79% of infants were born appropriate for gestational age

22% of this group had postnatal growth failure

Implications: We can improve outcomes in AGA infants but more
work needs to be done for appropriate for gestational age (SGA)
ones
Controlled Trials Of
Outcomes Of An
All Human Milk Diet
Study
Design
Sullivan et al.,
J Pediatr 2010
Effect Of Donor Human Milk Fortifier
(HMF) On NEC
Decrease in NEC with
donor derived HMF of
50%, surgical NEC
80%. Number needed
to treat: 8-10
Sullivan et al.,
J Pediatr 2010
Results
N = 24 Bov (formula) and 29 Hum (all HM protein)
Cristofalo et al. J Pediatr 2013:163;1592-5.
Group Characteristics
Abrams et al, Breastfeed Med 2014;9:281-5.
Overall Outcomes
Outcome Models
Study Conclusions

Provision of an exclusively human milk diet during
the early postnatal period, a diet devoid of cow milk
protein, is associated with lower risks of death, NEC,
NEC requiring surgery, and sepsis in extremely
premature infants

The cost of major complications of extreme
prematurity, such as sepsis and NEC, is very high.
Lifetime costs are likely much higher because of the
increased risk of long-term neurodevelopmental
problems in infants who have had NEC requiring
surgery
Cost/Benefit Of NEC vs. Exclusively
Human Milk-Based Diet In Extremely Low
Birth Weight (ELBW)
Cost/Length of Stay over and above cost of ELBW with no NEC
Medical NEC
Surgical NEC
LOS (days)
+11.7 days
+43.1 days
Cost (2011 US$)
+$74,004
+$198,000
Infants fed with 100% human milk-based products had:
• Total expected costs of hospitalization resulting is savings of:
• 3.9 NICU days
• $8,167 per each ELBW
Vaidyanathan, et al., 2011
A Research Agenda For An All Human
Milk Based Diet For High Risk And
Preterm Infants

Comparison with non-cow milk based fortification

Evaluation of larger infants

Effects on congenital bowel and congenital heart
disease

Long term neurocognitive benefits

Effects on breast-feeding success in hospital and
after discharge
Conclusions

Human milk is the optimal primary food for preterm
infants

Benefits to decreased rates of NEC are substantial

Optimal methods of fortification when needed remain
uncertain

Available data suggest that fortification with an all
human milk diet leads to excellent growth and low
rates of NEC

Expansion of this approach to other populations
needs further investigation
Thanks for
making it to
the end!
[email protected]
Q & A With Dr. Abrams
 What
is your experience with
using the Human Milk Cream
product to fortify feeds for ELBW
infants? When might you use
this product, in addition to 26
cal/oz fortified human milk?
 Do
you start breast milk right
away in the VLBW (i.e. day 1)? If
so, and the mom is unable to
pump enough milk, would you
start banked milk day 1, start with
a formula and transition, or keep
on hyperal only waiting for the
pumped milk to come in?
 Have
Human Milk-based
Fortifiers been approved for
use anywhere outside of the
United States?
 Can
you please speak to the
apparent increase in the rate of
ROP in the 2nd study?
(Cristofalo?)
Can you please comment on the fact
that the bovine group in the studies
included formula in their diet in addition
to cow milk fortifier? Was a sub-group
analysis done comparing all HM diet
(including HM fortifier) with all HM diet
with cows-milk fortifier? Are there plans
to study an all human milk group with
HM foritifier vs all human milk with cow's
milk fortifier?

 It
seems like the AAP has placed
NICUs on notice that the use of
cow milk formula in VLBW is not
standard of care. Why do you
think we are slow to adopt this
change? Or have you seen a
marked increase in the use of
banked breast milk?
What are the most successful
techniques you have used to
persuade mothers who had no plan to
breastfeed to provide some or any of
their milk? What is the cost of human
milk based fortifiers compared to
cow's milk fortifiers? What countries
have more milk banks and greater
human milk available?

 Do
you have any suggestions on
how to encourage mothers to
donate breastmilk to milk banks?
Have any studies identified the
most common reasons mothers
choose not to provide breastmilk?
I
have heard of mothers, mostly
from foreign countries, sharing
their breastmilk with others; what
are the dangers associated with
this? Are there any studies on
this? Do you know what countries
have the highest and lowest rates
of breastfeeding?
Do you feel that there might be less need for
human milk based human milk fortifiers now that
we have second generation HMF (extensively
hydrolyzed protein with higher protein)? Is anyone
studying 100% human milk with bovine fortifiers
compared to 100% HM with HM based fortifiers?
Are we concerned with supply of human milk based
human milk fortifiers if this becomes the gold
standard? Are we concerned with Prolacta
recruiting moms who would otherwise donate to
HMBANA approved milk banks?

 What
is your hospital's protocol for
introducing bovine based fortifiers
after an infant has been receiving
an all human milk based diet? Do
you begin to use bovine based
fortifiers at a certain age/weight?
 Are
you familiar with the practice
of starting half strength feeds or
can offer evidence to oppose it?
 How
do you get around the cost
of Prolacta when there is no
third cost reimbursement?
 In
your slide on supplementation of
HM options, you mention that
supplementation with non-cow milk
based products is an option. Which
products are you referring to?
 Do
you get informed consent for
using banked milk in your preterm
population? If so what if the mother
says no? Given the risk of NEC, etc.
how forceful are you with that
decision in a VLBW infant?
 Do
you have challenges with
hospitals not willing to place a
human milk fortifier on formulary
due to cost?

Use Of An Entirely Human Milk-based Diet In Very Low Birth Weight

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