Growth and Health Outcomes in Donor Human Milk Fed VLBW

Infants:Results from the DoMINO RCT

Deborah L O’Connor and Sharon Unger on behalf of the GTA DoMINO Feeding Group

Disclosure

• Drs. O’Connor and Unger serve in leadership roles at the Rogers Hixon Ontario Human Donor Milk Bank

• They lead a research program

with the aim to optimize use of human milk for Preterm Infants

Objectives 1. Review the most current systematic

review examining the efficacy and safety of donor human milk compared to preterm formula as a supplement.

2. Present growth, morbidity and neurodevelopment results from the DoMINO RCT conducted in the Greater Toronto and Hamilton area in Canada.

3. Future directions for human milk research.

Own Mother’s Milk

Own Mother’s Milk is the most appropriate source of nutrition for all infants including preterm infants:

• Well tolerated

• Associated with a reduction in late onset sepsis and NEC

• Associated with a reduction in non-specific gastroenteritis, severe lower respiratory tract infections, atopic dermatitis, asthma (young children), obesity, type 1 and 2 diabetes, childhood leukemia and sudden infant death syndrome.

• Duration and exclusivity of own mother’s milk feeding associated with superior neurocognitive development

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

Potential Risk of Donor Milk as a Supplement: Cochrane Review

Mean rate of weight gain was <15 g/kg/d in 6 of 8 trials for infants fed donor milk

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

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

Unger S, Gibbins S, Zupancic J, O’Connor DL: DoMINO: BMC Pediatrics 14:123, 2014

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 centres (Level III)

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 Level II

Inclusion/Exclusion

Inclusion • <1500 g

Exclusion • Severe congenital or chromosomal anomlies that

may contribute to poor neurodevelopment • Reasonable potential infant would be transferred

to a NICU where we did not have ethics approval

Milk Preparation Room

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 • Once donor milk was fortified, a protein

modular was added (0.4 g/dl)

Feeding Guidelines

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 Own Mother’s Milk and Duration of Feeding

Intervention

Donor Milk (n=181)

Preterm Formula (n=182) P-value

Unpublished data to be presented

*Median (1st and 3rd quartiles)

Mortality and Major Morbidities Donor Milk Preterm Formula P-value

(n=181 ) (n=182 )

Unpublished data to be presented

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

Unpublished data to be presented

Length-for-age Z-score: Study Day 1 to End of Feeding

Intervention

Unpublished data to be presented

Head Circumference-for-age Z-score: Study Day 1 to End of

Feeding Intervention

Unpublished data to be presented

Cognitive, Language at Motor Development at 18-24 Months CA

Unpublished data to be presented

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: To be presented

• Future directions: Research in this area is very thin. Work is required in optimizing mother’s own milk, donor milk and fortifiers.

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/