donor human milk for very low birth weight infants...donor human milk for very low birth weight...

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