James W. Hansen

Growth, Efficacy, and Safety of Feeding an Iron-Fortified Human Milk Fortifier

Objective. Survival rates for preterm infants who weigh between 501 and 1500 g at birth have continued to improve over time. In response to this continuing decrease in birth weight of surviving preterm infants, Enfamil Human Milk Fortifier has recently been reformulated to meet the nutritional requirements of these smaller, more rapidly growing infants. It now provides an increased protein level of 1.1 g/58 kJ, a decreased carbohydrate level of 0.2 g/58 kJ, and a combined linoleic and α-linolenic fatty acid content of 157 mg/58 kJ. As these very small preterm infants have an increased requirement for dietary iron, the fortifier has been supplemented with 1.44 mg/58 kJ of iron, an amount of iron similar to that provided in a typical iron-fortified term infant formula. An iron-fortified product obviates the need for administration of an iron supplement, a hyperosmolar-inducing intervention. The purpose of this prospective, double-blind, randomized, controlled study was to evaluate growth, safety, and efficacy in a population of very low birth weight (VLBW) preterm infants who received human milk fortified with either the reformulated iron-fortified powdered human milk fortifier test product (HMF-T) or a powdered commercially available human milk fortifier control product (HMF-C). Methods. Infants who weighed ≤1500 g, had a gestational age ≤33 weeks postmenstrual age, and had an enteral intake of at least 100 mL/kg per day of unfortified human milk were stratified by gender and birth weight and randomized to receive HMF-T or HMF-C product from study day 1 to study day 28, hospital discharge, or the termination of human milk feedings, whichever came first. Unless medically indicated, investigators were not to administer iron supplements from study days 1 to 14. Infants were assessed serially for growth; enteral and parenteral intake; serum chemistry and hematologic values; clinical histories, including the administration of blood transfusions; feeding tolerance; respiratory outcomes; and morbidities, including adverse events. Results. Of the 181 participating infants in this study, 96 received HMF-T and 85 received HMF-C. At randomization, there were no significant differences in infant characteristics between the fortifier groups. The percentage of participants who remained in the study for 28 days was similar between fortifier groups (57% HMF-T, 46% HMF-C). For both fortifier groups, the most frequent reasons for discontinuing the study before study day 28 were unavailability of human milk and hospital discharge. Rate of weight gain was similar between the fortifier groups (17.5 ± 0.53 g/kg per day for HMF-T and 17.3 ± 0.59 g/kg per day for HMF-C). Mean achieved weight, length, and head circumference were comparable between groups across the 28-day study period. Total protein intake from enteral and parenteral nutrition was significantly greater for the HMF-T fortifier group; however, this difference did not result in any difference in growth between the 2 fortifier groups. An analysis of the growth and energy intake data of a subset of the intent-to-treat population who adhered more strictly to the study feeding protocol yielded results similar to those seen for the intent-to-treat population. There were no clinically significant differences in the results of laboratory studies between the groups at study days 0, 14, and 28. Anemia of prematurity was prevalent in both study groups; by study day 28, median hematocrit levels were 27.0% (interquartile range [IQR]: 24.0%–29.6%) for the HMF-T group and 26.0% (IQR: 24.0%–31.0%) for the HMF-C group. Median ferritin levels were 77.0 ng/mL (IQR: 37-155 ng/ml) for HMF-T and 92.0 ng/mL (IQR: 33-110 ng/mL) for HMF-C. There were no significant differences between the study fortifier groups in regard to the receipt of medically indicated iron supplements on or before study day 14 or in the administration of blood transfusions before study day 0 or from study days 0 through 14. However, from study day 15 to study day 28, fewer HMF-T infants (n = 12) required a blood transfusion than did HMF-C infants (n = 20). Although the higher levels of iron in the HMF-T fortifier (1.44 mg vs 0.35 mg for HMF-C per 4 packets of powdered fortifier) did not prevent anemia per se, it did reduce the frequency of one of the most serious outcomes of anemia: the need for a blood transfusion. There was no statistically significant difference between fortifier groups in regard to feeding tolerance. Rates of suspected sepsis (26% HMF-T vs 31% HMF-C) and confirmed sepsis (5% HMF-T, 7% HMF-C) were low as were the rates of suspected necrotizing enterocolitis (NEC; 6% HMF-T and 5% HMF-C) and confirmed Bells stage 2 or more NEC (1% HMF-T and 1% HMF-C). There were no statistically significant differences between the study fortifier groups in regard to the incidence of confirmed and suspected sepsis and NEC. Conclusion. Both human milk fortifiers studied are safe, are well tolerated, and facilitate comparable good growth; however, using the iron-fortified product may reduce the need for blood transfusions in VLBW infants. The similar low rates of suspected and confirmed NEC and sepsis seen in both fortifier groups in this study refutes the premise that the inclusion of iron in fortifiers will increase the incidence of sepsis and NEC. Indeed, the incidence for NEC and sepsis for both groups in this study was lower than is reported for VLBW infants and similar to that seen for infants who are fed human milk.

Growth, biochemical status, and mineral metabolism in very-low-birth-weight infants receiving fortified preterm human milk.

We compared the growth, biochemical status, and mineral status of 30 very-low-birth-weight infants randomly assigned to receive preterm human milk (Group I, 10 infants) from their own mothers, fortified preterm human milk (Group II, 8 infants), or a high-caloric-density premature formula (Group III, 12 infants). Added to the infants own mothers milk, a human milk fortifier at full strength provided additional protein (60:40 whey/casein, 0.7 g/dl), calories (4 kcal/oz), and minerals. Volume of intake, feeding tolerance, and complications were similar in the three groups. Infants receiving fortified preterm human milk showed growth, biochemical status, and mineral status similar to those receiving high-caloric-density formula, but infants receiving fortified preterm human milk grew faster (12.0 +/- 3.2 vs. 8.9 +/- 1.1 days/300 g, p less than 0.05), had higher serum protein (4.6 +/- 0.5 vs. 4.2 +/- 0.2 g/dl, p less than 0.05), and tended to have better mineral status (higher serum calcium, lower alkaline phosphatase, and higher serum phosphorus, none individually significant) than infants receiving preterm human milk alone. This study supports previous observations that fortified preterm human milk provides nutritional advantages for very-low-birth-weight infants.

Can the elimination of lactose from formula improve feeding tolerance in premature infants

Abstract Objective: To determine whether a low-lactose formula (LLF, Study design: Prospective, randomized, controlled trial involving 306 infants Results: One hundred forty-nine infants were assigned to receive LCF, of which 99 infants received LCF only. One hundred fifty infants were assigned to receive LLF, of which 102 infants received LLF only. The remaining infants received LCF or LLF plus some quantity of human milk or human milk alone. Infants receiving LLF had improved enteral caloric intake and weight gain, reached full feeds faster, had less gastric residual, spent less time without oral intake, and had fewer feedings stopped than the LCF group. The number of cases of NEC and suspected NEC was similar in both groups. Conclusion: Low-lactose premature infant formula improved feeding tolerance. There was no evidence that LLF altered the incidence of NEC, but the incidence of NEC in this study was too low to draw conclusions. (J Pediatr 1999;135:587-92)

Calcium and phosphorus requirements in bone mineralization of preterm infants

We studied postnatal bone mineralization, as measured by photon absorptiometry, in 36 preterm infants (birth weight less than 1600 gm) who were fed (1) a commercial premature formula containing 117 mg calcium and 58.8 mg phosphorus per 100 kcal, (2) the same formula containing a higher concentration of phosphorus (82 mg/100 kcal), (3) the same formula with higher concentrations of calcium (140 mg/100 kcal) and phosphorus (82 mg/100 kcal), or (4) their mothers milk. Serum calcium, phosphorus, protein, albumin, bicarbonate, 25-hydroxyvitamin D, and alkaline phosphatase levels were measured at the start of the study and every 2 weeks until the infants achieved a weight of 1900 gm. Birth weights and gestational ages were similar in all four groups. The human milk group had lower serum phosphate and bone mineral values than those in the three formula groups. Bone mineral content was similar in the three formula groups. However, only the formulas of the first and third groups allowed approximation of the intrauterine bone mineralization curve. Bone mineral content in infants fed human milk was below the intrauterine rate.

Effects of increased calcium and phosphorous formulas and human milk on bone mineralization in preterm infants.

Summary: By photon absorptiometry, extrauterine bone mineralization was evaluated in preterm infants (< 1,600 g birth weight) fed either (a) a commercial premature formula containing 117 mg calcium, 58.5 mg phosphorus/100 kcal, (b) the same formula containing higher phosphorus (82 mg/100 kcal), (c) the same formula with higher calcium (140 mg Ca) and phosphorus (82 mg/100 kcal), or (d) their own mothers milk. All infants had serum protein, albumin, calcium, phosphorus, bicarbonate, 25-hydroxy-vitamin D, and alkaline phosphatase levels done at the start of the study and every 2 weeks until they weighed 1,900 g. At the start of the study, birth weight and gestational ages were similar in all four groups. There were no biochemical differences among the four groups except for a lower serum P in the human milk group. The human milk group had lower bone mineralization rate compared with the three formula groups. Bone mineral content was similar in the three formula-fed groups. However, only formulas containing 117 mg Ca and 58.5 mg P or 140 mg Ca and 82 P mg/100 kcal approximated intrauterine bone mineralization. Human milk fed infants did not approximate and were significantly different from the intrauterine rate.

Calciuria and aminoaciduria in very low birth weight infants fed a high-mineral premature formula with varying levels of protein

To assess the influence of protein intake on renal excretion of calcium and amino acids and on bone mineralization in preterm infants, we randomly selected within weight group strata 27 infants who weighed < 1500 gm at birth (nine per group) to be fed a high-mineral (calcium, 940 mg/L; phosphorus, 470 mg/L) premature formula with one of the following protein contents: formula A, 3.0 gm/100 kcal; formula B, 2.7 gm/100 kcal; and formula C, 2.2 gm/100 kcal. Mean (+/- SD) daily weight gain was greater in infants receiving the higher protein intakes for the first 30 days (formula A, 24.8 +/- 5.1 gm; formula B, 20.5 +/- 3.8 gm; formula C, 16.2 +/- 5.9 gm (analysis of variance: p < 0.01; C < A, p < 0.05)). Bone mineral content did not differ at any time point, and all groups had a high prevalence of generalized aminoaciduria (4 weeks: formula A, 56%; formula B, 71%; formula C, 75%). Urinary calcium corrected for creatinine (in milligrams per milligram) increased as protein content decreased (2 weeks: formula A, 0.16 +/- 0.10; formula B, 0.20 +/- 013; formula C, 0.44 +/- 0.33 (C > A, C > B, p < 0.05); 4 weeks: formula A, 0.23 +/- 0.15; formula B,0.34 +/- 0.47; formula C, 0.49 +/- 0.22 (C > A, p < 0.01). We conclude that the high mineral content and other components of premature formulas result in a higher growth rate and may increase protein requirements. Failure to meet protein requirements may result in underutilization of absorbed calcium and increased renal excretion of calcium. In preterm infants, higher protein intake probably supports rather than jeopardizes bone mineral accretion, and reduces rather then increases calciuria.