Feeding Strategies for Premature Infants: Beneficial Outcomes of Feeding
Fortified Human Milk Versus Preterm Formula
Richard J. Schanler, MD*‡; Robert J. Shulman, MD*§; and Chantal Lau, PhD§
ABSTRACT. Background. In a large-scale study of
feeding strategies in premature infants (early vs later
initiation of enteral feeding, continuous vs bolus tube-
feeding, and human milk vs formula), the feeding of
human milk had more effect on the outcomes measured
than any other strategy studied. Therefore, this report
describes the growth, nutritional status, feeding toler-
ance, and health of participating premature infants who
were fed fortified human milk (FHM) in comparison
with those who were fed exclusively preterm formula
(PF).
Methods. Premature infants were assigned randomly
in a balanced two-way design to early (gastrointestinal
priming for 10 days) versus late initiation of feeding
(total parenteral nutrition only) and continuous infusion
versus intermittent bolus tube-feeding groups. The type
of milk was determined by parental choice and infants to
receive their mother’s milk were randomized separately
from those to receive formula. The duration of the study
spanned the entire hospitalization of the infant. To eval-
uate human milk versus formula feeding, we compared
outcomes of infants fed >50 mL z kg21 z day21 of any
human milk (averaged throughout the hospitalization)
with those of infants fed exclusively PF. Growth, feeding
tolerance, and health status were measured daily. Serum
indices of nutritional status were measured serially, and
72-hour nutrient balance studies were conducted at 6 and
9 weeks postnatally.
Results. A total of 108 infants were fed either >50
mL z kg21 z day21 human milk (FHM, n 5 62) or exclu-
sively PF (n 5 46). Gestational age (28 6 1 weeks each),
birth weight (1.07 6 0.17 vs 1.04 6 0.19 kg), birth length
and head circumference, and distribution among feeding
strategies were similar between groups. Infants fed FHM
were discharged earlier (73 6 19 vs 88 6 47 days) despite
significantly slower rates of weight gain (22 6 7 vs 26 6
6 g z kg21 z day21), length increment (0.8 6 0.3 vs 1.0 6 0.3
cm z week21), and increment in the sum of five skinfold
measurements (0.86 6 0.40 vs 1.23 6 0.42 mm z week21)
than infants fed PF. The incidence of necrotizing entero-
colitis and late-onset sepsis was less in the FHM group.
Overall, there were no differences in any measure of
From the *Children’s Nutrition Research Center and Sections of ‡Neona-
tology and §Pediatric Gastroenterology, Department of Pediatrics, Baylor
College of Medicine, Houston, Texas.
This work is a publication of the USDA/ARS Children’s Nutrition Research
Center, Department of Pediatrics, Baylor College of Medicine and Texas
Children’s Hospital, Houston, Texas.
The contents of this publication do not necessarily reflect the views or
policies of the USDA, nor does mention of trade names, commercial prod-
ucts, or organizations imply endorsement by the US government.
Received for publication Sep 18, 1998; accepted Jan 20, 1999.
Reprint requests to (R.J.S.) 1100 Bates St, Houston, TX 77030-2600. E-mail:
schanler@bcm.tmc.edu
PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad-
emy of Pediatrics.
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feeding tolerance between groups. Milk intakes of in-
fants fed FHM were significantly greater than those fed
PF (180 6 13 vs 157 6 10 mL z kg21 z day21). The intakes of
nitrogen and copper were higher and magnesium and
zinc were lower in group FHM versus PF. Fat and energy
absorption were lower and phosphorus, zinc, and copper
absorption were higher in group FHM versus PF. The
postnatal retention (balance) surpassed the intrauterine
accretion rate of nitrogen, phosphorus, magnesium, zinc,
and copper in the FHM group, and of nitrogen, magne-
sium, and copper in the PF group.
Conclusions. Although the study does not allow a
comparison of FHM with unfortified human milk, the
data suggest that the unique properties of human milk
promote an improved host defense and gastrointestinal
function compared with the feeding of formula. The
benefits of improved health (less sepsis and necrotizing
enterocolitis) associated with the feeding of FHM out-
weighed the slower rate of growth observed, suggesting
that the feeding of FHM should be promoted actively in
premature infants. Pediatrics 1999;103:1150 –1157; forti-
fied human milk, preterm formula, premature infants, nu-
tritional support.
ABBREVIATIONS. GI, gastrointestinal; FHM, fortified human
milk; NEC, necrotizing enterocolitis; PF, preterm formula; GRV,
gastric residual volume; TPN, total parenteral nutrition; Ca, cal-
cium; P, phosphorus; Mg, magnesium; Zn, zinc; Cu, copper.
T
he American Academy of Pediatrics’ recent
statement on the recommendations for breast-
feeding full-term infants acknowledges the
benefits of human milk in the management of pre-
mature infants.1 The beneficial effects generally re-
late to improvements in host defense, digestion and
absorption of nutrients, neurodevelopment, gastro-
intestinal (GI) function, as well as psychological ef-
fects on the mother.2 Human milk, especially, is suit-
able for meeting many needs of premature infants,
providing that their nutritional status is monitored
carefully.2 The exclusive feeding of unfortified hu-
man milk in premature infants, however, has been
associated with poorer rates of growth and nutri-
tional deficits during and beyond the period of hos-
pitalization.3–12 As the goal for nutritional support is
to meet the intrauterine rates of growth and nutrient
retention, nutrient supplementation is necessary to
optimize the use of human milk in the feeding of
premature infants.13–15
There is a concern, however, that nutrient supple-
mentation of human milk might affect the intrinsic
host defense properties of the milk.16,17 A recent ran-
domized comparison of premature infants fed forti-
fied human milk (FHM) versus those fed partially
supplemented human milk indicated that the com-
bined incidence of infection and necrotizing entero-
colitis (NEC) was greater in the infants fed FHM.18
However, when evaluated separately, neither mor-
bidity differed significantly between groups. Note-
worthy in that study was the acknowledgment that
most human milk-fed premature infants also receive
significant quantities of preterm formula (PF). Thus,
that comparison may have been affected by the large
proportion of PF (;50% of the milk intake) given to
both study groups.19
As part of a prospective study of feeding strategies
in premature infants (time of initiation of feeding,
tube-feeding method, and type of milk), it was ob-
served that the feeding of human milk had more
effect on the outcomes measured than any other
strategy studied.20 Therefore, this report describes
the role of diet separately by comparing the growth,
feeding tolerance, health outcomes, biochemical in-
dices of nutritional status, and nutrient absorption
and retention of premature infants fed predomi-
nately FHM versus PF.
METHODS
Study Design
Study infants, enrolled within 96 hours of birth, were partici-
pants in a feeding study where they were assigned randomly in a
balanced two-way design to early (GI priming from day 4 to day
14) versus late initiation of feeding (total parenteral nutrition
[TPN] only) and continuous infusion versus intermittent bolus
tube-feeding method.20 The type of milk was determined by pa-
rental choice and infants to receive their mother’s milk were
randomized separately from those to receive formula. This report
describes differences between infants fed either predominantly
FHM (their own mothers’ milk plus Enfamil Human Milk Forti-
fier, Mead Johnson Nutritionals, Evansville, IN) or PF (Enfamil
Premature Formula 24, Mead Johnson Nutritionals, Evansville,
IN). Comparisons of the nutrient composition of these milks have
been published.21 Growth, duration of hospitalization, skin-to-skin
contact and parental involvement, feeding tolerance, and health
outcomes (episodes of sepsis and NEC) were assessed serially.
Biochemical indices of nutritional status were measured every 2
weeks and nutrient retention and absorption were measured at 6
and 9 weeks’ postnatal age. The duration of the study spanned the
entire hospitalization of the infant. The criteria for hospital dis-
charge were uniform among attending physicians, ie, satisfactory
weight gain while receiving full oral feeding, maintenance of
thermal stability, and resolution of acute medical conditions.22
Beginning day 15, milk intake was increased daily by 20
mL z kg21 z day21. Human milk fortifier was added to human milk
when the intake reached 100 mL z kg21 z day21 and continued
until either the infant attained a body weight of 2 kg or consumed
all feedings orally and ad libitum. After day 15, the total milk
intake was monitored daily to ensure a body weight gain of at
least 15 g z kg21 z day21. Because of the inability of many mothers
to provide sufficient quantities of milk to meet their infants’ needs,
there was a wide range in the intake of any human milk, fortified
and unfortified. Therefore, the cumulative intake of any human
milk throughout the hospitalization was computed. Because we
desired to compare the outcomes of feeding predominantly FHM
versus exclusive PF, we defined predominant human milk feeding
to include all infants whose average human milk intake during
hospitalization was above the mean intake (50 mL z kg21 z day21)
of all infants fed human milk.
Mothers brought their milk to the Texas Children’s Hospital
Milk Bank each day. The procedures for milk expression, collec-
tion, and storage have been published.23 A 24-hour pool of milk
was thawed, sufficient human milk fortifier was added, and the
milk was divided into appropriate syringes for feeding. FHM was
stored at refrigerator temperature until used within 24 hours. The
study was approved by the Baylor College of Medicine Institu-
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tional Review Board for Human Subject Research. Informed writ-
ten consent was obtained from parents before enrollment.
Study Population
The feeding strategies study enrolled 171 premature infants
from the nurseries of Texas Children’s Hospital based on the
following criteria: 26 to 30 weeks’ gestation (as determined by a
combination of maternal dates and early antenatal ultrasound),
gestational age agreement between the two methods #2 weeks,
appropriate weight for gestational age, postnatal age #96 hours,
absence of major congenital malformations, fraction of inspired
oxygen ,0.60 by 72 hours, and informed written consent obtained
from parents. Among the total enrollment, 108 infants were the
subjects of this report, 62 of whom were fed predominantly hu-
man milk and 46 of whom were fed PF exclusively. The excluded
63 infants were fed a mixture of FHM (,50 mL z kg21 z day21) and
PF.
Outcome Measures
Body weight was measured at the same time each day by using
electronic scales. Frontooccipital circumference, crown-heel
length, and bilateral skinfold thicknesses at biceps, triceps, sub-
scapular, suprailiac, and lateral thigh sites were measured every 2
weeks by using methods previously published.24 Knee-heel length
was measured every 2 weeks by using a knemometer.25 The rate of
growth was computed by linear regression of serial measurements
for each subject from the time of minimum weight to discharge.
Bone mineral content of the distal 1⁄3 of the radius of the left arm
was measured at the beginning and the end of the study by using
portable single-photon absorptiometry (Model SP-2 scanner, Lu-
nar Radiation Corp, Madison, WI).
Feeding tolerance was assessed daily by the following charac-
teristics: gastric residual volume ([GRV] determined by aspiration
of gastric contents from the indwelling orogastric tube every 3
hours in all infants), spitting, abdominal distention and/or ten-
derness, stool number, hematochezia, and the number of hours
feedings were stopped. NEC was defined as clinical signs plus
pneumatosis intestinalis on abdominal radiographs (confirmed by
at least 2 clinicians). Sepsis was defined as clinical signs plus at
least one positive blood culture in conjunction with antibiotic
therapy for a minimum of 10 days. Late-onset sepsis was defined
as sepsis occurring after 7 days’ postnatal age.
Serum indices of protein and mineral nutritional status were
measured every 2 weeks. Automated laboratory techniques were
used to measure serum concentrations of calcium (Ca), phospho-
rus (P), magnesium (Mg), and albumin, alkaline phosphatase ac-
tivity, and blood urea nitrogen concentrations (Cobas Fara, Roche
Diagnostics Systems, Montclair, NJ) as well as serum concentra-
tions of sodium and bicarbonate (Vitros 950, Johnson & Johnson
Diagnostics, New Brunswick, NJ). The hematocrit was measured
by standard centrifugation methods.
Nutritional balance studies were conducted for 72 hours at 6
and 9 weeks postnatally to determine absolute and incremental
changes in the absorption and retention of energy, nitrogen, fat,
Ca, P, Mg, zinc (Zn), and copper (Cu). The methods for the
continuous collections of urine and feces and quantitative mea-
surement of milk intake have been reported previously.20,24 Car-
mine red was used to demarcate the fecal collection. The balance
(net retention) of each nutrient was calculated as the difference
between intake and the sum of urine and fecal losses during the
72-hour interval. Percent absorption was defined as the difference
between intake and fecal losses expressed as a percentage of
intake.
Data Analyses
All infants receiving PF exclusively and those who received
.50 mL z kg21 z day21 of any human milk averaged throughout
hospitalization were evaluated from birth to hospital discharge.
ANOVA and repeated measures ANOVA were used to determine
differences between groups for continuous variables. x2 and logis-
tic regression analyses were used to assess differences with respect
to dichotomous outcomes. Statistical significance was set at the 5%
level of probability. Unless indicated otherwise, the data are ex-
pressed as mean 6 SD values.
1151
 RESULTS TABLE 2. Growth Outcomes
Study Subjects and Parents Fortified Preterm
Human Milk Formula
The characteristics of the 108 infants are shown in
Table 1. Because of differences between groups in Regain birth weight (days) 12 6 6* 12 6 4
antenatal steroid exposure, this variable was used as Complete tube-feeding (days)† 28 6 7 36 6 17
Full oral feeding (days) 62 6 18 60 6 20
a covariate in subsequent analyses of outcomes. The Age at 2 kg (days)‡ 59 6 13 51 6 12
proportion of infants with an Apgar score .6 at 5 Weight gain (g z kg21 z day21)‡ 22 6 7 26 6 6
minutes was 85% and 87%, in FHM and PF, respec- Length increment (cm z week21)† 0.79 6 0.27 1.00 6 0.26
tively. Thirteen percent of mothers who provided Frontooccipital circumference 0.88 6 0.26 0.93 6 0.18
milk to their infants had no intent to breastfeed had increment (cm z week21)
Knee-heel length increment 2.6 6 0.8 3.1 6 0.8
they delivered a term infant. The FHM group moth- (mm z week21)‡
ers had completed more years of school than mothers Sum of skinfolds at 5 sites 0.86 6 0.40 1.23 6 0.42
of group PF. The FHM group also had more skin-to- (mm z week21)†
skin contact with their mothers, 9 6 10 (median 5 6) Discharge weight (g)† 2428 6 389 2998 6 1245
sessions versus 0.5 6 1.0 (median 5 0) sessions in * Values are mean 6 SD.
group PF, P , .001. Parents of infants in group FHM †,‡ Differences between groups: †P # .001, ‡ P # .01.
were more likely to visit (median, 78 vs 48 visits) and
hold (median, 300 vs 54 minutes) their infant than
parents of infants in group PF, respectively, P , .001. increments also were significantly less in FHM than
However, maternal educational level, the number of PF groups (Fig 1). There was no significant difference
sessions of skin-to-skin contact, parent holding, and between groups in the absolute or increment in ra-
parent visiting were not significantly correlated with dius bone mineral content (median, 1.2 vs 1.9
the duration of hospitalization. Nevertheless, despite mg z cm21 z week21, in FHM vs PF, P 5 .3).
a body weight difference of 500 g, the FHM group Clinical Outcomes
was discharged from the hospital approximately 2
weeks earlier than the PF group (Tables 1 and 2). There was 1 death in the FHM group and 3 deaths
in the PF group. Although there were differences in
Growth Outcomes the duration of oxygen therapy, there were no dif-
The attainment of complete tube-feeding was ear- ferences between groups in the use of artificial sur-
lier in group FHM than PF (see Table 2). This factant, duration of mechanical ventilation, or inci-
achievement was related to a shorter duration of dence of bronchopulmonary dysplasia, patent
TPN usage (25 6 8 vs 37 6 35 days, P 5 .01) because ductus arteriosus, and intraventricular hemorrhage
of better feeding tolerance in FHM versus PF, respec- (Table 3). The FHM group had a significantly lower
tively. As feeding volumes were advanced from day incidence of NEC and late-onset sepsis than the PF
15 to complete tube-feeding, FHM had significantly group. There was an inverse relationship between
fewer gastric residuals and less hours when feedings the number of positive blood cultures and the intake
were withheld than PF (see below). There were no of human milk throughout hospitalization (r 5
differences between groups in the achievement of 20.26, P 5 .007) (Fig 2). The relationship between the
full oral feeding. The rate of growth (weight gain and number of positive blood cultures and the intake of
linear growth) was significantly lower in the FHM PF throughout hospitalization, however, was not sta-
than PF group (Table 2). Increments in the sum of tistically significant (r 5 20.02, P 5 .80). There were
skinfold thicknesses at five sites differed significantly no differences between groups in the age at diagno-
between FHM and PF groups. Individual skinfold sis of NEC or late-onset sepsis. The type of microor-
ganisms isolated from blood cultures was similar to
published reports of late-onset sepsis in very low
TABLE 1. Characteristics of Study Infants birth weight neonates.26 Approximately 52% of iso-
Fortified Preterm Formula
Human Milk (n 5 46)
(n 5 62)
Birth weight (g) 1069 6 169* 1044 6 185
Gestational age (wk) 27.9 6 1.2 27.9 6 1.1
Sex (% males) 53 59
Ethnicity (% Hispanic, black, 18, 24, 58, 0 33, 26, 39, 2
white, Asian)
Maternal education (y)† 15.0 6 2.5 12.9 6 1.5
Antenatal steroid exposure, 43 (69) 19 (46)
n (%)‡
Randomization to GI 38 (61) 22 (48)
priming, n (%)
Randomization to bolus 29 (47) 25 (54)
tube-feeding, n (%)
Duration of study (days of 73 6 19 88 6 47
hospitalization)†
Abbreviation: GI, gastrointestinal. Fig 1. Rate of increase in skinfold thickness during hospitaliza-
* Values are mean 6 SD. tion. Significant differences between groups at all sites, P , .01.
†,‡ Differences between groups: † P 5 .03, ‡ P 5 .004. Values are mean 6 SEM.

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TABLE 3. Clinical Outcomes
Fortified
Human Milk
Oxygen therapy (days)† 19 6 21*
NEC, n (%)‡ 1 (1.6)
NEC surgery (n) 0 3
Late-onset sepsis, n (%)§ 19 (31)
Late-onset sepsis (no. of episodes 0.3 6 0.5
per infant)\
Positive blood cultures (no. per 0.5 6 0.9
infant)‡
NEC or late-onset sepsis, n (%)‡ 19 (31)
Abbreviation: NEC, necrotizing enterocolitis.
* Values are mean 6 SD.
†,‡,§,\ Differences between groups: † P 5 .02, ‡ P # .01, § P 5 .07,
\ P 5 .03.
lates were Staphylococcus coagulase–negative, 24%
Staphylococcus aureus, 6% Escherichia coli, 4% Entero-
coccus, 4% Klebsiella, 4% Enterobacter, 2% Serratia, and
2% Candida.
There were significant differences in feeding toler-
ance during the advancement of feedings, from day
15 to the attainment of complete tube-feeding. Dur-
ing this interval, there were fewer GRVs .2
mL z kg21 (3 6 7% vs 7 6 9% of any GRV) and .50%
of 3 hours of feeding (0.3 6 0.8% vs 0.9 6 2.0% of any
GRV) in FHM than PF, respectively, P , .05. There
were significantly fewer hours when feeding was
withheld in FHM than PF (47% vs 69% of infants, P ,
.04). For the entire study, however, there were no
significant differences between groups in the follow-
ing assessments of feeding tolerance: the median
number of episodes of emesis, abdominal distention,
GRV, bilious GRV, number of hours feedings were
withheld, and abnormal abdominal radiographs.
However, despite the overall absence of major dif-
ferences in feeding tolerance, fewer of the FHM
group received antigastroesophageal reflux medica-
tions (eg, metoclopramide, bethanecol, ranitidine,
and cisapride), 16% versus 39%, respectively, P 5
Fig 2. Relationship between the num-
ber of positive blood cultures and the
cumulative intake of human milk
throughout hospitalization, r 5 20.26,
P 5 .007. Several points overlap.
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.007. The FHM group had significantly more stools
Preterm than the PF group; the median number throughout
Formula hospitalization was 164 versus 127, respectively,
33 6 41 P 5 .02.
6 (13)
22 (48) Indices of Nutritional Status
0.6 6 0.7 There were no differences between groups in the
1.2 6 1.7 mean or the number of abnormal values for serum
Ca, P, Mg, alkaline phosphatase activity, albumin,
25 (54) sodium, or blood urea nitrogen. However, the FHM
group had significantly more serum bicarbonate val-
ues ,20 mmol/L than the PF group, P 5 .04. A
hematocrit ,25% also was more common in FHM
than PF groups, P 5 .001. In addition, the FHM
group received more supplementation with enteral
acetate preparations for low serum bicarbonate con-
centrations (34% vs 15%; P 5 .03) and more sodium
supplementation for low serum sodium concentra-
tions (39% vs 22%; P 5 .06).
Milk and Nutrient Intakes
Total fluid intake differed between groups, pri-
marily a result of the greater intake of human milk
prescribed to meet desired goals for minimum gains
in body weight (Table 4). The FHM group received
84 6 20% of all their milk as human milk (median
93%); 22 infants received 100% human milk through-
out hospitalization. Human milk fortifier was used
for 37 6 13 days (range, 15 to 79 days). The average
milk and nutrient intakes during and between the
balance studies, while infants were receiving full
enteral nutrition, are given in Table 4. There were no
differences in fluid, energy, or nutrient intake be-
tween the first and the second balance study, at 6 and
9 weeks’ postnatal age. Significant differences be-
tween the FHM and PF group, however, were noted
for intakes of milk, nitrogen, Mg, Zn, and Cu.
1153
TABLE 4. Milk and Nutrient Intakes PF group, 32 6 15 versus 40 6 14 hours, respectively,
Component Fortified Preterm P 5 .01.
(unit z kg21 z day21) Human Milk Formula
Overall intakes throughout DISCUSSION
hospitalization
Total fluid intake (mL)‡ 158 6 7* 147 6 14 The use of multinutrient fortifiers for human milk-
Total human milk intake 96 6 23 0 fed premature infants has increased in neonatal cen-
(mL)‡ ters. Mineral supplementation of unfortified human
Total formula intake (mL)‡ 20 6 25 92 6 33
Intakes during and between
milk throughout hospitalization may improve linear
balance studies (enteral growth and bone mineralization during and beyond
feeding period)† the neonatal period.14,27–29 Supplementation with
Milk (mL)‡ 180 6 13 157 6 10 both Ca and P also results in a normalization of
Energy (kcal) 134 6 23 129 6 11 biochemical indices of mineral status: serum Ca, P,
Nitrogen (mg)§ 662 6 297 553 6 44
Fat (g) 6.0 6 1.8 6.0 6 0.5 and alkaline phosphatase activity; urinary excretion
Calcium (mg) 196 6 22 192 6 15 of Ca and P.11,30 Sodium supplementation has been
Phosphorus (mg) 118 6 13 120 6 9 demonstrated to normalize serum sodium.31,32 Pro-
Magnesium (mg)‡ 7.9 6 1.1 9.1 6 0.7 tein and energy supplementation have been shown
Zinc (mg)§ 1.9 6 0.4 2.1 6 0.2
Copper (mg)§ 247 6 47 218 6 40 to improve rates of weight gain and indices of pro-
tein nutritional status, ie, blood urea nitrogen and
* Values are mean 6 SD.
† Changes in intakes from 6 to 9 weeks were not significant.
serum albumin.8,33,34
‡,§ Differences between groups: ‡ P # .001, § P # .01. However, despite the advantages to nutritional
Conversion factors: 1 kJ 5 4.184 kcal, 1 mmol N 5 14 mg, 1 mmol status, there is a concern that the addition of a large
Ca 5 40 mg, 1 mmol P 5 31 mg, 1 mmol Mg 5 24 mg, 1 mmol quantity of supplements may affect the intrinsic host
Zn 5 65 mg, 1 mmol Cu 5 64 mg. defense properties as well as the GI tolerance of
human milk.16 –18,35 For ethical reasons relating to
Nutrient Absorption and Retention standard of care and our experience with human
Despite increases with maturity, fat and energy milk fortification, we could not conduct a compari-
absorption were significantly less in the FHM than son of FHM with unfortified human milk. We chose
the PF group at both times of measurement (Fig 3). instead to compare FHM with the default feeding in
The percent fat absorption correlated positively with our nursery, PF. This comparison with PF demon-
the rate of weight gain, r 5 0.595, P , .001. The strated that the fortification of human milk promoted
percent absorption of P, Zn, and Cu differed between adequate nutritional status without compromising
groups; Ca and Mg absorption increased over time host defense or feeding tolerance. Indeed, predomi-
(Fig 4). There was significantly greater net retention nant FHM feeding was associated with significantly
(balance) of nitrogen, P, and Cu in the FHM than the lower morbidity from NEC and late-onset sepsis and
PF group at both 6 and 9 weeks, P , 0.01. Nitrogen better feeding tolerance compared with exclusive
balance declined similarly from 6 to 9 weeks, in both feeding of PF. We caution against the overinterpre-
the FHM and the PF group, P , .001. To compare tation of these results. Although the definition of the
postnatal retention (balance) with intrauterine accre- human milk group (average, .50 mL z kg21 z day21
tion for each nutrient, we used the percent attain- throughout hospitalization) was determined before
ment of intrauterine accretion (Fig 5). The retention the analyses, this group also received PF. However,
of most nutrients surpassed the intrauterine accre- the FHM group was unique in that the infants re-
tion rate; only Ca retention in infants fed PF was ceived a significantly greater quantity of human milk
below the intrauterine estimates. The carmine red than infants in other studies of fortified human milk.
intestinal transit time, averaged for both 6- and Nevertheless, the ideal model to study these relation-
9-week studies, differed between the FHM and the ships would be to evaluate exclusive human milk

Fig 3. Percent absorption of energy, fat, and

nitrogen at 6 and 9 weeks. Significant differ-
ences between groups and over time, *P , .001.
Values are mean 6 SEM.

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Fig 4. Percent absorption of minerals at 6 and
9 weeks. Significant differences between
groups, *P , 0.001, **P , 0.01. Significant dif-
ferences over time, †P 5 .03, ††P 5 .05. Values
are mean 6 SEM.
feeding, using donor human milk if mother’s milk is
unavailable.
The low incidence of NEC and late-onset sepsis in
group FHM is compatible with other reports of pro-
tective effects of human milk in premature in-
fants.9,36 –38 The mechanism underlying the protective
effects is unknown. Some reports suggest that the
protective effects are related to the high immuno-
globulin A content of human milk.39 The numerous
bioactive substances in human milk also may play a
role in the local protective effects of human milk.40,41
The protection afforded by FHM also may be ex-
plained, at least partially, by the more frequent ses-
sions of skin-to-skin contact between mother and
infant in the FHM group. Skin-to-skin contact can be
viewed as the neonatal nursery equivalent of the
enteromammary pathway for host defense of the
infant.42 Frequent skin-to-skin sessions may stimu-
late maternal antibody production to produce a milk-
containing antibody against nosocomial pathogens.
Therefore, there are several possible explanations for
the reduced episodes of NEC and late-onset sepsis in
the FHM group.
Our large study suggests that more attention to the
nutritional aspects of fortification is warranted. We
observed slower rates of weight gain and linear
growth in the FHM group compared with the PF
group. The lesser increments in skinfold thickness, in
conjunction with the greater nitrogen retention, sug-
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Fig 5. Net nutrient retention expressed as a
percentage of intrauterine accretion rate. The
dotted line represents 100% of the intrauterine
accretion rate. Significantly different from
100% intrauterine accretion rate, *P , .001,
**P 5 .02, ***P 5 .01. Significant difference
between groups, †P 5 .003, ††P 5 .01, †††P 5
.005. Values are mean 6 SEM.
gest that infants in group FHM were leaner than
those in group PF. The lesser rate of growth might be
detrimental if it prolonged hospitalization, but, par-
adoxically, group FHM had a significantly shorter
hospitalization. Thus, we question the relevance of
the lower rate of weight gain in the FHM group.
Further investigations of the growth outcomes in this
group are ongoing.
There are many factors that affect the duration of
hospitalization. Similar objective criteria in each
group were used for discharge. Infants fed FHM
were healthier, having less NEC and late-onset sep-
sis, but also, these infants had more interaction with
their parents, through visits, holding, and skin-to-
skin contact. However, we did not observe any rela-
tionship between parent interaction and the duration
of hospitalization. Thus, our data do not support the
enhanced bonding effect of parental contact.43 There
is no way to assess whether these parenting oppor-
tunities affected, in other ways, the decision for hos-
pital discharge. Nevertheless, a shorter hospitaliza-
tion has tremendous economic advantages in terms
of the cost of health care.
The balance study data indicate that the net reten-
tion of most nutrients was significantly above intra-
uterine references and that Mg, Zn, and Cu are in
excess in the FHM group versus the PF group. These
data support the formulation of human milk fortifi-
ers with less of these nutrients.
1155
 Moreover, the surplus of nutrients also may be a
concern because of potential nutrient interactions.
This is particularly apparent in the comparison of fat
absorption between groups. Although increasing
over time, probably with maturation of intestinal
function, fat absorption in group FHM was signifi-
cantly less than that of group PF. In addition, fat
absorption correlated significantly with weight gain.
It is unclear, however, why fat absorption was so
low. There are differences between the fat composi-
tion of FHM and PF.21 However, the greater quantity
of medium-chain fatty acids in PF has not been as-
sociated with better fat absorption.44 The relationship
between fat absorption and mineral supplementation
also has been studied.24,45 The addition of a large
quantity of minerals to human milk may have cre-
ated an unfavorable milieu for the human milk lipid
system. We speculate that the milk fat globule may
have been disrupted, with liberation of free fatty
acids that, in turn, combined with the minerals to
form insoluble soaps in the intestinal tract. There is
some confirmation that the impaired fat absorption is
related to the large mineral content of the fortified
human milk. European human milk fortifiers contain
a lesser amount of minerals (eg, 50 vs 90 mg Ca to be
added to 100 mL human milk) and estimates of fat
absorption in infants fed the European preparations
are significantly greater than those reported here.46
Thus, additional investigations, including studies
targeted at less mineral supplementation, are needed
to determine if fat absorption can be optimized.
We did not observe marked differences in the bio-
chemical measures of nutritional status between
groups, because both groups received more than
minimal nutrient intakes to meet their needs. How-
ever, low serum bicarbonate concentrations and
treatment with acetate preparations were signifi-
cantly more common in the FHM group than the PF
group. The reasons for the mild acidosis and the
need for base supplements in the FHM group are
unclear. We might expect a greater acid load to ac-
company the rapid growth and skeletal mineraliza-
tion of premature infants.47 The FHM group may
have had additional reasons for a mild acidosis. The
greater stool output may have contributed to more
bicarbonate loss, and the greater lactose intake may
have resulted in more unabsorbed carbohydrate
reaching the colon for fermentation to volatile fatty
acids. Furthermore, the greater citrate content of for-
mula provides more buffering capacity. As the pro-
cess appears to be transient, intestinal and renal mat-
uration eventually eliminate the continuing need for
acetate supplements in group FHM.47
CONCLUSION
In summary, based on our earlier publication and
the data in this report, we suggest that this large
study of feeding strategies in premature infants dem-
onstrated that the type of milk received has more
impact than the time it is initiated or the method in
which it is given. Less morbidity and a shorter du-
ration of hospitalization are associated with predom-
inant FHM feeding. Increased use of predominantly
FHM feeding should be endorsed in all neonatal
1156 FORTIFIED HUMAN
Downloaded MILK
from VERSUS PRETERM FORMULA
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nurseries. Efforts to enhance maternal lactation are
needed, to provide quantitatively more human milk
to premature infants. Further refinement of human
milk fortifiers, specifically those directed at reducing
the large quantity of mineral supplements, is war-
ranted.
ACKNOWLEDGMENTS
This study was supported by the National Institute of Child
Health and Human Development, Grant RO-1-HD-28140, and the
General Clinical Research Center, Baylor College of Medicine/
Texas Children’s Hospital Clinical Research Center, Grant MO-1-
RR-00188, National Institutes of Health. Partial funding also was
provided by the USDA/ARS under Cooperative Agreement 58 –
6250-6 – 001.
We thank Pamela Burns, RN, Christina Valentine, RD, CNSD,
Leanne Renfro, RN, Ellen Newton-Lovato, RN, the nursery staff of
the Neonatal General Clinical Research Center and neonatal nurs-
eries at Texas Children’s Hospital, and Nancy Hurst, RN, and the
staff of the Lactation Program at Texas Children’s Hospital for
their expertise, Charles Imo for laboratory assistance, J. Kennard
Fraley for database management, and Idelle Tapper for secretarial
skills. We thank Dr William C. Heird for his critique of the
manuscript.
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Submitted by Student
1157
 Feeding Strategies for Premature Infants: Beneficial Outcomes of Feeding
Fortified Human Milk Versus Preterm Formula
Richard J. Schanler, Robert J. Shulman and Chantal Lau
Pediatrics 1999;103;1150
DOI: 10.1542/peds.103.6.1150

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 Feeding Strategies for Premature Infants: Beneficial Outcomes of Feeding
Fortified Human Milk Versus Preterm Formula
Richard J. Schanler, Robert J. Shulman and Chantal Lau
Pediatrics 1999;103;1150
DOI: 10.1542/peds.103.6.1150

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/103/6/1150

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