Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Supplementation with human milk protein improves growth of small premature infants fed human milk. Evaluation of a long-chain polyunsaturated fatty acid supplemented formula on growth, tolerance, and plasma lipids in preterm infants up to 48 weeks postconceptional age. A novel infant formula milk with added long-chain polyunsaturated fatty acids from single-cell sources: a study of growth, satisfaction and health. Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier. Growth and nutrient intakes of human milk-fed preterm infants provided with extra energy and nutrients after hospital discharge. School-milk intervention trial enhances growth and bone mineral accretion in Chinese girls aged 10-12 years in Beijing. Changes in growth and metabolism in very low birthweight infants fed with fortified breast milk. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and unsupplemented preterm human milk.
Despite potential benefits, human milk may fail to meet preterm infants' nutrient requirements. We tested the hypothesis that fortified breast milk, fed alone or with preterm formula, would improve neurodevelopment and growth at 18-mo follow-up without adverse short-term clinical or biochemical consequences. Two hundred seventy-five preterm infants from two medical centers (birth weight < 1850 g; mean gestation 29.8 +/- 2.7 wk) whose mothers chose to provide breast milk were randomly assigned to receive for a mean of 39 d a multinutrient fortifier or control supplement containing phosphate and vitamins. Breast milk comprised 47.6% and 46.4% of enteral intake in fortified and control groups, respectively; preterm formula supplements were used when insufficient breast milk was available. Overall, there were no significant growth advantages with fortification; although, when breast milk exceeded 50% of intake, fortification promoted faster weight gain (an advantage of 1.6 g.kg-1.d-1; 95% CI: 0.1, 3.1; P < 0.05). Compared with control infants, the fortified group showed 1) higher plasma urea from week 2 (P = 0.04), 2) higher plasma calcium (mean 2.34 +/- 0.01 compared with 2.27 +/- 0.02 mmol/L; P = 0.003), 3) a greater rise in alkaline phosphatase by week 6 (P = 0.04), 4) more clinical infections (suspected plus proven; 43% compared with 31%, P = 0.04), 5) a nonsignificantly increased incidence of necrotizing enterocolitis (5.8% compared with 2.2%, P = 0.12), and 6) higher white cell and platelet counts. Developmental scores at 18 mo were slightly but not significantly higher in the fortified group. This study confirmed that breast milk fortifiers can improve short-term growth (when breast milk intakes are high); but beneficial effects on long-term development remained unproven. Future research is required to evaluate potential adverse consequences and explore more optimal fortification strategies. We investigated the influence of human milk protein and medium-chain triglyceride supplementations of human milk feedings on the growth of very low birth weight infants during their first weeks of life. A group of 44 preterm infants with birth weights of less than 1,520 g and a mean gestational age of 30.3 weeks was randomly divided into four groups to receive plain human milk or human milk supplemented with human milk protein (0.9 g/dL), with medium-chain triglycerides (1 g/dL), or with both. The medium-chain triglyceride oil supplementation did not influence the growth of these infants. The infants given supplementary protein gained weight faster during weeks 4 to 6 than those without (18.5 +/- 0.7 v 15.1 +/- 0.6 g/kg/d; mean +/- SEM; P = .001). After 4 weeks of age the infants given supplementary protein had a mean weight gain equal to the mean intrauterine rate, in contrast to the infants of the other groups, who grew more slowly until age 6 weeks. Furthermore, we found a correlation between serum albumin concentration and weight gain during the seventh week of life (P = .018). The length growth velocity for the infants with protein supplementation was 0.99 +/- 0.06 cm/wk (mean +/- SEM) and for those without 0.83 +/- 0.05 cm/wk (P = .043). There was no difference in growth of head circumference between the groups. We conclude that human milk protein supplementation improves the growth of small premature infants fed human milk, and that the protein concentration of bank milk is insufficient for their adequate growth. The last trimester of pregnancy is a period of rapid accretion of long-chain polyunsaturated fatty acids, both in the central nervous system and the body as a whole. Human milk contains these fatty acids, whereas some preterm infant formulas do not. Infants fed formulas without these fatty acids have lower plasma and erythrocyte concentrations than infants fed human milk. Preclinical and clinical studies have demonstrated that single-cell sources (algal and fungal) of long-chain polyunsaturated fatty acids are bioavailable. A balanced addition of fatty acids from these oils to preterm formula results in blood fatty acid concentrations in low birth weight infants comparable to those of infants fed human milk.
                In the present study the growth, acceptance (overall incidence of discontinuation, reasons for discontinuation, overall incidence and type of individual adverse events), and plasma fatty acid concentrations were compared in three groups of infants fed a long-chain polyunsaturated fatty acid-supplemented preterm infant formula, an unsupplemented control formula, or human milk. The study was prospective, double-blind (formula groups only), and randomized (formula groups only). Two hundred eighty-eight infants were enrolled (supplemented formula group, n = 77; control formula group, n = 78; human milk group, n = 133).
                Anthropometric measurements at enrollment, at first day of full oral feeding, and at both 40 and 48 weeks postconceptional age did not differ between the formula groups, whereas the human milk-fed group initially grew at a lower rate. The incidence of severe adverse events was rare and not significantly different between formula groups. The groups fed either human milk or supplemented formula had long-chain polyunsaturated fatty acid concentrations higher than those in the control formula group.
                The results of this study demonstrate the safety and efficacy of a preterm formula supplemented with long-chain polyunsaturated fatty acids from single-cell oils. To evaluate the growth, feeding and health of babies fed a novel infant formula milk with added long chain polyunsaturated fatty acids (LCPs) produced from single-cell sources, at concentrations similar to those found in mature breast milk.
                Randomized double-blind control trial.
                One-hundred and forty healthy, full-term infants of birth weight 2.5-4.5 kg born at the Maternity Department, East Glamorgan General Hospital, Wales, whose mothers had already decided to bottle feed.
                Subjects were randomized to two groups; one (control group) to receive a standard formula milk and the other to receive the trial milk with added LCPs. Milks were supplied in a double-blind fashion and given for the first 12 weeks of life. Anthropometric measurements were made at recruitment, 3 months, 6 months and 1 y. Feeding diaries were completed at 6 weeks and 3 months, and a parental record was kept of any ill health suffered by the subjects during the first year of life.
                Of 140 infants recruited, 31 did not complete the protocol. Small but statistically significant differences were found only in the subscapular skinfold thickness at 6 weeks and 3 months, that in the trial group being slightly higher, but unlikely to be of any clinical importance. No differences were found in the feeding patterns of the infants in the two groups. Stool patterns were similar, as were the frequencies of illness and allergy.
                This study supports the view that LCPs from single-cell sources do not have detrimental effects on the growth, feeding and general health of infants. 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 alpha-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).
                Infants who weighed < or =1500 g, had a gestational age < or =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.
                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 Bell's 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.
                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. The purpose of this pilot study was to determine whether mixing a multinutrient fortifier to approximately one half of the human milk fed each day for a finite period after discharge improves the nutrient intake and growth of predominantly human milk-fed low birth weight infants. We also assessed the impact of this intervention on the exclusivity of human milk feeding.
                Human milk-fed (> or = 80% feeding per day) low birth weight (750-1800 g) infants (n = 39) were randomly assigned at hospital discharge to either a control or an intervention group. Infants in the control group were discharged from the hospital on unfortified human milk. Nutrient enrichment of human milk in the intervention group was achieved by mixing approximately one half of the human milk provided each day with a powdered multinutrient human milk fortifier for 12 weeks after discharge. Milk with added nutrients was estimated to contain approximately 80 kcal (336 kJ) and 2.2 g protein/100 mL plus other nutrients. Intensive lactation support was provided to both groups.
                Infants in the intervention group were longer during the study period, and those born < or = 1250 g had larger head circumferences than infants in the control group. There was a trend toward infants in the intervention group to be heavier at the end of the intervention compared with those in the control group. Mean protein, zinc, calcium, phosphorus, and vitamins A and D intakes were higher in the intervention group.
                Results from this study suggest that adding a multinutrient fortifier to approximately one half of the milk provided to predominantly human milk-fed infants for 12 weeks after hospital discharge may be an effective strategy in addressing early discharge nutrient deficits and poor growth without unduly influencing human milk feeding when intensive lactation support is provided. A 2-year milk intervention trial was carried out with 757 girls, aged 10 years, from nine primary schools in Beijing (April 1999 - March 2001). Schools were randomised into three groups: group 1, 238 girls consumed a carton of 330 ml milk fortified with Ca on school days over the study period; group 2, 260 girls received the same quantity of milk additionally fortified with 5 or 8 microg cholecalciferol; group 3, 259 control girls. Anthropometric and bone mineralisation measurements, as well as dietary, health and physical-activity data, were collected at baseline and after 12 and 24 months of the trial. Over the 2-year period the consumption of this milk, with or without added cholecalciferol, led to significant increases in the changes in height (> or =0.6 %), sitting height (> or =0.8 %), body weight (> or 2.9 %), and (size-adjusted) total-body bone mineral content (> or =1.2 %) and bone mineral density (> or =3.2 %). Those subjects receiving additional cholecalciferol compared with those receiving the milk without added 25-hydoxycholecalciferol had significantly greater increases in the change in (size-adjusted) total-body bone mineral content (2.4 v. 1.2 %) and bone mineral density (5.5 v. 3.2 %). The milk fortified with cholecalciferol significantly improved vitamin D status at the end of the trial compared with the milk alone or control groups. It is concluded that an increase in milk consumption, e.g. by means of school milk programmes, would improve bone growth during adolescence, particularly when Ca intake and vitamin D status are low. Human milk is often inadequate nutritionally for preterm infants. We investigated the effect of adding a commercially prepared milk fortifier to human (maternal or bank) milk and measured changes in lower leg length velocity (LLLvel) using knemometry, weight gain and biochemical indices of nutrition. Babies were allocated to one of three feed groups, in a semi-randomized fashion, to receive human milk alone (group I), fortified human milk (group II) or a preterm formula (group III). The birthweights (median and R) and birth gestations (median and R) of the three groups were as follows: group I 1099 g (654-1248 g) and 28 wk (26-32 wk); group II 838 g (742-1340g) and 31 wk (28-36); group III 1136g (624-1552g) and 32 wk (27-36 wk). All babies who received fortified milk either showed significant (p = 0.0004) acceleration in LLLvel during the period studied, or maintained their pre-study period velocity. This increase in LLLvel was comparable to that achieved by a group of babies given a standard preterm infant formula (p < 0.001). By comparison, the control group's change in LLLvel was more modest (p = 0.04). Babies who received human milk with the fortifier added had the lowest serum levels of alkaline phosphatase at the end of the study period when compared to the other two groups. Other biochemical indices were similar in the three feed groups. No adverse clinical events were encountered which could be attributed to the use of the breast milk fortifier. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed human milk provided by their mother; this milk supplemented with bovine milk protein, calcium, phosphorus, and sodium; or pasteurized term human milk with the same supplement were monitored from the time desired intake was tolerated until weight reached 2200 g. The supplement resulted in greater rates of weight gain (20.5 +/- 2.3 vs 16.4 +/- 2.2 g.kg-1.d-1) and nitrogen retention (353 +/- 76 vs 270 +/- 53 mg.kg-1.d-1), increase in plasma transthyretin (TTR) concentration (7 +/- 16 vs -3 +/- 9 mg.L-1.wk-1), a higher mean plasma albumin concentration (34 +/- 3 vs 32 +/- 4 g/L), and a higher plasma TTR concentration at discharge (100 +/- 22 vs 75 +/- 24 mg/L). All these variables correlated significantly with total nitrogen intake, suggesting that the differences are attributable to the protein content of the supplement. The supplement also resulted in greater rates of calcium and phosphorus accretion but the plasma alkaline phosphatase activity of the supplemented vs the unsupplemented groups did not differ.
There is insufficient evidence to make recommendations for practice. Further research should evaluate the practice of supplementation of human milk with fat. This may best be done in the context of the development of multicomponent fortifiers. Both short term growth outcomes and long term growth and neurodevelopmental outcomes should be evaluated. Adverse effects should be evaluated.