Benefits of maternal and donor human milk for
Howard Heimana,1, Richard J. Schanlera,b,⁎
aDivision of Neonatal-Perinatal Medicine, Schneider Children's Hospital at North Shore, North Shore University Hospital,
300 Community Drive, Manhasset, NY 11030, USA
bDepartment of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
metabolic and gastrointestinal immaturity, immunologic insufficiency, and the demands of
associated medical conditions. The beneficial effects of human milk extend to the feeding of
premature infants. While human milk enhances immunity, nutritional concerns arise because the
milk may not meet the expanded nutrient requirements of the very low birth weight (VLBW, less
than 1500 g) premature infant. Human milk fortifiers are available to provide optimum nutrition.
This review summarizes the benefits and limitations of human milk for the premature infant.
© 2006 Elsevier Ireland Ltd. All rights reserved.
Nutrition support of the premature infant must be designed to compensate for
Donor human milk;
1. Key guidelines
• The nutrient components of human milk exhibit wide
variability mandating nutrient supplementation, special
handling, and monitoring of infant growth and nutritional
• Mother's own milk with nutrient supplementation enhances
the growth, development, and immunity of premature
• Extraordinary efforts should be made to use mother's own
milk because the advantages of non-nutrient components
in human milk are significantly diminished by storage and
2. Research directions
• Investigate donor milk processing by alternative techni-
ques to preserve the non-nutritive advantages while
preventing disease transmission.
delivery of mother's own milk.
• Evaluate long-term developmental benefits of feeding
human milk in premature infants.
The beneficial effects of human milk, well recognized for the
term infant, extend to the feeding of premature infants.
status. Because of their specialized nutritional needs, the
human milk-fed premature infant may require nutrient sup-
plementation, or fortification,to maintain optimal nutritional
status while deriving benefits from enhanced host defenses,
neurological development, and gastrointestinal function.
Nutritional supplementation is suggested toensure nutritional
⁎ Corresponding author. Neonatal-Perinatal Medicine, North Shore
University Hospital, 300 Community Drive, Manhasset, NY 11030, USA.
Tel.: +1 516 562 4665; fax: +1 516 562 4516.
E-mail addresses: firstname.lastname@example.org (H. Heiman),
email@example.com (R.J. Schanler).
1Tel.: +1 516 562 4665; fax: +1 516 562 4516.
0378-3782/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
available at www.sciencedirect.com
Early Human Development (2006) 82, 781–787
adequacy of human milk for the premature infant. Inadequate
nutrientintakesarise because ofthe variabilityinthe nutrient
contents of the milk to meet the quality and quantity of the
premature infants' nutritional needs. The result is an
unpredictable nutrient intake for an infant who receives a
restricted intake and cannot feed ad libitum. The following
article reviews the effects of human milk on the premature
infant, comparing and contrasting mother's own milk and
donor human milk.
4. Variability in milk composition
The adequacy of nutrient intake is compromised by the var-
iability in nutrient composition, both inherent to milk and
imposed by circumstances of collection, storage in refrig-
erator and freezer, and distribution of the milk. A large var-
iation in the energy and protein contents of human milk
brought to the neonatal nursery by the mother is observed
. The most variable nutrient in human milk is fat, the
from mother to mother, and within a single milk expression
[2,3]. As human milk is not homogenized, upon standing, the
fat content separates from the body of milk and floats to the
top. Muchofthe variation in energy content ofmilk asused in
the nursery is a result of differences in and/or losses of fat in
the unfortified milk [4–6]. In one report, the range in fat
contents of milk brought to the nursery was 2.2 to 4.7 g/dl
. Therefore, when collecting, mixing, and/or storing milk,
efforts must be directed to avoid allowing the fat to separate
from the milk and be discarded inadvertently. The use of
continuous tube-feeding methods also reduces fat delivery to
the infant compared with intermittent-bolus feeding .
Should the clinical condition mandate continuous tube-
feeding, three strategies will maximize nutrient delivery.
First, the milk syringe should be oriented with tip upright
short length of feeding tube should be used, minimizing loss
of fat on tubing surfaces. Third, the syringe should be
emptied completely into the infant at end of the infusion.
This practice will ensure the least loss of fat because the fat
will flow along with the reminder of the milk.
The within-feed change in fat content (from foremilk to
hindmilk) can also be used to benefit the premature infant if
the mother's milk production is in excess of the infant's need.
foremilk and can be utilized to provide significantly more
energy-dense fat for enhanced growth . As fat is the most
volumes to allow fractionation into foremilk and hindmilk,
Because exogenous fat does not mix with human milk, the fat
is best utilized if given in divided doses directly into the
feeding tube before a tube-feeding.
There is a significant decline in the content of protein from
transitional to mature milk, which contributes to the problem
of nutrient variability. Although concentrations of protein and
sodium decline through lactation, the nutrient needs of the
premature infant remain higher than those of term infants.
Therefore, the decline in milk concentration precedes the
reduction in nutrient needs and results in an inadequate
content of other human milk nutrients (e.g., calcium,
phosphorus) has less variability through lactation. Despite
increased bioavailability, the mineral content remains too low
of zinc in human milk declines through lactation and, in the
case of the premature infant the level is below requirement.
Technical reasons associated with collection, storage, and
of available nutrients (e.g., vitamin C, vitamin A, riboflavin).
5. Donor milk composition: the effect of
Donor human milk is generally obtained from women who
deliver term infants later in their lactation so the milk
composition is similar to the lower nutrient content found in
donor milk alters some of the immunologic and nutritional
loss of vitamin C (40%), lysozyme (40%), lactoferrin (30%),
lipase activity (25%), sIgA (40%), and specific sIgA antibody
(from 0 to 60%) . The phagocytic activity of the
refrigerated milk is reduced (40%) and the number of cellular
elements increases. There also is a marked increase in free
fatty acids with refrigerator storage suggesting spoilage .
Freezing at −20 °C for as long as 3 months also affects the
components in the milk. There is a small decrease in total IgA
concentration of lysozyme by up to 20%, and nearly
completely destroys the white blood cells.
donor human milk must be pasteurized . Currently, the
Holder pasteurization technique is the most common method
employed (62.5 °C for 30 min). The Holder pasteurization
process results in a variable loss of milk components: sIgA
(20–50%), total IgA (0 to 50%), lactoferrin (0 to 65%),
lysozyme (0 to 65%), lymphocytes (100%), lipase (100%),
alkaline phosphatase (100%) [8,10–12]. Cytokine concentra-
tions also decline following pasteurization, and there is a
suggestion that more pro-inflammatory than anti-inflamma-
tory cytokines are retained .
Short time high-temperature (STHT) processing is an
alternate strategy of rapid heating (72 °C×5–15 s) and
cooling of the milk with potentially less destruction of milk
components, although it has been subjected only to a small
sIgA, 0 to 25% loss of total IgA, and 0 to 85% loss of lactoferrin
following STHT processing [12,14,15]. There are variable
effects of STHT processing on the lysozyme content of the
milk, from 20% to 40% loss to 290% gain following processing
[12,14]. Thus, storage in refrigerator and/or freezer and
contact with containers forhumanmilks, and heatprocessing
for donor milk together affect many components of the milk,
and, presumably, their efficacy (see below).
6. Growth of premature infants fed unfortified
mother's own or donor human milk
When compared with supplemented human milk or formula,
premature infants fed unfortified human milk have slower
782H. Heiman, R.J. Schanler
rates of growth and nutritional deficits, during and beyond
their hospital stay [16–20]. When fed to premature infants
(birth weight 1.0 to 1.4 kg) term, pooled, unpasteurized
donor milk resulted in a rate of weight gain that was 50% of
similar infants fed formula . When fed term, pooled,
pasteurized donor milk, premature infants (birth weight≤
1.6 kg) had a slower weight gain (approximately 16 g/day)
than formula fed infants (27 g/day) . The early postnatal
rates of weight gain in seven donor human milk studies were
recently reviewed and the majority of studies (all but 1)
found slower growth in the premature infants fed pasteur-
ized donor milk compared with formula . The review also
found that infants fed donor milk had lesser increments
in length and skinfold thickness but only 1 out of 5 studies
found lesser gain in head circumference compared with
similar infants fed formula. Many of the outcome measures
reported for growth were not standardized across studies so
it was not possible to perform meta-analysis on these out-
comes . When used as a supplement to mother's own
milk, a diet of donor milk was associated with significantly
slower growth compared with a supplement of formula in
weight, head circumference and skinfold thickness, but not
in length .
There are several limitations to the above comparisons.
First, only seven studies were included and the total sample
size for most outcomes was small. Second, these studies
were initiated over 20 years ago and they may no longer be
clinically relevant to contemporary practice, where survival
of premature infants has greatly improved, and feeding
practices have changed. Third, the methodological quality of
most of the studies was poor in terms of randomization,
blinding of caregivers and assessors, and assessment of
confounding which may have introduced bias. Finally,
substantial heterogeneity among studies makes it difficult
to pool evidence across studies. Nevertheless, growth
appears limited with the feeding of unfortified milk, and
specifically with donor milk.
7. Nutritional outcomes of premature infants
fed unfortified mother's own or donor human
Indices of protein nutritional status, e.g., blood urea
nitrogen, serum albumin, total protein, and transthyretin
(prealbumin), are lower and continue to decline over time
when premature infants are fed unfortified human milk
[16,19,23]. As a consequence of the low intakes of calcium
and phosphorus, infants fed unfortified human milk have
progressive decreases in serum phosphorus, increases in
serum calcium, and increases in serum alkaline phosphatase
activity compared with infants fed preterm formula
[17,24,25]. Follow-up investigations of such infants at
18 months report that infants having the highest alkaline
phosphatase in-hospital had as much as a 2 cm reduction in
age found that the neonatal serum alkaline phosphatase was
negatively associated with attained height . These data
suggest that long-term mineralization might be affected by
neonatal diet. The low intake of sodium from milk, may be
associated with late hyponatremia, especially if diuretics are
also used. Without a zinc supplement the feeding of human
milk leads to zinc deficiency in the premature infant [28,29].
Premature infants fed pasteurized mature donor milk have a
greater prevalence of hyponatremia (50% vs. 20%), higher
alkaline phosphatase values, and lower serum phosphorus
concentrations than similar infants fed formula .
8. Effects of unfortified mother's own milk on
Early prospective studies reported lower rates of infection in
premature infants receiving fresh human milk compared with
necrotizing enterocolitis (NEC) was reduced significantly by
feeding premature infants unfortified human milk, either
exclusively or partially supplemented with either formula or
pasteurized donor human milk compared with feeding a sole
diet of formula . That study identified the highest risk for
NEC in the group of infants born before 28 weeks gestation.
The receipt of human milk was associated with significant
protection from NEC at all gestation groups greater than
27 weeks. When compared with unfortified human milk
feeding, the receipt of formula was associated with a 2.5 fold
increase in NEC (95% confidence interval 1.2 to 5.2, p<0.02)
for all cases and a 6.5-fold increase (95% CI=1.9 to 22,
p<0.001) for confirmed cases of NEC as identified from
surgical pathology or postmortem examination. A significant
3-fold increase in NEC was also seen when a diet of exclusive
formula feeding was compared with formula used as a
supplement to human milk: confidence interval for all cases
was 1.5 to 5.7, p<0.005 and for confirmed cases 1.4 to 6.5,
In a randomized comparison in Mexico City, premature
infants receiving human milk had markedly lower rates of
NEC, diarrhea, and urinary tract infection, and received
fewer days of antibiotic treatment than those fed formula
. A small study in the U.S. reported that premature
infants had less nosocomial sepsis (OR 0.38, CI=0.15 to 0.95,
can also be extended to premature infants.
9. Effects of unfortified donor human milk on
Donor milk is an alternative when obtained from established
human milk banks that follow specific quality control pro-
tocols, such as those from the Human Milk Banking As-
sociation of North America (http://www.hmbana.org/). The
treatment and overall processing of the milk affects the
protection afforded human milk. Indeed, NICU infants
receiving pasteurized donor milk plus infant formula had
significantly greater infectious morbidity than those receiv-
ing either a sole diet of pasteurized milk, or fresh milk with
and without formula supplementation . These data sug-
gest that the pasteurization process reduces the protective
power of the milk.
Donor milk given as a sole diet is likely associated with a
lower risk of NEC, compared to formula. Tyson et al. 
studied premature infants fed unpasteurized donor milk and
found a lower but non-significant relative risk of NEC=0.39
(95% confidence interval=0.01 to9.4), but used this outcome
783Benefits of maternal and donor human milk for premature infants
asan exclusion forhis study .Boyd et al.  summarized
studies of pasteurized donor milk conducted more than
20 years ago and no individual study found a statistically
significant protective effect of donor milk on NEC. However,
as there was homogeneity of the relative risk ratios in each
study, their meta-analysis of 3 studies observed a 79% re-
duction in confirmed NEC, relative risk ratio of 0.21 (95%
NEC in formula fed infants is ∼5–20%, approximately 18.5
premature infants (95% CI=9.7 to 200) would need to be fed
donor milk to prevent one case of NEC. The effect on NEC of
donor milk that is supplemented with formula, however, is
inconclusive. Donor milk was associated with a significantly
lower rate of mild, culture-negative, diarrhea in a small
population of premature infants .
10. Human milk fortification
The nutrient deficits that arise from feeding unfortified
human milk can be corrected with nutrient supplementation.
Protein and energy supplementations are associated with
improved rates of weight gain, nitrogen balance, and indices
of protein nutritional status: blood urea nitrogen, serum
albumin, total protein, and transthyretin [19,37]. The ef-
ficacy of protein fortification of human milk (∼1.5 g protein/
kg/day added to human milk) was of short-term benefit
resulting in increases in weight gain, and increments in
length and head circumference growth. Protein enrichment
was associated with improved catch-up growth in compro-
mised premature infants compared to healthier infants .
Although the measured gains were small, the effects were
Supplementation with both calcium and phosphorus
resulted in normalization of biochemical indices of mineral
status: serum calcium, phosphorus, and alkaline phosphatase
activity, and urinary excretion of calcium and phosphorus
[40,41]. Mineral supplementation of unfortified human milk
has been associated with improved linear growth and
increased bone mineralization during and beyond the neo-
natal period . A normalization of serum sodium has been
reported following the supplementation of unfortified
human milk with sodium .
A systematic review that addressed multi-nutrient for-
tification of human milk included a meta-analysis of ten
controlled trials (more than 600 infants, birth weight less
than 1850 g) of human milk fortification compared with the
nutrient fortifiers to human milk resulted in short-term im-
provements in weight gain, increments in length and head
circumference, and bone mineral content during hospital
Donor milk has been studied in comparison to preterm
formula as a replacement for mother's own milk . Infants
were assigned randomly to be fed fortified pasteurized donor
milk (n=81) or preterm formula (n=92) if their mother's own
milk was unavailable. The study was blinded and the data
were analyzed by intention-to-treat. Donor milk or formula
represented approximately 50% of the total milk diet of the
study infants. The rate of weight gain was less for infants
receiving fortified pasteurized donor human milk than
preterm formula, despite the former group receiving a
greater milk intake and more nutritional supplements. Thus,
to achieve optimal growth, more attention needs to be given
to infants receiving donor milk, even if it is fortified by usual
11. Effects of fortified human milk on
A theoretical concern with human milk fortification is that
the added nutrients may affect the intrinsic host defense
system of the milk. Fortunately, this has not been the pub-
lished experience. In a retrospective review of cases,
premature infants fed fortified human milk had a 26% in-
cidence of documented infection compared with 49% in
formula-fed infants . Results of a randomized trial of
multi-nutrient fortified human milk indicated no increase in
either confirmed infection or NEC compared with infants fed
partially-supplemented human milk (with vitamins, electro-
of confirmed infection and NEC, however, were significantly
greater in the group fed fortified human milk compared with
the group fed partially-supplemented human milk. The data,
however, are difficult to interpret because study infants in
both groups received more than 50% of their diet as preterm
Infants predominantly (averaged as more than 50 ml/kg/
day, approximately 1/3 of full milk feeding)  or ex-
clusively  fed human milk had significantly less late-onset
sepsis and NEC and a shorter hospital stay compared with
infants fed preterm formula. Those infants receiving a
combination of mother's milk and preterm formula had the
highest incidence of late-onset sepsis and/or NEC. The study
identified a dose of human milk that was protective. This
dose of mother's milk, >50 ml/kg/day, subsequently was
shown to protect against late-onset sepsis in a 4-week study
of premature infants when compared with lesser daily doses
of human milk, 1 to 24 and 25 to 49 ml/kg . A multi-
center study of feeding identified that late-onset sepsis was
related to dose of human milk as percentage of enteral
feedings; the greater the dose of mother's milk received, the
lower the incidence of sepsis. Those infants with late-onset
sepsis were fed human milk later and of fewer total days
duration . A large multi-center study in Norway
suggested that early feeding of extremely premature infants
with human milk, and subsequently fortified human milk,
was associated with significantly less late-onset sepsis and
improved survival . Thus, the theoretical concern that
the nutrient supplements affect the intrinsic host defense
system of human milk does not appear justified. Indeed, the
meta-analysis comparing infants fed unfortified and fortified
human milk did not identify any difference in NEC .
The use of fortified pasteurized donor human milk has
been investigated as a replacement if no mother's own milk
was available . Infants were assigned randomly to be fed
fortified pasteurized donor milk (n=81) or preterm formula
(n=92) if their mother's own milk was unavailable. The study
was blinded and the data were analyzed by intention-to-
treat. Donor milk or formula represented approximately 50%
of the total milk diet of the study infants. There were no
differences between groups for the major outcome, late-
onset sepsis and/or NEC, or for any other infection-related
event, hospital stay, and number of deaths. Infants who
784H. Heiman, R.J. Schanler
less late-onset sepsis and/or NEC, and total infection-related
events, and had a significantly shorter hospital stay. With
respect of infection-related events and hospital stay, when
compared with a sole diet of mother's own milk, donor milk
offered no short-term advantage over preterm formula for
feeding the extremely premature infant .
Although a reduction in infectious morbidity in human
milk-fed premature infants has been reported in nearly a
by methodological issues that are compounded by the in-
ability to perform truly randomized trials in human milk-fed
premature infants . There also appear to be factors
inherent in the mother's choice to provide breast milk, and
differences in sociodemographic variables affecting parental
contact between study groups [44,53]. Thus, the data should
be interpreted as an estimate of an effect; mother's own milk
appears to be a powerful factor in protecting the premature
infant from infectious morbidity.
12. Effects of human milk on
A meta-analysis of breast-feeding and cognitive develop-
ment suggests that beneficial effects are small but signifi-
cantly favor breast-feeding . Several reports suggest that
the diet in the NICU might affect long-term neurodevelop-
mental outcomes in premature infants. An 8 year follow-up
of 300 premature infants (approximately 1.4 kg and 31 weeks
gestation at birth) observed that when factors affecting
intelligence quotient (social class, maternal education,
infant gender, and duration of mechanical ventilation)
were considered in a regression model, the receipt of breast
milk in the NICU was associated with an 8 point advantage
. A cohort of adolescents was followed since their NICU
stay as premature infants and significant cognitive and
psychomotor benefits were ascribed to the feeding of human
milk [56–58]. In a large study of premature infants 30 weeks
gestation and birth weight approximately 1.3 kg fed either
human milk or preterm formula, a human milk diet was
associated with significantly greater scores in behavioral
visual acuity at 2 to 6 months corrected age compared with
preterm formula . The effect of human milk on cognitive
indices was also seen at 12 months corrected age and, in
infants with chronic lung disease, a significant benefit of a
human milk diet was observed in psychomotor indices. These
observations were adjusted for HOME Inventory, maternal
intelligence testing, smoking, and birth weight.
A large multi-center follow-up study of more than 1000
extremely low birth weight infants who had extensive
nutritional data collected during their hospitalization was
conducted to determine the relationship between human
milk intake in-hospital and neurodevelopmental outcome at
18 to 22 months of age . Neonatal birth weight,
gestational age, intraventricular hemorrhage status, sepsis,
bronchopulmonary dysplasia, and hospital stay were similar
between those never receiving (25%) and those who received
human milk (75%). There were differences in socioeconomic
variables, race and ethnicity, educational attainment, and
parity between groups. When adjusted for these variables as
well as biological confounders, there were significantly
positive effects for human milk intake on mental and motor
development. The magnitude of the effect was greatest in
the highest quintile of human milk-fed infants. The impact of
feeding 110 ml/kg/day of human milk would be an increase
in Bayley MDI score of 5 points (1/3 of an S.D.) . Others
have reported that this 5-point difference would have a
significantly meaningful effect on the outcome of ELBW
In comparisons of sole diets of donor milk and formula, no
significant differences in long-term neurodevelopmental
outcomes have been reported . However, as supplements
to formula, one study has identified an advantage to psy-
donor milk compared with similar infants fed term formula
. Thus, human milk feeding affects the neurodevelop-
mental outcomes of premature infants, possibly because of
the polyunsaturated fatty acids or cholesterol in the milk.
13. Effects of human milk on feeding tolerance
Infants fed their mother's own milk fortified with commercial
fortifiers achieved full enteral feedings significantly earlier
than those infants receiving preterm formula . Feeding
had less feeding intolerance (2.4% vs. 23%) and took more
than 3 weeks to tolerate full feedings (5% vs. 17%) than
formula, respectively [20,63].
Clinicians have questioned whether the addition of
commercial formula-derived human milk fortifiers affects
feeding tolerance in premature infants. The feeding of
fortified human milk was not associated with feeding
intolerance, as manifested by abdominal distention, vomit-
ing, changes in stool frequency, or volume of gastric aspirate
in one study comparing multi-nutrient fortified vs. partially-
supplemented (vitamins, electrolytes, and phosphorus)
human milk . An investigation of feeding tolerance
indices 5 days before vs. 5 days after addition of human
milk fortifier found that of the ten indices assessed, only
gastric residual volume≥2 ml/kg and emesis were statisti-
cally significantly greater after the addition of fortifier.
However, infants manifesting these feeding tolerance indices
were no more likely to have delays in achieving full tube-
feeding or full oral feeding than infants not experiencing
increases in feeding tolerance indices . Furthermore, no
differences in feeding tolerance were reported in a meta-
analysis comparing premature infants fed fortified human
milk or unfortified human milk . Moreover, several
randomized trials of human milk fortifiers did not demon-
strate any differences in feeding tolerance among commer-
cial products [65–67]. Lastly, in comparison with infants fed
preterm formula, those fed fortified human milk had similar
tolerance to feeding . Thus, concerns about feeding
tolerance should not dissuade clinicians from using human
14. In-hospital feeding practices
The use of multi-nutrient fortification of human milk for
premature infants born weighing less than 1500 g is
recommended [68–70]. It is noteworthy that human milk
fortifiers, more so than preterm formulas, differ in their
785Benefits of maternal and donor human milk for premature infants
nutrient contents throughout the world. A fortifier should be
chosen that provides at minimum a multi-nutrient mixture,
including protein, fat, calcium, phosphorus, zinc, sodium,
iron, and multivitamins. A variety of protocols are used for
feeding fortified human milk. In one such protocol, human
milk is fortified when the infant achieves an enteral intake of
100 ml/kg/day. The volume is maintained while the concen-
tration is increased by the addition of fortifier. The intake of
fortified human milk is then advanced daily to maintain a
body weight gain of greater than 15 g/kg/day. There are
inconclusive data to support a role for pasteurized donor
Human milk feeding is associated with substantial benefits to
the premature infants' health. Mother's own milk with
nutrient supplementation is associated with reduced infec-
tious and inflammatory disease, enhanced neurodevelop-
mental outcome, and, in a carefully designed nutritional
program, is associated with healthy early postnatal growth
patterns. Donor milk, because of the manner in which it is
collected, processed, and stored substantially diminishes the
advantages ascribed to mother's own milk. An enlightened,
comprehensive and supportive lactation program is recom-
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