CRITICAL APRAISER ADOLFINA VITRIA

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 21 feeding, we compared outcomes of infants fed >50 mL z kg 21 z day 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 21 21 kg z day 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 21 21 kg z day ), length increment (0.8 6 0.3 vs 1.0 6 0.3 cm z 21 week ), and increment in the sum of five skinfold 21 measurements (0.86 6 0.40 vs 1.23 6 0.42 mm z week ) 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 feeding tolerance between groups. Milk intakes of in-fants fed FHM were significantly greater than those fed PF (180 6 21 21 13 vs 157 6 10 mL z kg z day ). 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;103:11501157; 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.

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.

statement on the recommendations for breast-feeding full-term infants acknowledges the benefits of human 1 milk in the management of pre-mature infants. The beneficial effects generally re-late to improvements in host defense, digestion and absorption of nutrients, neurodevelopment, gastro-intestinal (GI) function, as 2 well as psychological ef-fects on the mother. Human milk, especially, is suit-able for meeting many needs of premature infants, providing2that their nutritional status is monitored carefully. 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 hos312 pitalization. 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 1315 premature infants. There is a concern, however, that nutrient supplementation of human milk might affect the intrinsic host 16,17 defense properties of the milk. A recent ran-domized comparison of premature infants fed forti-

he American Academy of Pediatrics' recent

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fied human milk (FHM) versus those fed partially supplemented human milk indicated that the com-bined incidence of infection and necrotizing entero-colitis 18 (NEC) was greater in the infants fed FHM. 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 19 milk intake) given to both study groups. As part of a prospective study of feeding strategies in premature infants (time of initiation of feeding, tubefeeding method, and type of milk), it was ob-served that the feeding of human milk had more effect on the 20 outcomes measured than any other strategy studied. 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 twoway design to early (GI priming from day 4 to day 14) versus late initiation of feeding (total parenteral nutrition [TPN] only) and 20 continuous infusion versus intermittent bolus tube-feeding method. 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 21 have been published. 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 22 resolution of acute medical conditions. 21 Beginning day 15, milk intake was increased daily by 20 mL z kg z 21 day . Human milk fortifier was added to human milk when the intake 21 21 reached 100 mL z kg z day 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 21 21 ensure a body weight gain of at least 15 g z kg z day . 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 21 21 above the mean intake (50 mL z kg z day ) 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 23 storage have been published. 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-

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 human milk and 46 of whom were fed PF exclusively. The excluded 63 21 21 infants were fed a mixture of FHM (,50 mL z kg z day ) 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 24 previously published. Knee-heel length was measured every 2 weeks 25 by using a knemometer. The rate of growth was computed by linear regression of serial measurements for each subject from the time of 1 minimum weight to discharge. Bone mineral content of the distal 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 characteristics: 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 20,24 reported previously. 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 21 21 .50 mL z kg z day of any human milk averaged throughout hospitalization were evaluated from birth to hospital discharge. ANOVA and repeated measures ANOVA were used to determine differences 2 between groups for continuous variables. x 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.

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RESULTS Study Subjects and Parents

TABLE 2.

Growth Outcomes Fortified Human Milk Preterm Formula 12 6 4 36 6 17 60 6 20 51 6 12 26 6 6 1.00 6 0.26 0.93 6 0.18 3.1 6 0.8 1.23 6 0.42 2998 6 1245

The characteristics of the 108 infants are shown in Table 1. Because of differences between groups in antenatal steroid exposure, this variable was used as a covariate in subsequent analyses of outcomes. The proportion of infants with an Apgar score .6 at 5 minutes was 85% and 87%, in FHM and PF, respec-tively. Thirteen percent of mothers who provided milk to their infants had no intent to breastfeed had they delivered a term infant. The FHM group moth-ers had completed more years of school than mothers of group PF. The FHM group also had more skin-to-skin contact with their mothers, 9 6 10 (median 5 6) sessions versus 0.5 6 1.0 (median 5 0) sessions in group PF, P , .001. Parents of infants in group FHM 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. However, maternal educational level, the number of sessions of skin-to-skin contact, parent holding, and parent visiting were not significantly correlated with the duration of hospitalization. Nevertheless, despite a body weight difference of 500 g, the FHM group was discharged from the hospital approximately 2 weeks earlier than the PF group (Tables 1 and 2).
Growth Outcomes

Regain birth weight (days) Complete tube-feeding (days) Full oral feeding (days) Age at 2 kg (days) 21 21 Weight gain (g z kg z day 2) 1 Length increment (cm z week ) Frontooccipital circumference 21 increment (cm z week ) Knee-heel length increment 21 (mm z week ) Sum of skinfolds at 5 sites 21 (mm z week ) Discharge weight (g)

12 6 6* 28 6 7 62 6 18 59 6 13 22 6 7 0.79 6 0.27 0.88 6 0.26 2.6 6 0.8 0.86 6 0.40 2428 6 389

* Values are mean 6 SD. , Differences between groups: P # .001, P # .01.

increments also were significantly less in FHM than PF groups (Fig 1). There was no significant difference between groups in the absolute or increment in ra-dius 21 bone mineral content (median, 1.2 vs 1.9 mg z cm z 21 week , in FHM vs PF, P 5 .3).
Clinical Outcomes

The attainment of complete tube-feeding was ear-lier in group FHM than PF (see Table 2). This achievement was related to a shorter duration of TPN usage (25 6 8 vs 37 6 35 days, P 5 .01) because of better feeding tolerance in FHM versus PF, respec-tively. As feeding volumes were advanced from day 15 to complete tube-feeding, FHM had significantly fewer gastric residuals and less hours when feedings were withheld than PF (see below). There were no differences between groups in the achievement of full oral feeding. The rate of growth (weight gain and linear growth) was significantly lower in the FHM than PF group (Table 2). Increments in the sum of skinfold thicknesses at five sites differed significantly between FHM and PF groups. Individual skinfold

TABLE 1.

Characteristics of Study Infants Fortified Human Milk (n 5 62) Preterm Formula (n 5 46) 1044 6 185 27.9 6 1.1 59 33, 26, 39, 2 12.9 6 1.5 19 (46) 22 (48) 25 (54) 88 6 47

There was 1 death in the FHM group and 3 deaths in the PF group. Although there were differences in the duration of oxygen therapy, there were no dif-ferences between groups in the use of artificial sur-factant, duration of mechanical ventilation, or inci-dence of bronchopulmonary dysplasia, patent ductus arteriosus, and intraventricular hemorrhage (Table 3). The FHM group had a significantly lower incidence of NEC and late-onset sepsis than the PF group. There was an inverse relationship between the number of positive blood cultures and the intake of human milk throughout hospitalization (r 5 20.26, P 5 .007) (Fig 2). The relationship between the number of positive blood cultures and the intake of PF throughout hospitalization, however, was not sta-tistically significant (r 5 20.02, P 5 .80). There were no differences between groups in the age at diagno-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 birth 26 weight neonates. Approximately 52% of iso-

Birth weight (g) Gestational age (wk) Sex (% males) Ethnicity (% Hispanic, black, white, Asian) Maternal education (y) Antenatal steroid exposure, n (%) Randomization to GI priming, n (%) Randomization to bolus tube-feeding, n (%) Duration of study (days of hospitalization)

1069 6 169* 27.9 6 1.2 53 18, 24, 58, 0 15.0 6 2.5 43 (69) 38 (61) 29 (47) 73 6 19

Abbreviation: GI, gastrointestinal. * Values are mean 6 SD. , Differences between groups: P 5 .03, P 5 .004.

Fig 1. Rate of increase in skinfold thickness during hospitaliza-tion. Significant differences between groups at all sites, P , .01. Values are mean 6 SEM.

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TABLE 3.

Clinical Outcomes Fortified Human Milk Preterm Formula 33 6 41 6 (13) 3 22 (48) 0.6 6 0.7 1.2 6 1.7 25 (54)

.007. The FHM group had significantly more stools than the PF group; the median number throughout hospitalization was 164 versus 127, respectively, P 5 .02.

Oxygen therapy (days) NEC, n (%) NEC surgery (n) Late-onset sepsis, n (%) Late-onset sepsis (no. of episodes per infant)\ Positive blood cultures (no. per infant) NEC or late-onset sepsis, n (%)

19 6 21* 1 (1.6) 0 19 (31) 0.3 6 0.5 0.5 6 0.9 19 (31)

Indices of Nutritional Status

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 coagulasenegative, 24% Staphylococcus aureus, 6% Escherichia coli, 4% Enterococcus, 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 21 interval, there were fewer GRVs .2 mL z kg (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, P5

There were no differences between groups in the mean or the number of abnormal values for serum Ca, P, Mg, alkaline phosphatase activity, albumin, 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.

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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TABLE 4.

Milk and Nutrient Intakes Fortified Human Milk Preterm Formula

Component 21 21 (unit z kg z day ) Overall intakes throughout hospitalization Total fluid intake (mL) Total human milk intake (mL) Total formula intake (mL) Intakes during and between balance studies (enteral feeding period) Milk (mL) Energy (kcal) Nitrogen (mg) Fat (g) Calcium (mg) Phosphorus (mg) Magnesium (mg) Zinc (mg) Copper (mg)

PF group, 32 6 15 versus 40 6 14 hours, respectively, P 5 .01.

DISCUSSION

158 6 7* 96 6 23 20 6 25

147 6 14 0 92 6 33

180 6 13 134 6 23 662 6 297 6.0 6 1.8 196 6 22 118 6 13 7.9 6 1.1 1.9 6 0.4 247 6 47

157 6 10 129 6 11 553 6 44 6.0 6 0.5 192 6 15 120 6 9 9.1 6 0.7 2.1 6 0.2 218 6 40

* Values are mean 6 SD. Changes in intakes from 6 to 9 weeks were not significant. , Differences between groups: P # .001, P # .01. Conversion factors: 1 kJ 5 4.184 kcal, 1 mmol N 5 14 mg, 1 mmol Ca 5 40 mg, 1 mmol P 5 31 mg, 1 mmol Mg 5 24 mg, 1 mmol Zn 5 65 mg, 1 mmol Cu 5 64 mg.

Nutrient Absorption and Retention

Despite increases with maturity, fat and energy absorption were significantly less in the FHM than the PF group at both times of measurement (Fig 3). The percent fat absorption correlated positively with the rate of weight gain, r 5 0.595, P , .001. The percent absorption of P, Zn, and Cu differed between groups; Ca and Mg absorption increased over time (Fig 4). There was significantly greater net retention (balance) of nitrogen, P, and Cu in the FHM than the PF group at both 6 and 9 weeks, P , 0.01. Nitrogen balance declined similarly from 6 to 9 weeks, in both the FHM and the PF group, P , .001. To compare postnatal retention (balance) with intrauterine accre-tion for each nutrient, we used the percent attainment of intrauterine accretion (Fig 5). The retention of most nutrients surpassed the intrauterine accre-tion rate; only Ca retention in infants fed PF was below the intrauterine estimates. The carmine red intestinal transit time, averaged for both 6- and 9-week studies, differed between the FHM and the

The use of multinutrient fortifiers for human milk-fed premature infants has increased in neonatal cen-ters. Mineral supplementation of unfortified human milk throughout hospitalization may improve linear growth and bone mineralization during and beyond the neonatal 14,2729 period. Supplementation with both Ca and P also results in a normalization of biochemical indices of mineral status: serum Ca, P, and alkaline phosphatase 11,30 activity; urinary excretion of Ca and P. Sodium supplementation has been demonstrated to normalize 31,32 serum sodium. Pro-tein and energy supplementation have been shown to improve rates of weight gain and indices of pro-tein nutritional status, ie, blood urea 8,33,34 nitrogen and serum albumin. However, despite the advantages to nutritional status, there is a concern that the addition of a large quantity of supplements may affect the intrinsic host defense properties as well as the GI tolerance of human 1618,35 milk. For ethical reasons relating to standard of care and our experience with human milk fortification, we could not conduct a compari-son of FHM with unfortified human milk. We chose instead to compare FHM with the default feeding in our nursery, PF. This comparison with PF demon-strated that the fortification of human milk promoted adequate nutritional status without compromising host defense or feeding tolerance. Indeed, predomi-nant FHM feeding was associated with significantly lower morbidity from NEC and late-onset sepsis and better feeding tolerance compared with exclusive feeding of PF. We caution against the overinterpre-tation of these results. Although the definition of the human milk group (average, .50 mL z 21 21 kg z day throughout hospitalization) was determined before the analyses, this group also received PF. However, the FHM group was unique in that the infants re-ceived a significantly greater quantity of human milk than infants in other studies of fortified human milk. Nevertheless, the ideal model to study these relation-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.

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.

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 9,3638 effects of human milk in premature in-fants. The mechanism underlying the protective effects is unknown. Some reports suggest that the protective effects are related 39 to the high immuno-globulin A content of human milk. The numerous bioactive substances in human milk also may play a role in the local protective effects of human 40,41 milk. The protection afforded by FHM also may be ex-plained, at least partially, by the more frequent sessions 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 42 pathway for host defense of the infant. Frequent skin-toskin 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-

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 43 support the enhanced bonding effect of parental contact. There is no way to assess whether these parenting opportunities 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.
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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 21 composi-tion of FHM and PF. However, the greater quantity of medium-chain fatty acids in PF has not been 44 as-sociated with better fat absorption. The relationship between fat absorption and mineral supplementation also 24,45 has been studied. 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 46 significantly greater than those reported here. 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 biochemical 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 47 of premature infants. 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 47 group FHM.
CONCLUSION

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 6250-6001. 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.

REFERENCES
T American Academy of Pediatrics, Work Group on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 1997;100:10351039 T Schanler RJ. Suitability of human milk for the low birthweight infant. Clin Perinatol. 1995;22:207222 T Atkinson SA, Radde IC, Anderson GH. Macromineral balances in pre-mature infants fed their own mothers' milk or formula. J Pediatr. 1983; 102:99106 T Brooke OG, Onubogu O, Heath R, Carter ND. Human milk and preterm formula compared for effects on growth and metabolism. Arch Dis Child. 1987;62:917923 T Cooper PA, Rothberg AD, Pettifor JM, Bolton KD, Devenhuis S. Growth and biochemical response of premature infants fed pooled preterm milk or special formula. J Pediatr Gastroenterol Nutr. 1984;3:749754 T Atkinson SA, Bryan MH, Anderson GH. Human milk feeding in pre-mature infants: protein, fat and carbohydrate balances in the first two weeks of life. J Pediatr. 1981;99:6l7624 T Davies DP. Adequacy of expressed breast milk for early growth of preterm infants. Arch Dis Child. 1977;52:296301 T Kashyap S, Schulze KF, Forsyth M, Dell RB, Ramakrishnan R, Heird WC. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and unsupplemented preterm human milk. Am J Clin Nutr. 1990;52:254262 T Contreras-Lemus J, Flores-Huerta S, Cisneros-Silva I, et al. Decreased morbidity in preterm neonates fed their own mothers' milk. Biol Med Hosp Infant Mex. 1992;49:671677 T Stein H, Cohen D, Herman AAB. Pooled pasteurized breast milk and untreated own mother's milk in the feeding of very low birth weight babies: a randomized controlled trial. J Pediatr Gastroenterol Nutr. 1986; 5:242247 T Rowe JC, Wood DH, Rowe DW, Raisz LG. Nutritional hypophos-phatemic rickets in a premature infant fed breast milk. N Engl J Med. 1979;300:293296 Lucas A, Brooke OG, Baker BA, Bishop N, Morley R. High alkaline phosphatase activity and growth in preterm neonates. Arch Dis Child. 1989;64:902909 Ziegler EE, O'Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth. 1976;40:329341 Greer FR, McCormick A. Improved bone mineralization and growth in premature infants fed fortified own mother's milk. J Pediatr. 1988;112: 961969 Ronnholm KAR, Perheentupa J, Siimes MA. Supplementation with human milk protein improves growth of small premature infants fed human milk. Pediatrics. 1986;77:649653 Jocson MAL, Mason EO, Schanler RJ. The effects of nutrient fortification and varying storage conditions on host defense properties of human milk. Pediatrics. 1997;100:240243 Quan R, Yang C, Rubinstein S, Lewiston NJ, Stevenson DK, Kerner JA. The effect of nutritional additives on anti-infective factors in human milk. Clin Pediatr. 1994;33:325328

T T

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
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1. Lucas A, Fewtrell MS, Morley R, et al. Randomized outcome trial of human milk fortification and developmental outcome in preterm in-fants. Am J Clin Nutr. 1996;64:142151 2. Schanler RJ. Human milk fortification for premature infants. Am J Clin Nutr. 1996;64:249250 3. Schanler RJ, Shulman RJ, Lau C, Smith EO, Heitkemper MM. Feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method. Pediatrics. 1999;103:434439 4. Schanler RJ. The low birth weight infant: perinatal nutrition. In: Walker WA, Watkins JB. eds. Nutrition in Pediatrics: Basic Science and Clinical Applications. Hamilton, Ontario, Canada: BC Decker Inc; 1996:387407 5. American Academy of Pediatrics, Committee on Fetus and Newborn. Hospital discharge of the high-risk neonate: proposed guidelines. Pedi-atrics. 1998;102:411417 6. Hurst NM, Myatt A, Schanler RJ. Growth and development of a hos-pitalbased lactation program and mother's own milk bank. J Obstet Gynecol Neonatal Nurs. 1998;27:503510 7. Schanler RJ, Abrams SA. Postnatal attainment of intrauterine mac-romineral accretion rates in low birth weight infants fed fortified human milk. J Pediatr. 1995;126:441447 8. Michaelsen KF, Skov L, Badsberg JH, Jorgensen M. Short-term measure-ment of linear growth in preterm infants: validation of a hand-held knemometer. Pediatr Res. 1991;30:464468 9. Stoll BJ, Gordon T, Korones SB, et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr. 1996; 129:6371 10. Wauben IP, Atkinson SA, Grad TL, Shah JK, Paes B. Moderate nutrient supplementation of mother's milk for preterm infants supports ade-quate bone mass and short-term growth: a randomized, controlled trial. Am J Clin Nutr. 1998;67:465472 11. Abrams SA, Schanler RJ, Garza C. Bone mineralization in former very low birth weight infants fed either human milk or commercial formula. J Pediatr. 1988;112:956962 12. Abrams SA, Schanler RJ, Tsang RC, Garza C. Bone mineralization in former very low birth weight infants fed either human milk or com-mercial formula: one year follow-up observation. J Pediatr. 1989;114: 10411044 13. Schanler RJ, Garza C. Improved mineral balance in very low birth weight infants fed fortified human milk. J Pediatr. 1987;112:452456 14. Kumar SP, Sacks LM. Hyponatremia in very low-birth-weight infants and human milk feedings. J Pediatr. 1978;93:10261027

5. Roy RN, Chance GW, Radde IC, Hill DE, Willis DM, Sheepers J. Late hyponatremia in very low birthweight infants. Pediatr Res. 1976;52653l 6. Polberger SKT, Axelsson IA, Raiha NCR. Growth of very low birth weight infants on varying amounts of human milk protein. Pediatr Res. 1989;25:414419 7. Schanler RJ, Burns PA, Abrams SA, Garza C. Bone mineralization outcomes in human milk-fed preterm infants. Pediatr Res. 1992;31: 583586 8. Metcalf R, Dilena B, Gibson R, Marshall P, Simmer K. How appropriate are commercially available human milk fortifiers? J Paediatr Child Health. 1994;30:350355 9. Lucas A, Cole TJ. Breast milk and neonatal necrotizing enterocolitis. Lancet. 1990;336:15191523 10. El-Mohandes AE, Picard MB, Simmens SJ, Keiser JF. Use of human milk in the intensive care nursery decreases the incidence of nosocomial sepsis. J Perinatol. 1998;17:130134 11. Hylander MA, Strobino DM, Dhanireddy R. Human milk feedings and infection among very low birth weight infants. Pediatrics. 1998;102(3). URL: http://www.pediatrics.org/cgi/content/full/102/3/e38 12. Eibl MM, Wolf HM, Furnkranz H, Rosenkranz A. Prevention of necro-tizing enterocolitis in low-birth-weight infants by IgA-IgG feeding. N Engl J Med. 1988;319:17 13. Goldman AS. Immunologic system in human milk. J Pediatr Gastroen-terol Nutr. 1986;5:343345 14. Goldman AS, Frawley S. Bioactive components of milk. J Mammary Gland Biol Neoplasia. 1996;1:241242 15. Kleinman RE, Walker WA. The enteromammary immune system. Dig Dis Sci. 1979;24:876882 16. Tessier R, Cristo M, Velez S, et al. Kangaroo mother care and the bonding hypothesis. Pediatrics. 1998;102(2). URL: http://www. pediatrics.org/cgi/content/full/102/2/e17 17. Whyte RK, Campbell D, Stanhope R, Bayley HS, Sinclair JC. Energy balance in low birth weight infants fed formula of high or low medium-chain triglyceride content. J Pediatr. 1986;108:964971 18. Chappell JE, Clandinin MT, Kearney-Volpe C, Reichman B, Sawyer PW. Fatty acid balance studies in premature infants fed human milk or formula: effect of calcium supplementation. J Pediatr. 1986;108:439447 19. Boehm G, Muller DM, Senger H, Borte M, Moro G. Nitrogen and fat balances in very low birth weight infants fed human milk fortified with human milk or bovine milk protein. Eur J Pediatr. 1993;152:236239 20. Kildeberg P, Engel K, Winters RW. Balance of net acid in growing infants. Acta Paediatr Scand. 1969;58:321329

ARE WE A CANCER ON THE WORLD?

Aerial and satellite views of urban centers [bear] a striking similarity to images of cancerous tissue (particularly melanoma) invading the healthy surrounding tissue.

Browne MW. Will humans overwhelm the earth? New York Times. December 8, 1998

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CRITICAL APPRAISER
Apr. 20

BALITA SEHAT
DR. ADOLFINA VITRIA

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 P: What is the problem/patients?

On premature infants, 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. There is a concern, however, that nutrient supple-mentation of human milk might affect the intrinsic host defense properties of the milk. But there it was observed that the feeding of human milk had more effect on the outcomes measured than any other strategy studied. Fortified human milk (FHM) and preterm formula (PF)

I: Whats is the intervention?

C: What is the comparison This study compare the growth, feeding tolerance, health outcomes, biochemical indices of nutritional status, and nutrient absorption and retention of premature infants fed predomi-nately FHM versus PF O: What is the outcame? 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.
1a. R- Was the assignment of patients to treatments randomised? This paper: Yes 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 1b. R- Were the groups similar at the start of the trial? This paper: yes In this study infants enrolled within 96 hours of birth were participants. 171 premature infants from nurseries of Texan Childrens hopital meet the inklusion criteria. Among the total enrollmet, 108 infants were subject. 62 of whom were fed predominantly human milk and 46 of whom were fed PF exclusively. And the exluded 63 infants ere fed mixuter of FHM and PF. 2a. A Aside from the allocated treatment, were groups treated equally?

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This paper: Yes 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. Beginning day 15, milk intake was increased daily by 20 mL z kg z day. Human milk fortifier was added to human milk when the intake reached 100 mL z kg z day 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 kg z day. 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 kg z day) of all infants fed human milk. Mothers brought their milk to the Texas Children's Hospital Milk Bank each day. 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. Maternal educational level, the number of sessions of skin-to-skin contact, parent holding, and parent visiting were not significantly correlated with the duration of hospitalization 2b. A Were all patients who entered the trial accounted for? and were they analysed in the groups to which they were randomised? This paper: yes Comment: no drop out. 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 3. M - Were measures objective or were the patients and clinicians kept blind to which treatment was being received? This paper: ragu-ragu Comment: not mentioned in the journal that the measured was done blinded, but mentioned that all the measurement done by mechine/computerized What were the results?

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.
Will the results help me in caring for my patient? (ExternalValidity/Applicability) Not directly, because my Puskesmas do not care for premature infants, but it can help me to understand what may be do in hospital when i referred premature infants, then i can explain to the mother correctly. And this study make me more sure that human milk still best for infants

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