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Original Investigation |

Effect of Donor Milk on Severe Infections and Mortality in Very Low-Birth-Weight Infants The Early Nutrition Study Randomized Clinical Trial

Willemijn E. Corpeleijn, MD1,2; Marita de Waard, MD2; Viola Christmann, MD3; Johannes B. van Goudoever, PhD1,2; Marijke C. Jansen-van der Weide, PhD4; Elisabeth M. W. Kooi, PhD5; Jan F. Koper, MD5; Stefanie M. P. Kouwenhoven, BSc2; Hendrik N. Lafeber, PhD2; Elise Mank, BSc1; Letty van Toledo, PhD1; Marijn J. Vermeulen, PhD6; Ineke van Vliet, BSc2,6; Diny van Zoeren-Grobben, PhD7
[+] Author Affiliations
1Department of Pediatrics, Emma Children’s Hospital–Academic Medical Center, Amsterdam, the Netherlands
2Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands
3Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands
4Pediatric Clinical Research Office, Woman-Child Department, Academic Medical Center, Amsterdam, the Netherlands
5Division of Neonatology, University Medical Center Groningen, Beatrix Children’s Hospital, University of Groningen, Groningen, the Netherlands
6Department of Pediatrics, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, the Netherlands
7Department of Pediatrics, Isala Clinics, Zwolle, the Netherlands
JAMA Pediatr. 2016;170(7):654-661. doi:10.1001/jamapediatrics.2016.0183.
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Importance  Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mother’s milk when compared with formula. When own mother’s milk is not available, human donor milk is considered a good alternative, albeit an expensive one. However, most infants at modern neonatal intensive care units are predominantly fed with own mother's milk. The benefits of add-on donor milk over formula are not clear.

Objective  To determine whether providing donor milk instead of formula as supplemental feeding whenever own mother’s milk is insufficiently available during the first 10 days of life reduces the incidence of serious infection, necrotizing enterocolitis, and mortality.

Design, Settings, and Participants  The Early Nutrition Study was a multicenter, double-blind randomized clinical trial in very low-birth-weight infants (birth weight <1500 g) admitted to 1 of 6 neonatal intensive care units in the Netherlands from March 30, 2012, through August 17, 2014. Intent-to-treat analysis was performed.

Interventions  Infants received pasteurized donor milk or preterm formula during the first 10 days of life if own mother’s milk was not (sufficiently) available.

Main Outcomes and Measures  The primary end point was cumulative occurrence of serious infection (sepsis or meningitis), necrotizing enterocolitis, or mortality during the first 60 days of life.

Results  A total of 930 infants were screened for inclusion; 557 were excluded, resulting in 373 infants (183 receiving donor milk and 190 receiving formula) who were evaluated by intent-to-treat analysis (median birth weight, 1066 g; mean gestational age, 28.4 weeks). Own mother’s milk comprised 89.1% and 84.5% of total mean intake during the intervention period for the donor milk and formula groups, respectively. The incidence of the combined outcome was not different (85 [44.7%] [formula] vs 77 [42.1%] [donor milk]; mean difference, 2.6%; 95% CI, −12.7% to 7.4%). The adjusted hazard ratio was 0.87 (95% CI, 0.63-1.19; P = .37).

Conclusions and Relevance  In the current study, pasteurized donor milk and preterm formula as supplemental feeding during the first 10 days of life yielded similar short-term outcomes in very low-birth-weight infants regarding safety and efficacy when own mother’s milk availability was insufficient. Future studies investigating longer duration of use of human donor milk on short-term and long-term outcomes are necessary.

Trial Registration  trialregister.nl Identifier: NTR3225

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Figure 1.
Consort Diagram

aUse of data not allowed.

bParents withdrew consent but allowed use of all data, also during the follow-up period.

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Figure 2.
Event-Free Survival Curve for the Combined Incidence of Serious Infection, Necrotizing Enterocolitis, or Death by Intent-to-Treat Analysis
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The conclusions of the study are arbitrary and the title is incomplete.
Posted on May 6, 2016
Dr Panagiotis Mavridis
PhD, MSc, Paediatrician, Neonatologist, IBCLC
Conflict of Interest: None Declared
Dear Sir/Madam

I would like to point out that the fact that neonates included in the study were fed mainly with their own mothers milk (89.1% and 84.5% of total mean intake) is a major confounding factor. This is a fact that is not pointed out clearly enough in the summary of this study, making the title misleading. Readers could easily assume that there is no benefit from donor milk in general. If the authors would like to prove (or reject) a similar hypothesis, they would have to take into account the main form of alimentation as a confounding factor, which is difficult to do in a study like this one. However, it is not warranted to draw conclusions about the significance of the kind of supplementation when it was in such a small proportion of the total volume of nutrition (10,9-15,5%).
Posted on June 28, 2016
Arthur I Eidelman MD
Shaare Zedek Medical Center, Hebrew University School of Medicine, Jerusalem, Israel
Conflict of Interest: None Declared

To the Editor

The benefits of feeding the VLBW infants raw mothers-own -milk (MOM ) as opposed to formula are well established, particularly in its’ capacity to reduce the incidence of serious infections and NEC(1,2). What is the critical amount of formula that increases the risk of NEC has yet to be fully determined. Thus, the study of Corpeleijn(3) comparing the effect of supplementing mothers who could not supply sufficient M0M with either pasteurized donor human milk or preterm formula is welcome. The authors concluded that there was no significant benefit of supplementing with pasteurized donor milk as opposed to standard preterm formula,
In my opinion, there are serious study methodological problems that preclude such a conclusion. There is an absence of information if the feeding of the donor milk was comparable in amount and duration to supplementing with formula. The intervention was for scheduled “10 days or less”, but, there is no information how many actual days the infants in each group were supplemented, nor information how much was fed on each day and which days post partum this took place. No information was provided about what the infants were actually fed in the local hospitals, if bovine-based fortifiers were added, or how many infants were actually transferred and at what postpartum age. Forty two percent of the end point pathology occurred after 10 days, presumably while most of the infants where in the local hospitals. Thus, what they were fed and how varied was their care during the 60 day period are most important variables in interpreting any results.
The authors’ economic analysis is perplexing. The only valid calculation is cost per infant, not the operating budget , Donor milk is provided in the US at a cost 3-4 USD per ounce An infant who needs to be supplemented in the first 14 days would need on the order 3-10 ounces at an average cost that rarely exceeds 50 dollars. The hospital costs for an infant with NEC is 40,000 to 74,00 dollars(4). Thus the economic benefits of supplementing with donor human milk would more than cover the cost of supplementing the VLBW infants.
Further randomized studies are needed when “MOM is not consistently available”. However, until then, we should not generalize from incomplete studies such as that reported by Corpeleign(3) and donor pasteurized human milk should remain as the default choice for supplementing MOM in the VLBW infant.


1. Quigley M, McQuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews. 2014; Issue 4 Art No.: CD002971
2. Corpeleijn WE, Kouwenhoven SM, Paap MC et al, Intake of own mother’s milk during the first days of life associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life. Neonatology 2012;102:276-281
3. Corpeleijn WE, de Waard M, Christmann V, et al. The Early Nutrition Study: a Double blind randomized clinical trial on the effect of donor milk in premature infants. JAMA Pediatr. Published online May 02, 2016. doi:10.1001/jamapediatrics.2016.0183
4. Johnson TJ, Patel AL, Bigger, et al. Cost savings of human milk as a strategy to reduce the incidence of necrotizing enterocolitis in very low birth weight infants. Neonatology 2015;107:271-276
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