04-10-2016, 09:32 AM
An Exclusively Human Milk-Based Diet Is Associated with a Lower Rate
of Necrotizing Enterocolitis than a Diet of Human Milk and Bovine
Milk-Based Products
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Objective To evaluate the health benefits of an exclusively human milk–based diet compared with a diet of both
human milk and bovine milk–based products in extremely premature infants.
Study design Infants fed their own mothers’ milk were randomized to 1 of 3 study groups. Groups HM100 and
HM40 received pasteurized donor human milk–based human milk fortifier when the enteral intake was 100 and
40 mL/kg/d, respectively, and both groups received pasteurized donor human milk if no mother’s milk was available.
Group BOV received bovine milk–based human milk fortifier when the enteral intake was 100 mL/kg/d and
preterm formula if no mother’s milk was available. Outcomes included duration of parenteral nutrition, morbidity,
and growth.
Results The 3 groups (total n = 207 infants) had similar baseline demographic variables, duration of parenteral nutrition,
rates of late-onset sepsis, and growth. The groups receiving an exclusively human milk diet had significantly
lower rates of necrotizing enterocolitis (NEC; P = .02) and NEC requiring surgical intervention (P = .007).
Conclusions For extremely premature infants, an exclusively human milk–based diet is associated with signifi-
cantly lower rates of NEC and surgical NEC when compared with a mother’s milk–based diet that also includes
bovine milk–based products.
The health benefits of human milk for all infants, including those born extremely premature, have been increasingly
recognized.1 When compared with a diet of preterm formula, premature
infants have improved feeding tolerance and a lower incidence of lateonset
sepsis and necrotizing enterocolitis (NEC) when fed their mothers’
milk.2 It is a challenge for mothers of extremely premature infants, however,
to provide sufficient milk to meet their infants’ needs. In a recent study, only
30% of such mothers were able to supply 100% of their extremely premature infants’
needs.3 Pasteurized donor human milk would be an attractive proxy for
mother’s own milk, and donor milk banks have made milk available.4 Indeed,
a review of studies conducted in the 1980s, comparing donor human milk and
formula, suggested that donor milk was associated with a significantly lower
incidence of NEC.5 Those studies, however, did not include a large proportion
of extremely premature infants, and their nutritional protocols did not evaluate
human milk fortifiers (HMF) or contemporary preterm formula.
A randomized trial compared fortified pasteurized donor human milk with
preterm formula, both used as supplements when mother’s own milk was not
available.3 That study did not find a protective effect of donor human milk on
the combined incidence of late-onset sepsis and NEC but did note a significant
protective effect of mother’s own milk. The protocol in that
study differed from previous studies in that the pasteurized
donor human milk was fortified with bovine milk–based
products, and some of the infants in the donor milk group
were given preterm formula because of slower rates of
growth. Thus no contemporary trial has investigated the effects
of an exclusively human milk diet in extremely premature
infants.
The technology now exists to collect, pasteurize, and process
large quantities of screened donor human milk, labeled
with its basic nutrient contents, and prepared as either
a HMF or a donor milk alternative to mother’s own milk.6
This technology has prompted a randomized controlled trial
in extremely premature infants to evaluate an exclusive human
milk–based diet (that includes a human milk–based
HMF and donor human milk if no mother’s milk is available)
compared with the usual feeding protocol comprising
a mother’s milk diet (that includes a bovine milk–based
HMF and preterm formula if no mother’s milk is available).
We hypothesized that the health benefits (reduced duration
of parenteral nutrition [PN], late-onset sepsis, and NEC) of
an exclusively human milk–based diet would exceed those
of the usual diet containing bovine milk–based products
without detrimental effects on growth.
Methods
Infants were recruited from 12 neonatal intensive care units,
11 in the United States and 1 in Austria. Eligibility criteria
were as follow: birth weight 500 to 1250 g, intention to receive
mother’s milk, and ability to adhere to a feeding protocol
on the basis of the use of mother’s own milk, initiation of
enteral feeding before 21 days after birth, and initiation of PN
within 48 hours of birth. Infants were excluded if there
were major congenital malformations or a high likelihood
of transfer to a non-study institution during the study
period.
Randomization was performed in blocks of 4 on strata de-
fined by birth weight (500 to 750 g, 751 to 1000 g, and 1001 to
1250 g), and whether the infant was appropriate- or smallfor-gestational-age
(defined as 2 standard deviations below
the mean weight for gestational age on the basis of intrauterine
growth charts7
). Separate block randomization schemes
were prepared for each of the strata and performed centrally.
The investigators were not aware of the block size. The need
to ensure proper handling of mother’s own milk precluded
true blinding of the infants’ caregivers.
Sample size calculation was based on the primary outcome
of duration of PN, a surrogate of feeding tolerance and neonatal
morbidity. The mean duration of PN in extremely premature
infants fed their mother’s fortified milk was 18 11
days (Meier and Blanco, personal communication). To
demonstrate a 40% reduction in PN days in either study
group, a sample size of 62 infants per group was needed for
a 2-sided alpha error of 2.5% and power of 90%. To account
for 2 interim analyses by the independent Data Safety Monitoring
Board, and an estimated proportion of protocol non adherence of 5%, the final sample was 69 infants per group.
The study was approved by the institutional review boards
of each center and written informed consent was obtained
from the parents or legal guardians of all subjects before
enrollment. Registered with Clinicaltrials.gov reg. #
NCT00506584.
Infants were enrolled if their mothers intended to provide
their own milk. When enteral nutrition was initiated, all
study infants received their own mothers’ milk but differed,
as randomized, by the type of HMF they received and the
type of milk they were given if no mother’s own milk was
available. Groups HM100 and HM40 received pasteurized
donor human milk–based HMF (Prolact+ H2
MF; Prolacta
Bioscience, Monrovia, California) when the enteral intake
was 100 mL/kg/d and 40 mL/kg/d, respectively, and both
groups received pasteurized and standardized 20 kcal/oz donor
human milk (Neo20 Prolacta Bioscience) if no mother’s
milk was available. Group BOV received the usual feeding
protocol of bovine milk–based HMF when the enteral intake
was 100 mL/kg/d and preterm formula if no mother’s own
milk was available.
The duration of study participation was the earliest of the
following milestones: 91 days of age, discharge from hospital,
or attainment of 50% oral feedings (ie, 4 complete oral feedings
per day). PN was initiated within 48 hours after birth.
Trophic feedings were initiated 1 to 4 days after birth and
were continued at 10 to 20 mL/kg/d as tolerated for up to 5
days. Subsequently, milk intake was increased by 10 to 20
mL/kg/d. Donor human milk–based HMF was added in
the HM40 group when milk intake reached 40 mL/kg/d
and in the HM100 group at 100 mL/kg/day. Bovine milkbased
HMF (Enfamil HMF; Mead Johnson, Evansville, Indiana;
or Similac HMF; Abbott Laboratories, Columbus, Ohio)
was added in the BOV group when milk intake reached 100
mL/kg/d. After the HMF was added, milk intake was increased
daily by 10 to 20 mL/kg to a maximum of 160 mL/
kg/d. The nutritional content of the fortified milks used in
the study is described in Table I (available at www.jpeds.
com).
Daily body weight and weekly recumbent length and head
circumference were recorded. Bronchopulmonary dysplasia
was defined as the use of supplemental oxygen at 36 weeks
postmenstrual age. Late-onset sepsis was defined as clinical
signs and symptoms consistent with sepsis occurring more
than 5 days after birth in association with the isolation of
a causative organism from a blood culture.3 In cases of coagulase-negative
Staphylococcus, at least 2 separate positive cultures
were required. NEC was defined as Bell Stage II disease
or greater, and abdominal radiographs were read by radiologists
unaware of study group assignment.8 At the conclusion
of the study, all cases of NEC were reviewed in a blinded fashion
by a panel of 8 of the study investigators. Feeding intolerance
was defined as gastric residuals greater than 50% of
the prior feeding or more than 2 mL/kg, bile- or bloodstained
gastric residuals, emesis, abdominal distention or
tenderness, changes in stool pattern or consistency, presence
of blood in the stool. Feeding intolerance was quantitated by the number of days that feedings were withheld for $12
hours.
Statistical Analyses
The 3 study groups were compared by use of an intent-totreat
paradigm, any randomized infant remained in their
group for the final analyses. Kaplan-Meier9 estimates for
the distribution of PN days were compared among study
groups with the log-rank test. The Wilcoxon rank-sum test
was used for 2-way comparisons. Three-way comparisons
used either the 1-way analysis of variance for normally distributed
data or the Kruskal-Wallis test for nonnormal
data. Categorical data were compared by use of the c2 test
with the P value determined by an exact procedure (StatXact
7; Cytel Software Corporation, Cambridge, Massachusetts).