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Donor Human Milk for Very Low
Birth Weight Infants
Sharon L Unger, MD, FRCP(C)
Disclosure
Medical Director
Rogers Hixon Ontario Human Donor Milk Bank
Primary Investigator with Dr Deborah O’Connor
OptiMoM and MaxiMoM Research Programs
Objectives
1. Review the evidence for the use of
human donor milk for very low birth
weight infants
2. Present growth and morbidity results
from the DoMINO donor milk RCT
conducted in Canada
3. Future directions for human milk
research
Mother’s Own Milk
Preterm Infants fed mothers’ own milk
have:
• fewer severe infections
• less NEC
• less colonization of pathogenic organisms
• decreased length of hospital stay
• improved neurodevelopmental outcome
Kim JH and Unger S. CPS Position Statement on Milk Banking. Paediatr Child Health 2010;15(9):595-8; U.S. Department of
Health and Human Services. The Surgeon General’s Call to Action to Support Breastfeeding. Washington, DC, 2011
Effect of Breast Milk Feeding on
Neurodevelopment*
Outcome Parameter Estimate
(For each 10 ml/kg/d
HM intake)
P-value
Cognitive Score (MDI) 0.53 0.0002
Motor Score (PDI)
0.63 <0.0001
Behavioural Rating
Scale (BRS)
0.82 0.0025
Vohr et al Pediatrics 2006;118(1):e115-23; Vohr et al Pediatrics 2007;120(4):e 953-9
*Statistically controlled for demographic and clinical
confounders
So why not just feed
mother’s own milk?
Most Mothers of Very Preterm
Infants are Unable to Provide a
Sufficient Volume of Milk
• Immaturity of the mammary secretory cell
• Mother may be ill
• Stress
• Mother and Infant may be separated
• Mothers are pump-dependent
Processing Donor Milk
Freezing, storage, and
transport
Thawing and
Bacterial culture
Batching
Pasteurization
Culture of batch
Milk analysis
Freezing
Courier to institution
Pasteurization Process Impacts the
Nutritional Composition of Human Milk
• Stage during lactation when milk is collected
• Freezing and thawing
• Heat Treatment
• Container Changes
• Feeding Tubes
Bioactive Components in Human Milk
Ewaschuk JB et al Appl Physiol Nutr Metab 36:175-182, 2011
Adiponectin Gonadotropin Mucins
α-Lactoglobulin Glutathione peroxidase Ν-Acetyl-glucosamine
Antisecretory lectins Granulocyte-colony stimulating factor Nucleotide-hydrolyzing antibodies
α-Tocopherol GRP Neurotensin
Ascorbate Haptocorrin Neutrophils
β-Carotene Hepatocyte growth factor NGF
B-cells Human-chorionic gonadotropin Nucleotides
β-Defensin-1 Hypothalamus-related hormones Oligosaccharides
Bifidogenic peptides (hLACFR-la) IFN-γ Osteoprotegerin
Bididus factor IGF-1 Peptide YY
Bombesin IGF-11 Platelet activating factor acetylhydrolase
Catalase IL-1 receptor agonist Prebiotics
Complement (C3, C4) IL-1b Prolactin
Complement receptors (CF2, CD21) IL-2, -4, -5, -6, -8, -10, -12, -13, -16, -18 Protease inhibitors
Cortisol Insulin RANTES
Cysteine κ-Casein sCD14
EGF, HB-EGF Lactadherin Somatostatin
Erythropoeitin Lactoferrin Substance P
Estrogen, progesterone Lactoperoxidase T-cells
Fibroblast growth factor LCFA-DHA, AA TGF-α
Free secretory protein Leptin TGF-β
Gangliosides Leukocytes Thyroid hormones
Gastrin Lysozyme TLRs
Ghrelin Macrophages TNF-α
GIP MCFA Vasoactive intestinal peptide
MCP-1
Effect of Holder Pasteurization
on Breastmilk Components
O’Connor DL Curr Opin Clin Nutr Metab Care 18:269-275, 2015.
Important Points About the
Systematic Review
• Study Selection criteria Randomized or quasi-randomized studies included
9 trials included: Raiha 1976; Davies 1977; Schultz 1980; Gross
1983; Tyson 1983; Lucas 1984a; Lucas 1984b; Schanler 2005;
Cristofalo 2013
• Characteristics of randomized subjects 1070 infants; Most <1800 g and 32 weeks gestational age
(clinically stable)
Most trials excluded SGA infants
• Enteral feeds 4 trials compared term formula vs donor milk
5 trials compared preterm formula vs donor milk
Only the two most recent trials used nutrient fortification
Formula versus Donor Milk for Feeding
Preterm or Low Birth Weight Infants: NEC
Cochrane Database of Systematic Reviews 22 APR 2014 DOI: 10.1002/14651858.CD002971.pub3
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002971.pub3/full#CD002971-fig-0006
Cochrane Database of Systematic Reviews 22 APR 2014 DOI: 10.1002/14651858.CD002971.pub3
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002971.pub3/full#CD002971-fig-00122
Formula versus Donor Milk for Feeding
Preterm or Low Birth Weight Infants:
Feeding Intolerance
Cochrane Database of Systematic Reviews 22 APR 2014 DOI: 10.1002/14651858.CD002971.pub3
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002971.pub3/full#CD002971-fig-0003
Formula versus Donor Milk for Feeding
Preterm or Low Birth Weight Infants:
Weight Gain
Cochrane Database of Systematic Reviews 22 APR 2014 DOI: 10.1002/14651858.CD002971.pub3
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002971.pub3/full#CD002971-fig-0004
Formula versus Donor Milk for Feeding
Preterm or Low Birth Weight Infants:
Length Gain
Cochrane Database of Systematic Reviews 22 APR 2014 DOI: 10.1002/14651858.CD002971.pub3
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002971.pub3/full#CD002971-fig-0005
Formula versus Donor Milk for Feeding
Preterm or Low Birth Weight Infants:
Head Circumference Gain
Authors’ Conclusions
• Many of the trials very old; more mixed feeding in current
NICUs; only two trials used nutrient-enriched human milk
Applicability to current practice
If you start adding nutrients to donor milk to correct
growth will you negatively impact NEC-protection?
• High risk preterm infants excluded from many studies—i.e.
SGA infants
• Future studies should ensure caregivers and assessors are
blind to intervention
• Data on long-term outcomes lacking
Donor Milk for Improved
Neurodevelopmental Outcomes
DoMINO ISRCTN35317141; Registered 08/2010
What Will Be Our Primary
Outcome Measure?
• Sample size required to examine NEC made
RCT not feasible
• Neurodevelopment might be more appropriate
Associated with dose of own mother’s milk-fed (Vohr et al Pediatrics 2006;118[1]:e115-23; Vohr et al Pediatrics 2007;120[4]:e 953-9)
Associated with early growth and nutrition (Ehrenkranz RA et al 2006; Pediatrics 117[4]:1253-1260)
Hypotheses
In VLBW infants, when mothers’ own milk is unavailable, provision of pasteurized donor human milk compared to preterm formula during initial hospitalization will:
• improve neurocognitive development at 18-24 months CA
• reduce neonatal mortality and morbidity
• support growth
• Produce a gut microbial community composition more like the exclusively mother’s own milk fed infant
• show an acceptable cost effectiveness from a
societal perspective?
Study Design
• Multi-centered double-blinded RCT
4 recruiting tertiary care centres
Total of 18 hospitals participating
• Infants randomized within 96 hr of birth
using a 3rd party service
• Infants continue to receive study feedings
after transfer to a participating community
hospital
Inclusion/Exclusion
Inclusion • <1500 g
Exclusion • Severe congenital or chromosomal anomalies
that may contribute to poor neurodevelopment
• Reasonable potential infant would be transferred
to a NICU where we did not have ethics approval
Details of Donor Milk
• Mother’s Milk Bank of Ohio
Milk expressed in the 1st 3 months
postpartum
• Back-up: Calgary Mother’s Milk Bank
Feeding Guidelines
Once donor milk was fortified, a protein modular was added (0.4 g/dl)
Milk Preparation Room
Rouge Valley Health System
Frequency and Duration of
Follow-up
Subject Disposition
Current participants
(n=316)
Deaths (n=37)
*Target:
363 randomized infants
Infants Approached to
Participate
(n=840)
Declined
(n=477)
Infants Randomized
(n=363)
Withdrawn from
feeding intervention
but consent to follow
outcome (n=34)
Withdrawals from
the study (n=10)
Baseline Characteristics
Donor Milk
(n=181)
Preterm Formula
(n=182) P-value
Sex, n (%) NS
Female 80 (44.2) 88 (48.4)
Male 101 (55.8) 94 (51.6)
Birth weight, g, mean + SD 995+273 996+272 NS
Birth Size, n (%) NS
Singleton 121 (66.9) 113 (62.1)
Multiple 60 (33.1) 69 (37.9)
Small for gestational age, n (%) 21 (11.6) 24 (13.2) NS
Apgar score at 5 min, mean + SD 6.9+2.3 7.0+2.4 NS
Maternal Age, yr, 31.4+5.9 32.6+6.4 NS
Mother's Education, n (%)
High School or less 49 (29.0) 39 (22.3) NS
College/vocational diploma 47 (27.8) 55 (31.4)
Baccalaureate 46 (27.2) 46 (26.3)
Post Baccalaureate 27 (16.0) 27 (20.0)
Exposure to Mother’s Own Milk
and Duration of Feeding
Intervention
Donor Milk
(n=181)
Preterm Formula
(n=182) P-value
Days in Feeding Intervention 66 (43, 91)* 61 (44, 91) NS
Own Mother’s Milk Intake
Total, ml 7,156 (1,512, 13,993) 6,653 (811, 13,340) NS
ml/kg/d 87 (21, 128) 88 (16, 128) NS
*Median (1st and 3rd quartiles)
Mortality and Major Morbidities
Donor Milk Preterm Formula P-value
(n=181 ) (n=182 )
Death, n (%)
yes 17 (9.4) 20 (11.0) NS
Confirmed sepsis, n (%)
yes 44 (24.3) 36 (19.8) NS
Confirmed NEC (Stage II or >), n (%) 3 (1.7) 12 (6.6) 0.0315
NEC I or > 7 (3.9) 20 (11.0) 0.0089
NEC Requiring Surgery 3 (1.66) 8 (4.4) NS
Chronic Lung Disease, n (%)
yes 44 (25.1) 37 (20.7) NS
Severe ROP, n (%)
yes 7 (3.9) 8 (4.6) NS
Serious Brain Injury
yes 38 (21.0) 27 (20.3) NS
Blinded NEC evaluation
Team: neonatology and radiology
Evaluation: clinical course, x-rays,
ultrasounds, surgical course, pathology
Criteria: Stage 1: systemic and gastrointestinal symptoms with
non-specific x-ray changes
Stage 2: systemic and gastrointestinal symptoms with
specific x-ray changes
Stage 3: deterioration of vital signs/ septic shock +/-
pneumoperitoneum
Weight-for-age Z-score: Study
Day 1 to End of Feeding
Intervention
-3
-2.5
-2
-1.5
-1
-0.5
0
Study Day 1 End of Intervention
Weight-for-age Z-Score: Study Day 1 to End of Feeding Intervention
Donor Milk
Preterm Formula
Treatment: NS Time: <0.0001 Treat*Time: NS
Length-for-age Z-score: Study
Day 1 to End of Feeding
Intervention
-4
-3
-2
-1
0
Study Day 1 End of Intervention
Length-for-age Z-Score: Study Day 1 to End of Feeding Intervention
Donor Milk
Preterm Formula
Treatment: NS Time: <0.0001 Treat*Time: NS
Head Circumference-for-age Z-
score: Study Day 1 to End of
Feeding Intervention
-3
-2
-1
0
Study Day 1 End of Intervention
Head circumference-for-age Z-Score: Study Day1 to End of Feeding Intervention
Donor Milk
Preterm Formula
Treatment: NS Time: 0.0827 Treat*Time: NS
DoMINO Analyses
• Primary outcome – neurodevelopment
• Secondary analysis – remove exclusive mother’s own milk
• Microbiome outcomes
• Health economics outcomes
Current recommendations for human
donor milk in Ontario, Canada
Eligibility:
• <1500 g at birth
• <32 weeks 6 days at birth
• GI or cardiac surgery
Duration:
• 4 weeks
• Until 32 weeks and 6 days
http://www.milkbankontario.ca/
Distribution of Cases of NEC according to GA and
Postmenstrual age (PMA) in the Study Cohort
Yee W H et al. Pediatrics 2012;129:e298-e304
©2012 by American Academy of Pediatrics
Is There An Advantage of an Exclusive
Human Milk Diet for NEC Prevention?
Infants fed mothers’ own milk randomized to:
1. HM100
2. HM40
3. BOV
*Sullivan et al Journal of Pediatrics 2010;156:562-7.
mother’s own milk +/- donor milk
human milk based fortifier
mother’s own milk +/- preterm formula
bovine milk based fortifier
Is There An Advantage of an Exclusive
Human Milk Diet for NEC Prevention?
*Sullivan et al Journal of Pediatrics 2010;156:562-7.
Unanswered question:
Was it the donor milk
or the human milk
based fortifier that
resulted in the
significant reductions
in NEC?
OptiMoM Program
• Comparison of human milk-based and bovine milk-based
fortification; (feeding tolerance, growth, GIT microbiome,
gut inflammation)
• Long-term follow-up of DoMINO babies at Kindergarten;
(neurodevelopment, neuroimaging, body composition,
genotyping)
• Comparison of higher versus lower protein intake (5.0 vs
3.5 g/kg/d); (neurodevelopment, neuroimaging, growth,
body composition, morbidity)
Conclusions
• Cochrane Review: Use of donor milk compared to formula as a supplement is associated with a lower risk of NEC in VLBW infants but growth outcomes are inconsistent with optimal neurodevelopment.
• DoMINO Trial: Evidence of NEC protection with fortification not appearing to diminish this. No obvious differences in growth between infants fed donor milk or formula.
• Future directions: Research in this area is very thin. Work is required in optimizing mother’s own milk, donor milk and fortifiers.
Acknowledgements
• Investigators
• Site Investigators
• Helpful Allies
• Study Staff of DoMINO/OptiMoM