Growth of Preterm Infants Fed Nutrient-Enriched or Term Formula After Hospital Discharge

Growth of Preterm Infants Fed Nutrient-Enriched or Term

Formula After Hospital Discharge

Jane D. Carver, PhD, MS*; Paul Y. K. Wu, MD‡; Robert T. Hall, MD§; Ekhard E. Ziegler, MD

储

;

Roberto Sosa, MD¶; Joan Jacobs, MS#; Geraldine Baggs, MS#; Nancy Auestad, PhD#;

and Beate Lloyd, PhD#

ABSTRACT. Objective. At hospital discharge, pre-term infants may have low body stores of nutrients, deficient bone mineralization, and an accumulated en-ergy deficit. This double-blind, randomized study eval-uated the growth of premature infants with birth weights

<1800 g who were fed a 22 kcal/fl oz nutrient-enriched postdischarge formula (PDF) or a 20 kcal/fl oz term-infant formula (TF) from hospital discharge to 12 months’ corrected age (CA).

Methods. Infants were randomized to PDF or TF a few days before hospital discharge with stratification by gender and birth weight (<1250 g or>_{1250 g). The} for-mulas were fed to 12 months’ CA. Growth was evaluated using analysis of variance controlling for site, feeding, gender, and birth weight group. Interaction effects were also assessed. Secondary analyses included a repeated measures analysis and growth modeling.

Results. One hundred twenty-five infants were ran-domized; 74 completed to 6 months’ CA and 53 to 12 months’ CA. PDF-fed infants weighed more than TF-fed infants at 1 and 2 months’ CA, gained more weight from study day 1 to 1 and 2 months’ CA, and were longer at 3 months’ CA. There were significant interactions between feeding and birth weight group—among infants with birth weights<1250 g, those fed PDF weighed more at 6 months’ CA, were longer at 6 months’ CA, had larger head circumferences at term 1, 3, 6, and 12 months’ CA, and gained more in head circumference from study day 1 to term and to 1 month CA. The repeated measures and growth modeling analyses confirmed the analysis of variance results. The PDF formula seemed to be of par-ticular benefit for the growth of male infants. Infants fed the PDF consumed less formula and had higher protein intakes at several time points. Energy intakes, however, were not different.

Conclusions. Growth was improved in preterm in-fants fed a nutrient-enriched postdischarge formula after hospital discharge to 12 months’ CA. Beneficial effects were most evident among infants with birth weights <1250 g, particularly for head circumference

measurements. Pediatrics 2001;107:683– 689; nutrition, preterm, low birth weight, growth.

ABBREVIATIONS. VLBW, very low birth weight; CA, corrected age; PDF, postdischarge formula; TF, term formula.

A

lthough adequate nutrition is critical in the

management of small preterm infants, no

feeding standard exists that is comparable to

the breast milk standard for term infants. Present

recommendations are designed to provide nutrients

to approximate the rate of growth and composition

of weight gain for a normal fetus of the same

postconceptional age without inducing metabolic

stress.

_{However, many preterm infants who retain}

nutrients at these levels remain growth retarded

rel-ative to a fetus or newborn of comparable

postcon-ceptional age. The delay in catch-up growth is

attrib-utable in part to the slow initial growth during

hospital stay and to the initial postnatal weight loss,

which may be at least 10% of body weight

_and

which may not be regained for 2 weeks or more in

infants with very low birth weights (VLBW).

Typical hospital discharge weights for preterm

in-fants in the United States are 1800 to 2000 g. At

discharge, preterm infants may have low body stores

of nutrients,

_{deficient bone mineralization,}

_{and an}

accumulated energy deficit of 3780 to 5460 kJ.

_{At 40}

weeks’ postmenstrual age, preterm infants are

gen-erally smaller than term infants, and they are

pro-jected to have higher nutrient requirements. They

may remain growth retarded for several years,

have higher rates of childhood morbidity and

mor-tality,

_{have undermineralized bones,}

_have

fail-ure to thrive,

_{and often experience delays in}

neu-rodevelopment

_{that can persist to school}

age.

Aggressive nutritional management during

hospi-talization promotes earlier onset of and more rapid

rates of postnatal growth of preterm infants,

which may be associated with later developmental

advantages.

_{Studies by Kashyap et al}

_have

demonstrated that hospitalized preterm infants can

effectively use, without metabolic stress, higher

con-centrations of protein and energy than are typically

fed. Less is known about the nutritional needs of the

postdischarge preterm infant relative to the term

infant. Preterm infants may be discharged from the

hospital on breast milk, formula designed for term

From the *University of South Florida College of Medicine, Department of Pediatrics, Division of Neonatology, Tampa, Florida; ‡Los Angeles County and University of Southern California School of Medicine, Division of Neonatal-Perinatal Medicine, Los Angeles, California; §Children’s Mercy Hospital, Kansas City, Missouri;储University of Iowa Hospitals and Clinics, Iowa City, Iowa; ¶All Children’s Hospital, St Petersburg, Florida; and #Ross Products Division, Abbott Laboratories, Columbus, Ohio.

Received for publication Mar 24, 2000; accepted Sept 7, 2000.

Reprint requests to (J.C.) University of South Florida College of Medicine, Department of Pediatrics, Division of Neonatology, 17 Davis Blvd, Suite 200, Tampa, FL 33606. E-mail: jcarver@med.usf.edu

infants, or postdischarge formula designed for

pre-term infants. The potential benefit of postdischarge

formulas is being increasingly recognized.

Im-proved growth

_{and bone mineralization}

_have

been reported in preterm infants fed

nutrient-en-riched formulas after hospital discharge.

The purpose of the present study was to determine

if feeding a nutrient-enriched formula designed for

the nutritional needs of preterm infants after hospital

discharge would result in improved growth

com-pared with infants fed a standard formula designed

for term infants.

METHODS AND MATERIALS Study Design

A controlled, double-blind, randomized, parallel study was designed to evaluate the growth of premature infants fed 1 of 2 different formulas from hospital discharge to 12 months’ corrected age (CA). Infants were randomized to 22 kcal/fl oz postdischarge formula (PDF) or 20 kcal/fl oz term formula (TF) 2 to 4 days before hospital discharge, at which time body weight was expected to be 1800 to 2300 g. The first day of study formula feeding was desig-nated as study day 1. Infants were measured at study visits that corresponded to term (40 weeks after last menstrual period), and to 1, 2, 3, 6, 9, and 12 months’ CA. Blood samples were obtained at term, 3 months’, and 9 months’ CA. Dietary intakes and mea-sures of formula tolerance were recorded for 3 days before each study visit in booklets provided to parents.

This protocol was approved by the Institutional Review Board for the Protection of Human Subjects at each institution.

Participants

Preterm infants were recruited from hospitals in 6 cities (Los Angeles, CA, Tampa, FL, St Petersburg, FL, Kansas City, MO, Iowa City, IA and Ft Lauderdale, FL). Inclusion criteria included birth weightⱕ1800 g, gestational age⬍37 weeks, and previous parental decision not to provide breast milk for their infant. In-fants with severe bronchopulmonary dysplasia, cardiac, respira-tory, gastrointestinal, or other systemic diseases were excluded. At the time study feedings were initiated, infant weights were 1635 to 2715 g (PDF), and 1640 to 2800 g (TF), and their postnatal ages were ⬎1 week. There were no restrictions on the type of feeding before study entry. Parental informed consent was ob-tained before infants entered the study.

The randomization schedule, prepared by the Biostatistics De-partment of Ross Products Division, was stratified for gender and birth weight group (⬍1250 g,ⱖ1250 g). Participants who did not complete the study were not replaced.

Study Feedings

Study formulas were the 22 kcal/fl oz nutrient-enriched PDF or a commercially available 20 kcal/fl oz TF. Both formulas were provided by Ross Products Division, Abbott Laboratories, Colum-bus, Ohio. The PDF provided higher quantities of protein, most minerals, and vitamins per 100 kcal than TF (Table 1). The ratio of whey to casein proteins in PDF was 50:50, and the fat blend consisted of 45% soy oil, 30% coconut oil, and 25% medium-chain triglyceride oil. The TF had a whey to casein ratio of 20:80, and its fat blend consisted of 60% soy oil and 40% coconut oil. Clinically labeled ready-to-feed formulas were provided in 4-fl oz bottles for inhospital use and in 32-fl oz cans for use after hospital discharge. At the time of hospital discharge, parents were given a supply of formula and were instructed to feed only the study formula to 4 months’ CA. From 4 to 12 months’ CA, infants continued to receive the assigned formula, and parents were instructed to con-form to the American Academy of Pediatrics recommendations regarding the inclusion of other foods.1_{Clinic visits were} sched-uled to correspond to term, and to 1, 2, 3, 6, 9, and 12 months’ CA. At each clinic visit, infants were weighed nude and head cir-cumference and length were measured. Each site was requested to have the same examiners obtain anthropometric measurements at each visit; measurements were made in duplicate. Measurements that did not meet these criteria were not included in the analyses.

All centers were provided with O’Leary recumbent length boards (Ellard Instrumentation, Inc, Seattle, WA), head circumference measuring tapes (Similac Inser-Tape, Associated Visual Commu-nications, Canton, OH) and weights for calibrating scales.

Blood Sampling and Analyses

At the term, 3, and 9 months’ CA visits, blood samples (⬃1 mL) were obtained using the Tenderfoot Premie heel incision device (International Technidyne Corp, Edison, NJ) or from a peripheral vein by venipuncture. Only nonhemolyzed samples were ana-lyzed. Hemoglobin concentrations in blood obtained by heel inci-sion were determined using the HemoCue AB (HemoCue, Inc, Mission Viejo, CA) while those obtained by venipuncture were determined using a Coulter STKS Automated CBC Spectropho-tometer analyzer or a Model M430 Coulter Counter (Coulter Elec-tronics, Hialeah, FL). Remaining blood was centrifuged and serum was transferred to polypropylene tubes and frozen. The samples were shipped on dry ice to Ross Products Division where serum levels of albumin, prealbumin, and retinol-binding protein were determined using the Behring Nephelometer 100 (Hoechst-AG, Frankfurt, Germany) and serum urea nitrogen was determined

TABLE 1. Content of Selected Nutrients in the PDF and TF per 100 kcal

Nutrient PDF TF

Protein, g 2.6 2.1

Fat, g 5.5 5.4

Carbohydrate, g 10.3 10.7 Linoleic acid, mg 750 1300

Vitamin A, IU 460 300

Vitamin D, IU 80 60

Vitamin E, IU 3.6 3.0

Vitamin K,␮g 11 8

Calcium, mg 105 73

Phosphorus, mg 62 56

Ca:P ratio 1.7 1.3

Magnesium, mg 9 6

Iron, mg 1.8 1.8

Zinc, mg 1.2 0.75

Manganese,␮g 10 5

Copper,␮g 120 90

Osmolarity, mosm/L 224 270 Renal solute load, mosm 17.9 14.3

TABLE 2. Demographic Data and Reasons for Early Exit for Infants Fed PDF or TF After Hospital Discharge

PDF TF

Sample size,n* 67 56

Birth weight, g 1292⫾46† 1249⫾49 Birth length, cm 38.8⫾0.5 38.6⫾0.6 Head circumference, cm 27.0⫾0.3 26.8⫾0.3 Gestational age, wk 30.0⫾0.4 30.0⫾0.4 Ethnicity,n

White 26 18

Black 11 12

Hispanic 29 23

Other 1 3

Gender,n(%)

Males 30 (45) 23 (41)

Early exit 31 26

Vomiting, constipation, or diarrhea

9 8

Study noncompliance 9 4

Illness or death unrelated to study feedings

10 6

Family moved 0 4

Other 3 4

* The sample size shown does not include 1 infant who never received study formula and another who was diagnosed with a genetic disorder.

using the Abbott Spectrum EPX Clinical Chemistry analyzer (Ab-bot Laboratories, Irving, TX).

Statistical Methods

Growth data were analyzed at each time point using a 3-way analysis of variance controlling for site, feeding group, gender, birth weight group, and interactions between feeding group and gender, feeding group and birth weight group, gender and birth weight group, and feeding, gender, and birth weight group. When significant interactions were found (P⬍.05), least squares means adjusted for the other variables in the model were used for com-parisons between feeding groups. Bonferroni adjustments to P

values were made for multiple comparisons. A posthoc analysis that included age at each study visit was also done at each time point. Longitudinal analysis of the growth data were also done using a mixed model repeated measures analysis controlling for site, birth weight group, feeding group, gender, and visit (PROC MIXED, SAS v6.09 Enhanced, Cary, NC). A growth modeling approach was applied to control for variability in the timing of clinic visits and for missed visits. A 3-parameter Gompertz31 model was used to fit a curve for each subject, using all available data (PROC NLIN, SAS v6.09 Enhanced, Cary, NC). Values for the exact, protocol-specified anthropometric values were estimated from the individual curves and analyzed using the same mixed model repeated measures analysis as described above.

Formula intake data (volume, protein, and energy per kg body weight per day) were analyzed at each time point using 3-way analysis of variance controlling for site, birth weight group,

gen-der, and interactions as described for growth. Blood biochemis-tries were analyzed at each time point using 1-way analysis of variance controlling for site.

In general, continuous data were evaluated using analysis of variance and categorical data using␹2_{tests of association or exact} tests. The null hypothesis was that growth of infants fed nutrient-enriched formula would be no greater than that of infants fed control formula. Hypothesis tests for growth were 1-sided with

␣⬍0.05 considered statistically significant. All other hypothesis tests were 2-sided 0.05 level tests.

RESULTS

One hundred twenty-five infants were

random-ized; 1 participant who was randomized never

re-ceived study formula and 1 was not included in the

analyses because of the diagnosis of a genetic

disor-der before hospital discharge. Birth anthropometrics,

gestational age, percentage of infants with

intrauter-ine growth restriction, ethnicity, gender

distribu-tions, and reasons for early exit from the study did

not differ between infants fed PDF and those fed TF

(Table 2). The postnatal ages of infants at study day

1, term, 1, 2, 3, 6, 9 and 12 months’ CA were 41

⫾

3,

70

⫾

3, 103

⫾

3, 132

⫾

4, 164

⫾

4, 247

⫾

4, 329

⫾

4,

438

⫾

5 days (PDF) and 43

⫾

4, 68

⫾

3, 99

⫾

3, 131

⫾

TABLE 3. Weight (g), Length (cm), and Head Circumference (cm) Measurements From Study Day 1 to 12 Months’ CA*

PDF TF PDF Versus TF†

PValues Main

Effects

Interaction Effects Study day 1

Weight 2068⫾40 (54) 2083⫾41 (46) .38 —

Length 44.3⫾0.4 (45) 43.9⫾0.4 (41) .14 —

Head circumference 31.5⫾0.2 (50) 31.8⫾0.2 (44) .11 — Term

Weight 3053⫾68 (54) 2867⫾67 (48) — .041

Length 48.0⫾0.3 (55) 47.3⫾0.3 (47) .06 —

Head circumference 34.7⫾0.2 (55) 34.4⫾0.2 (48) — .032 1 Mo

Weight 4092⫾97 (51) 3825⫾94 (44) .02 —

Length 52.3⫾0.4 (51) 51.6⫾0.4 (44) .10 —

Head circumference 37.1⫾0.2 (51) 36.7⫾0.2 (44) — .032 2 Mo

Weight 4968⫾112 (41) 4724⫾106 (40) .05 —

Length 55.8⫾0.4 (41) 55.1⫾0.3 (41) .06 —

Head circumference 38.6⫾0.2 (40) 38.7⫾0.2 (41) .40 — 3 Mo

Weight 5779⫾131 (43) 5518⫾124 (41) .06 —

Length 59.2⫾0.5 (43) 58.1⫾0.5 (41) .04 —

Head circumference 40.2⫾0.2 (42) 40.0⫾0.2 (41) — .042 6 Mo

Weight 7451⫾176 (39) 6993⫾177 (35) — .012

Length 65.5⫾0.5 (39) 63.9⫾0.5 (35) — .012

Head circumference 43.0⫾0.3 (37) 42.5⫾0.3 (35) — ⬍.012 9 Mo

Weight 8409⫾214 (39) 8111⫾229 (32) .14 —

Length 69.9⫾0.5 (38) 68.9⫾0.6 (31) .08 —

Head circumference 44.6⫾0.3 (37) 44.0⫾0.3 (31) .07 — 12 Mo

Weight 9356⫾270 (26) 8846⫾269 (27) — .043

Length 74.6⫾0.7 (27) 73.5⫾0.7 (27) .10 —

Head circumference 45.7⫾0.3 (27) 45.4⫾0.3 (27) — .012 * Data are reported as least square means⫾standard error of mean adjusted for site, gender and birth weight group and analyzed by analysis of variance controlling for site, feeding group, gender, and birth weight group.

†Pvalues are 1-sided for main effects and 2-sided for interactions.Pvalues with superscripts are for interactions as indicated: 1_{Feeding by gender by birth weight group interaction: among male infants with birth weight}ⱖ_{1250 g; PDF}⬎_TF,P⫽_.03. 2_{Feeding by birth weight group interaction: among infants with birth weight⬍1250 g; PDF⬎TF,P⬍.05.}

3, 161

⫾

4, 240

⫾

3, 330

⫾

4, 437

⫾

5 days (TF)

(mean

⫾

standard error of mean). The postnatal ages

were not different, except at the 6 months’ CA visit

(

P

⫽

.04). However, including postnatal age at the

study visits as an additional covariate in the analysis

of variances did not significantly affect the results.

Sample size varied at individual timepoints because

of dropouts and missed clinic appointments.

Anthropometric measurements at study day 1 did

not differ between infants fed PDF or TF. The

PDF-fed infants had greater weight, length, head

circum-ferences, and gains in these measures at several of

the subsequent visits (Tables 3 and 4), with

confir-matory longitudinal analyses using repeated

mea-sures and growth modeling.

PDF-fed infants weighed significantly more at 1

and 2 months’ CA, and gained more weight (g/d)

from study day 1 to each of these visits. There were

significant interactions between feeding and birth

weight group; among infants with birth weights

⬍1250 g, PDF-fed infants weighed more than TF-fed

infants at 6 months’ CA, and they gained more

weight from study day 1 to 12 months’ CA. There

were also significant interactions between feeding,

birth weight group, and gender; among male infants

with birth weights

⬍

1250 g, those fed PDF weighed

more at 12 months’ CA than those fed TF. From

study day 1 to term, there was a significant feeding

by gender interaction; among male infants, those fed

PDF gained more weight than those fed TF. The

repeated measures analysis similarly demonstrated a

significant interaction between feeding and birth

weight group (

P

⫽

.02); among infants with birth

weights

⬍

1250 g, those fed PDF weighed

signifi-cantly more (

P

⬍

.001). The growth modeling

anal-ysis showed a significant overall feeding effect, with

PDF-fed infants weighing significantly more than

TF-fed infants (

P

⫽

.044).

Infants fed PDF were significantly longer than

those fed TF at 3 months’ CA. At 6 months’ CA, there

was a significant interaction between feeding and

birth weight group; among infants with birth

weights

⬍1250 g, those fed PDF were longer than

those fed TF. The repeated measures analysis

simi-larly demonstrated an overall greater length for

PDF-fed infants (

P

⫽

.004), and the growth modeling

analysis showed a significant overall feeding effect,

with PDF-fed infants having greater lengths than

TF-fed infants (

P

⫽

.008).

For head circumference, there were significant

in-teractions between feeding and birth weight group at

term, 1, 3, 6, and 12 months’ CA; among infants with

TABLE 4. Gains in Weight (g/d), Length (mm/d), and Head Circumference (mm/d) from Study Day 1 to 12 Months’ CA*

PDF TF PDF Versus TF†

PValues Main

Effects

Interaction Effects Study day 1 to term

Weight 34.1⫾2.4 (45) 28.9⫾2.4 (40) — .041

Length 1.24⫾0.23 (38) 1.08⫾0.20 (34) .25 —

Head circumference 1.06⫾0.06 (43) 0.88⫾0.06 (38) .042 Study day 1 to 1 mo

Weight 34.1⫾1.3 (44) 30.8⫾1.3 (38) .02 —

Length 1.37⫾0.11 (37) 1.45⫾0.09 (33) .24 —

Head circumference 0.93⫾0.04 (41) 0.85⫾0.04 (36) — .022 Study day 1 to 2 mo

Weight 33.2⫾1.2 (36) 30.2⫾1.2 (34) .03 —

Length 1.34⫾0.07 (31) 1.33⫾0.06 (30) .44 —

Head circumference 0.81⫾0.03 (34) 0.76⫾0.03 (33) .08 — Study day 1 to 3 mo

Weight 31.2⫾1.1 (37) 29.5⫾1.0 (34) .10 —

Length 1.28⫾0.05 (31) 1.19⫾0.04 (30) .06 —

Head circumference 0.72⫾0.02 (34) 0.68⫾0.02 (32) .08 — Study day 1 to 6 mo

Weight 26.3⫾0.9 (33) 25.1⫾1.0 (28) .14 —

Length 1.01⫾0.04 (29) 0.98⫾0.03 (25) — .053

Head circumference 0.56⫾0.02 (31) 0.53⫾0.02 (27) .07 — Study day 1 to 9 mo

Weight 22.5⫾0.8 (33) 21.4⫾0.8 (27) .15 —

Length 0.89⫾0.03 (29) 0.84⫾0.02 (23) — ⬍.013

Head circumference 0.45⫾0.01 (32) 0.42⫾0.01 (25) ⬍.01 — Study day 1 to 12 mo

Weight 18.6⫾0.8 (21) 17.4⫾0.8 (23) — .014

Length 0.75⫾0.03 (18) 0.73⫾0.03 (20) .20 —

Head circumference 0.36⫾0.01 (21) 0.33⫾0.01 (22) — .034 * Data are reported as least square means⫾standard error of mean adjusted for site, gender, and birth weight group and analyzed by analysis of variance controlling for site, feeding group, gender, and birth weight group.

†Pvalues are 1-sided for main effects and 2-sided for interactions.Pvalues with superscripts are for interactions as indicated: 1_{Feeding by gender interaction: among male infants; PDF⬎TF,P⫽.01.}

2_{Feeding by birth weight group interaction: among infants with birth weight}ⱕ_{1250 g; PDF}⬎_TF,P⬍_.02. 3_{Feeding by gender by birth weight group interaction: no significant feeding effects within subgroups.}

birth weights

⬍

1250 g, those fed PDF had larger

circumferences than those fed TF (Fig 1). There were

also interactions between feeding and birth weight

group for head circumference gains (mm/d); among

infants with birth weights

⬍

1250 g, gains in head

circumference from study day 1 to term and to 1

month CA were greater for PDF-fed infants than for

TF-fed infants. From study day 1 to 12 months’ CA,

there was a significant feeding by gender by birth

weight group interaction; among male infants with

birth weight

⬍

1250, those fed PDF had greater gains

in head circumference than those fed TF. The

re-peated measures analysis demonstrated greater head

circumference growth among PDF-fed infants with

birth weights

⬍

1250 g (

P

⫽

.015), and the growth

modeling analysis demonstrated a significant

feed-ing by birth weight interaction (

P

⫽

.003), with

PDF-fed infants with birth weights

⬍

1250 g having

greater head circumferences than those fed TF (

P

⫽

.004).

After hospital discharge, energy intakes from

for-mula were not different among infants fed PDF

ver-sus TF (Table 5). However, the volume of formula

intake was lower (

P

⬍

.05) at 1 month CA and

protein intake from formula was higher (

P

⬍

.05) at

term, 2, and 3 months’ CA for the PDF-fed infants.

Serum levels of albumin and blood levels of

he-moglobin did not differ between diet groups (Table

6). Serum levels of prealbumin and retinol-binding

protein were higher in infants fed PDF; these

differ-ences were statistically significant at term and 9

months’ CA for prealbumin and at term for

retinol-binding protein. Serum urea nitrogen levels were

consistently significantly higher (

P

ⱕ

.01) for

PDF-fed infants.

Both formulas were well-tolerated. Stools of

PDF-fed infants were darker than those of TF-PDF-fed infants

at several time points.

DISCUSSION

During hospitalization, preterm infants,

particu-larly those born with very low birth weights, are fed

fortified human milk or preterm infant formulas to

try to achieve weight gain and bone mineralization

that approximate that of the reference fetus.

_These

infants often are fed unfortified breast milk or term

formulas after hospital discharge. This practice is

associated with poor somatic growth, developmental

delays, poor bone mineralization,

_and

insuffi-cient nutrient stores.

_{Strategies that are often}

used to fortify feedings for formula-fed infants after

hospital discharge may be inappropriate.

Fortifica-tion with energy alone, for example, may not be

sufficient because postdischarge preterm infants may

need additional intakes of specific nutrients and

higher nutrient to energy ratios to achieve optimal

growth and bone mineralization. Concentrating term

formulas to levels that would provide adequate

lev-els of protein and calcium may result in an

unaccept-able increase in osmolality or in the concentrations of

other nutrients.

In the present study, preterm infants were fed

either PDF, a nutrient-enriched 22 kcal/fl oz formula

designed for preterm infants after discharge, or TF, a

20 kcal/fl oz standard formula for term infants.

Infants fed PDF had improved growth compared

with those fed TF, with the most significant

benefi-cial effects seen among infants with birth weights

⬍

1250 g. Infants fed PDF also had greater gains in

weight and head circumference compared with those

fed TF, especially within the first 1 to 2 months after

discharge. The early differences in gains suggest a

particularly important effect of nutrient-enriched

feedings during the early postdischarge period.

Al-though a limitation of the present study is the

sig-nificant loss to follow-up among infants who exited

the study early, the improvements in growth were

found using 3 separate statistical approaches. Other

investigators have reported enhanced growth in

pre-term infants fed nutrient-enriched formula after

hos-pital discharge,

_{or after a weight of 1850 g}

was achieved.

_{Chan et al,}

_{however, reported no}

advantage to feeding nutrient-enriched formula to 8

weeks of age.

In agreement with other investigators, infants fed

the less calorically dense TF had higher volumes of

formula intake than those fed PDF.

_{This led to}

consumption of similar energy intakes despite a 10%

difference in caloric density. These data suggest

some ability of the infants to compensate for

differ-ences in energy density. Serum levels of prealbumin,

which are reported to correlate with weight and

length in VLBW infants,

_{were significantly higher}

among infants fed PDF at term and 9 months’ CA.

Serum urea nitrogen levels were higher among

fed infants at each time point, but mean values were

within reference ranges.

Poor somatic growth during the first year is

asso-ciated with delays in neurodevelopment of preterm

infants.

_{Small head circumference}

measure-ments, in particular, may have long-term prognostic

significance for later neurodevelopment in infants

born prematurely. Hack et al

_{reported that}

subnor-mal head size at 8 months of age predicted the 20

month Mental Development Index Score (Bayley’s

Scales of Infant Development) in VLBW infants,

while Gross et al

_{reported that head circumference}

at birth and postnatal head circumference, when

taken together, were strong predictors of early

de-velopmental outcome in VLBW infants. Hack and

colleagues

_{have suggested that the first year of life}

provides an important opportunity for human

so-matic and brain growth to compensate for earlier

deprivation. An effect of nutrition during this

vul-nerable period of brain development on long-term

developmental outcomes is suggested by studies in

which the feeding of nutrient-enriched formulas to

preterm infants during hospitalization was

associ-ated with improved neurodevelopmental outcomes

at 9 months,

_{18 months,}

_{and 7.5 to 8 years old.}

In the present study, the most significant effect seen

with feeding PDF versus TF was larger head

circum-ference measurements among infants born with birth

weights

⬍1250 g.

Provision of additional nutrients after hospital

dis-charge may be particularly beneficial for infants with

conditions that contribute to a relative increase in

morbidity, including the presence of chronic disease,

in utero growth retardation, or extremely low birth

weight. A particular growth benefit of

nutrient-en-riched formulas is indicated by the present study for

infants with birth weights

⬍1250 g. In addition, an

effect of gender on postdischarge responsiveness to

nutrient supplementation of preterm infants is

sug-gested by our data and those of Cooke et al,

_in

which the feeding of nutrient-enriched formulas

af-ter hospital discharge was of particular benefit for

male infants.

It is increasingly recognized that formulas

de-signed to meet the nutritional needs of term infants

are unlikely to provide the most appropriate

post-discharge nutrition for preterm infants. The results of

the present study demonstrated that the feeding of a

nutrient-enriched formula to preterm infants after

hospital discharge resulted in improved growth and

TABLE 5. Protein, Energy, and Volume Intakes From Formula From Term to Nine Months’ CA for Preterm Infants Fed PDF or TF From Hospital Discharge to 12 Months’ CA*

Term 1 Month 2 Months 3 Months 6 Months 9 Months

Volume intake, mL/kg/d

PDF 190⫾10 173⫾9a _{160⫾8 155⫾10 132⫾12 103⫾8}

TF 213⫾9 212⫾8b ₁₇₄⫾_{8 177}⫾_{9 147}⫾_{13 124}⫾₈

Protein intake, g/kg/d

PDF 3.7⫾0.2c _3.4⫾_{0.1 3.1}⫾_0.1c _3.0⫾_0.2e _2.6⫾_{0.2 2.0}⫾_0.1 TF 3.1⫾0.2d _{3.1⫾0.1 2.5⫾0.1}d _2.6⫾0.1f _{2.2⫾0.2 1.8⫾0.2} Energy intake, Kcal/kg/d

PDF 142⫾7 129⫾6 119⫾6 116⫾7 99⫾9 77⫾6

TF 144⫾7 144⫾6 118⫾6 120⫾6 100⫾9 84⫾6

* Data are expressed as least squares means⫾standard error of mean controlling for site, gender, and birth weight group (⬍1250 g,ⱖ1250 g). Different letter superscripts for comparisons of PDF versus TF indicate statistically significant differences.

ab_P⬍_.001 cd_P⬍.01 ef_P⬍_.05

TABLE 6. Serum Levels of Albumin (g/dL), Prealbumin (mg/dL), Retinol-Binding Protein (mg/dL) and Urea Nitrogen (mg/dL), and Blood Hemoglobin (g/dL) at term, Three, and Nine Months’ CA in Infants Fed PDF or TF After Hospital Discharge*

PDF TF PDF Versus TF

Term

Albumin 3.9⫾0.1 (27) 3.9⫾0.1 (25) NS

Pre-albumin 15.0⫾0.7 (27) 11.2⫾0.6 (25) ⬍0.01

Retinol-binding protein 3.3⫾0.3 (25) 2.5⫾0.3 (23) 0.05 Serum urea nitrogen 10.2⫾0.8 (15) 4.9⫾0.7 (15) ⬍0.01

Hemoglobin 10.2⫾0.3 (39) 10.6⫾0.3 (37) NS

3 months

Albumin 4.4⫾0.1 (14) 4.3⫾0.1 (20) NS

Pre-albumin 18.3⫾1.4 (13) 17.7⫾1.2 (18) NS

Retinol-binding protein 4.5⫾0.4 (13) 3.4⫾0.4 (17) NS Serum urea nitrogen 11.5⫾0.7 (8) 8.9⫾0.5 (15) 0.01

Hemoglobin 12.0⫾0.3 (25) 11.6⫾0.3 (25) NS

9 months

Albumin 4.6⫾0.1 (13) 4.4⫾0.1 (16) NS

Prealbumin 24.0⫾1.3 (12) 18.9⫾1.4 (13) 0.02

Retinol-binding protein 5.0⫾0.3 (12) 4.5⫾0.4 (13) NS Serum urea nitrogen 13.4⫾1.2 (7) 8.5⫾1.2 (9) 0.01

Hemoglobin 12.2⫾0.2 (25) 12.4⫾0.2 (19) NS

growth gains to 12 months’ CA compared with

feed-ing infants a formula designed for term infants. The

beneficial effects were most evident for infants with

birth weights

⬍

1250 g.

ACKNOWLEDGMENTS

This study was supported in part by Ross Products Division, Abbott Laboratories, Columbus, Ohio, and by NIH General Clin-ical Research Center Grant RR00059.

The assistance of Robin Carroll, MS, RD, LD; Michelle Atwood, BSN; Mary Reilly, RN; and the General Clinical Research Center nurses, Karen J. Johnson and Gretchen A. Cress, is gratefully acknowledged.

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DOI: 10.1542/peds.107.4.683

2001;107;683

Pediatrics

Jacobs, Geraldine Baggs, Nancy Auestad and Beate Lloyd

Jane D. Carver, Paul Y. K. Wu, Robert T. Hall, Ekhard E. Ziegler, Roberto Sosa, Joan

Hospital Discharge

Growth of Preterm Infants Fed Nutrient-Enriched or Term Formula After

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