Although the survival rate of very low birth weight (VLBW) infants has increased steadily (1), postnatal growth and development remain suboptimal. A causative factor is thought to be suboptimal nutrition. Nutritional needs of VLBW infants are high because of low fetal stores, poor absorption, excess intestinal and renal losses and rapid growth (2). Human milk reportedly provides advantages for preterm infants and is associated with higher developmental scores compared with formula (3). This effect may be attributable to hormones, growth factors, specific fatty acids, other bioactive factors or the higher bioavailability of nutrients in human milk. Nevertheless VLBW infants fed human milk often need additional protein and minerals in form of milk fortifiers to meet their nutritional needs. As human milk also contains low and highly variable concentrations of trace elements, VLBW infants may also require supplementation with trace elements, especially zinc (4), which is essential for metabolism, cell growth, immune defense and protection against oxygen radicals. Most European fortifiers, however, did not contain trace elements until 2002.
We defined zinc deficiency as serum zinc concentration <0.49 mg/L (5) and assumed that it would occur in 40% of VLBW infants (6). We hypothesized that supplementing human milk with a zinc-containing fortifier (100 μg/g) would significantly reduce the rate of zinc deficiency.
A bicentric, prospective, double-blinded, randomized trial was performed on infants <33 weeks gestation, birthweight 1000 to 1499 g, admitted to both Departments of Neonatology, Charité, Humboldt University Berlin. Singleton, twin or triplet infants were eligible, whereas infants small for their gestational age and infants with serious malformations and gastrointestinal diseases were excluded. To show a reduction in the rate of zinc deficiency from 40% to 10% with 80% power and type I error of 5% would require 29 patients in each arm. The protocol was approved by the local ethics committee and written informed consent was obtained from the parents.
All infants were fed mother’s milk or, if unavailable, donated human milk. Infants were enrolled from May 1999 to September 2000 and were randomized up to day 5 of life to receive as a supplement either 5% FM 85 (Nestlé, München, Germany) or 3% BMF (Numico, Friedrichsdorf, Germany) (Table 1). Balanced block randomization was performed at the nutritional service using random numbers. Clinical staff and parents were unaware of the infant’s group assignments.
The primary outcome variable was serum zinc concentration. Additional outcome variables included concentrations of copper, iron, manganese, selenium, iodine, calcium, phosphorus and magnesium in serum, red blood cells (RBCs) and human milk, inorganic phosphate, alkaline phosphatase (AP) activity, TSH, T4 and FT4 concentrations in serum, zinc in RBCs and iodine in urine at 3 and 6 weeks of life. Baseline concentrations of minerals and trace elements in serum and RBCs were measured once until the fifth day of life. Venous blood samples, 6-hour urine samples and 24-hour pooled samples of fortified human milk were collected at 3 and 6 weeks and stored at −20°C until analysis.
Body weight was measured daily using an electronic precision scale. Body length measured with a fixed headboard and a movable footboard, head circumference with a nonstretchable tape and lower leg length measured with a mini-knemometer (Walter Christ GmbH, Viernheim, Germany) were recorded weekly (7).
Enteral feeding was started on day 2 by giving 12 ml human milk per day as bolus tube feeding every 2 hours. When feeding tolerance was adequate, the daily milk volume was increased by 12 ml per day until complete enteral feeding (150 mL/kg per day) was achieved. Feeding tolerance was assessed by recording gastric residual volumes and their quality, and by clinical assessments of vomiting, abdominal distension and tenderness and stool characteristics. Additional parenteral nutrition with aminoacids, lipids, fat and water-soluble vitamins and trace elements (Pharmacia-Upjohn GmbH, Erlangen, Germany) was used when adequate enteral nutrition could not be achieved. Fortification of human milk was started when an enteral intake of 100 ml per day was reached or from day 7, whichever occurred first. Later all infants were additionally supplemented with enteral calcium and phosphorus depending on AP activity and inorganic phosphate in serum (measured every 14 days) and calcium/creatinine ratio in urine (measured weekly). All infants received enteral vitamin D 1000 IU daily from day 7 but no other enteral vitamins. When infants received recombinant erythropoietin, enteral iron was administered in a dose of 3–9 mg/kg/day depending on the transferrin saturation.
Trace element and mineral measurements were conducted at the Department of Molecular Trace Element Research, Hahn-Meitner-Institute, Berlin. We used instrumental neutron activation analysis for selenium and zinc, inductively coupled plasma mass spectrophotometry for zinc, selenium, copper and manganese and inductively coupled atomic emission spectrophotometry for zinc, copper, calcium, phosphorus, magnesium and iron determination. Independent analytical methods and certified reference materials were used for quality control (8,9). All reagents used were of suprapure or ultrapure grade. Inorganic phosphate in serum was determined using the phosphorus inorganic assay (Sigma-Aldrich Chemie GmbH, München, Germany). AP activity in serum was measured by means of ALKP analysis platelets (Vitros Chemistry Products). Thyroid hormones were measured by means of time-resolved immunoassays AutoDELFIA™ Neonatal hTSH kit, DELFIA® Neonatal T4 kit and AutoDELFIA™ Free Thyroxine (FT4) kit (Perkin-Elmer™, Wallac Oy, Turku, Finnland). Osmolality of fortified milk was determined in triplicate using automated freezing point assessment (Osmomat 030; Gonotec, Berlin, Germany).
Infants were evaluated from birth to 6 weeks of life. All data are given as median (25th–75th quartiles). Mann-Whitney U-test was used to analyze differences between groups (SPSS 10.0, PC+; SPSS, Chicago, IL). Longitudinal changes were evaluated with nonparametric variance analyses (10) using SAS (SAS Institute, Inc., Cary, NC). Significance was assumed at P value < .05.
Eighty-six VLBW infants were admitted. Two parents gave no informed consent and one infant was excluded because of severe malformations. Nine infants in the FM 85 group and 12 infants in the BMF group were excluded after randomization because of necrotizing enterocolitis, severe infection and need for parenteral nutrition after the 14th day of life (not significant). Thirty-four infants of the FM 85 group and 28 infants of the BMF group finished the protocol. Their clinical characteristics showed no differences (Table 2).
The predominant (>50%) feeding was mother’s own milk in 19 infants of the FM 85 group and in 17 infants of the BMF group and donated human milk in the others. Fortification was started at 7.5 (6–8) days in the FM 85 group and at 7.0 (6–8) days in the BMF group. Full enteral nutrition (>130 mL/kg per day) was reached at 14.5 (13–18) days in the FM 85 group and at 17.0 (13.5–21) days in the BMF group. The enteral intake of nutrients and osmolality of the fortified milk differed between the groups (Table 3). The cumulated additional supply of calcium during the study was 953 (621–1745) mg/kg in the FM 85 group and 933 (483–1448) mg/kg in the BMF group (not significant). The cumulated additional phosphorus intake was 643 (456–834) mg/kg in the FM 85 group and 461 (270–638) mg/kg in the BMF group (not significant). The daily additional supply of minerals is shown in Table 3. When infants received erythropoietin (22 infants in the FM 85 group and 20 infants in the BMF group), enteral iron was administered at a dose of 6 mg/kg/day without a difference between the study groups (data not shown). Intravenous aminoacids were given to 24 infants for 4.0 (0–8.0) days in the FM 85 group and to 21 infants for 4.5 (1.0–7.5) days in the BMF group (not significant). Thirteen infants in the FM 85 and 12 infants in the BMF group received lipids and fat-soluble vitamins (not significant). Trace element solutions were infused to 14 infants in the FM 85 group and to 13 infants in the BMF group (not significant). Red blood cell transfusions were given to 10 infants in the FM 85 group and six infants in the BMF group and plasma infusions were performed in 19 infants in the FM 85 group and in 15 infants in the BMF group (not significant).
Trace Element and Mineral Concentrations in Serum and RBCs
Results are shown in Table 4. Serum zinc concentrations <0.49 mg/L, were observed in one and four infants in the FM 85 and in one and two infants in the BMF group at 3 and 6 weeks, respectively (not significant), all of them without clinical symptoms. Despite doubled intake, serum zinc concentration in the BMF group was not different from that in the FM 85 group. Serum copper differed at 6 weeks and values below 0.3 mg/L were observed in nine infants of the FM 85 group and no infants in the BMF group (P < 0.01). In the BMF group, selenium concentration was higher in RBCs at 3 weeks and serum at 6 weeks (P < 0.05). Serum iodine was higher in the BMF group at 6 weeks (P < 0.01) although it had started from a higher baseline (P < 0.05). Manganese concentrations in serum and RBCs were not different despite a different intake. Concentrations of total phosphorus and inorganic phosphate in serum were higher in the BMF group at 3 weeks (P < 0.01). Inorganic phosphate below 48 mg/L was found in 11 and six infants in the FM 85 group and in two and four infants in the BMF group at 3 and 6 weeks, respectively (P < 0.05 at 3 weeks). AP activity was higher (P < 0.01) and more frequent above 500 IU/L (P < 0.05) in the FM 85 group at 6 weeks (Table 5). Serum magnesium values were higher in the BMF group at 3 and 6 weeks (P < 0.01). Magnesium below 15.8 mg/L was found in four and five infants in the FM 85 group and in one and no infants in the BMF group at 3 and 6 weeks (P < 0.05 at 6 weeks).
Nonparametric variance analyses confirmed for the most part the above-mentioned results and showed significant longitudinal differences between the groups with regarding to inorganic phosphate, magnesium, calcium, selenium, copper (P < 0.05) and iodine (P < 0.01). Interactions between groups and time of investigation were found for inorganic phosphorus, calcium (P < 0.05) and magnesium (P < 0.01). The differences between the concentrations of selenium, iodine and copper were stable until 6 weeks. No significant gender-specific differences within or between groups were found.
Thyroid hormone concentrations and urinary iodine excretion were not different between groups at 3 and 6 weeks of age. T4 concentrations in both groups at 3 and 6 weeks were found to be 50% lower than the lower limit of normal levels described for term infants. FT4 concentrations were also lower. TSH concentrations were in the normal range (Table 5).
Weight gain (after regained birth weight) was higher in the FM 85 group (P < 0.05). No differences between the groups were found for the time to regain or double birth weight or for growth velocity of body length, lower leg length and head circumference (Table 6).
Elevating zinc intake from 0.3 to 0.6 mg/kg/day did not influence serum zinc concentrations at 3 or 6 weeks. However, zinc deficiency, defined as serum concentration below 0.49 mg/L, was less frequent than expected from our previous study with infants partly fed preterm formula. Zinc bioavailability is twice as high from human milk as from formula (11). In the present study, no symptomatic zinc deficiency was observed. Subclinical zinc deficiency may lead to growth failure. Schanler et al. found a daily intake of 1.9 mg/kg zinc necessary for a daily weight gain of 22 g/kg (12). Nutritional committees recommend a daily intake of 0.8 to 1.0 mg/kg (4,13). Despite fortification, our zinc intake was lower in both groups and the higher intake in the BMF group did not influence weight gain. It remains difficult to meet zinc requirements because its concentration in maternal milk is highly variable, usually unknown and decreases during lactation. Frequently used parameters of zinc status are zinc concentration and AP activity in serum but serum is not the main zinc compartment in the body. Homeostasis is established between other compartments (e.g., bones, muscles, brain and liver). Different factors influence homeostasis by regulating intestinal absorption and urine excretion and therefore change serum zinc concentration. Serum concentration decreases with age and during rapid growth and may increase during stress, infection and catabolic metabolism. In the case of zinc deficiency serum concentration decreases only when the homeostatic capacity is exhausted. We excluded conditions that may have influenced serum zinc concentration (e.g., infection and cholestasis). Other factors, such as age, immaturity and growth velocity, were equal in both groups and therefore could not have influenced the results. Our serum zinc concentrations are somewhat higher than Oshiro et al.’s data measured in infants predominantly fed preterm formula (14). Metcalf investigated preterm infants fed fortified human milk and found similar zinc concentrations as in our study (15). Zinc in RBCs could be a useful long-term parameter but is obviously not sensitive during the first 6 weeks of life. Part of that can be attributed to transfusions of adult RBCs because compared with RBCs of VLBW infants they contain a higher concentration of zinc and have a longer half-life. We confirmed the results from Oshiro et al., who found decreasing serum and increasing RBC concentrations of zinc with increasing age (14).
Copper intake met recommendations (4,13) in the BMF group but not in the FM 85 group in which serum concentrations in one fourth of the infants fell below Sutton et al.’s limit of deficiency (16). L’Abbe investigated preterm infants fed preterm formula or fortified human milk and found a higher copper intake than in our study but not specified for fortified human milk. One month before hospital discharge serum copper concentrations were comparable with our results at 6 weeks in the BMF group (17). The copper intake described by Ehrenkranz et al. was higher than in the FM 85 group and similar to the BMF group (18). Airede found higher serum copper concentrations at 4 and 8 weeks in preterm infants <36 gestational weeks fed predominantly human milk compared with our study (19). The higher copper intake in the BMF group was followed by a significant higher copper concentration in serum in this group compared with the FM 85 group. Copper deficiency is difficult to diagnose because symptoms as osteopenia, apnoea, neutropenia, anaemia and edema can also be caused by other deficiencies or conditions. There are a few reports on copper deficiency in VLBW infants (16).
Selenium concentration in human milk was similar in both groups because it was not added to the fortifiers. The concentration was higher than in Australia (20) but lower than in Utah (21). Our intake met the recommendations for VLBW infants (4,13), but serum and RBC concentrations declined until the sixth week of life as previously described (20,22). Selenium concentration in serum was significant higher in the BMF group until 6 weeks, although baseline concentrations were higher. Our selenium concentrations in serum are similar to the results from Daniels et al. despite a lower intake (20,23). Smith et al. found a higher selenium intake, higher serum concentrations and no decline over time in serum and RBCs in breastfed VLBW infants (21). Daniels et al. described increasing serum selenium concentrations in breastfed term infants during the first weeks of life. It is not yet clear if the declining concentrations in serum and RBCs of VLBW infants are a result of an inadequate intake or whether an additional supplementation would be necessary (20).
Manganese deficiency caused by rapid growth and the inability of the fetal liver to accumulate manganese may develop in VLBW infants. The intake in both study groups was higher than recommended (4,13). Although enteral intake in the BMF group was clearly higher than in the FM85 group and than described by others (24), concentrations in serum and RBCs remained similar.
VLBW infants are at risk for osteopenia prematurorum because of a low mineral intake. To prevent deficiencies, the goal of enteral nutrition is to approach the fetal accretion rate. Schanler et al. predicted that a daily intake of 160 mg/kg calcium and 94 mg/kg phosphorus would be necessary (12). The recommended intake of calcium and phosphorus (4,13) was not met by both fortifiers. Both groups required additional mineral supplementation. In this manner mineral requirements were fullfilled in the BMF group but not in the FM 85 group, as shown by the elevated AP activity at 6 weeks and by the lower inorganic phosphate concentrations at 3 weeks (26). This confirms results shown by others (12,27–31). The intake of calcium and phosphorus in the FM 85 group is similar to data from Gross (32), although Gross found much lower concentrations of inorganic phosphate in serum than was seen in our study. The mineral intake in the BMF group was equal to Schanler and Garza’s data (25). Serum calcium concentrations in Schanler and Garza’s and Schanler et al.’s studies were similar to our results, whereas the concentrations of inorganic phosphate were half those seen in our study (25,33). Backström reported the combination of inorganic phosphate <57.6 mg/L and AP activity >900 IU/L as a screening to predict low bone mineral density in VLBW infants (26), whereas Faerk et al. could not confirm this at term (34). Lucas et al. found that AP >1200 IU/L was associated with a reduced length growth in the neonatal period and at 18 months of age (35). In osteopenia prematurorum, AP activity is increased, but the upper limit is under discussion. Rauch and Schoenau proposed 900 IU/L as the upper limit (36). Higher AP activities can also be attributable to high growth rates or to liver function disorders. We excluded liver function disorders. AP activities were similar (28) or somewhat higher than in other studies (25,32), but no AP activity exceeding 900 IU/L was observed.
The higher magnesium intake in the BMF group increased serum concentrations at 3 and 6 weeks. Serum concentrations decreased with age. These results are in line with those of Ariceta et al., who found magnesium concentrations inversely correlated to gestational age (37).
Thyroid hormones T4 and FT4 are important for brain development but their serum concentrations are low in VLBW infants and correlate with gestational age (38,39). The reasons are multifactorial including decreased thyroxine-binding globuline, iodine deficiency, immaturity of the hypothalamic-pituitary regulation of the thyroid and differences in peripheral tissue deiodination. Alimentary iodine deficiency should be avoided to decrease the risk of hypothyroxinaemia. Iodine intake in our study partly met the recommendations in the BMF group but was below the lower limit in the FM 85 group (4,13). Immature and sick preterm infants are in a negative iodine balance during the first weeks because they are unable to retain all ingested iodine (38,39). In addition to prematurity itself, serious complications such as infection, respiratory distress syndrome or intrauterine growth retardation can alter thyroid function. These complications did not occur in our infants during the investigation at 3 and 6 weeks. Nevertheless, the infants’ immaturity may have influenced our results. Serum iodine concentrations were significantly higher in the BMF group at 6 weeks of age, mainly because of a higher baseline concentration in this group. The intakes and the urinary concentrations of iodine were only slightly higher in the BMF group. The amounts of T4 and FT4 did not differ between the groups but were low.
Weight gain in our study was similar to that seen in other studies (18,31,40). Schanler et al. described a higher weight gain of 22 g/kg per day because of a higher intake of energy and zinc (12). Reis et al. used another fortifier with emulsifier and substituted carbohydrates with fat and found an improved nutrition and a higher weight gain of 18.4 g/kg per day (40). In our study, the energy surplus of 8 kcal/kg/day during the first 3 weeks provided by the fortifier FM 85 did significantly promote weight gain despite the very low zinc intake with this type of fortification. In addition, the feeding of high amounts of calcium and phosphorus may inhibit fat absorption in the intestine. Fortification with BMF results in lower osmolality of milk because of reduced carbohydrate content but increases the trace element and mineral concentration. This has been reported to be beneficial for the immature intestine (40). Growth velocity of body length and head circumference was higher in comparable studies than we measured (12,15,28,31,40). The lower leg length growth velocity measured in our study was one third lower than that described by others (12,27).
We conclude that despite doubled zinc intake in the BMF group compared with the FM 85 group, zinc status was not significantly different at 6 weeks of age. In this context, we have to take into account the limitation of serum zinc concentration as a marker of zinc deficiency. Increasing calcium and phosphorus intake, however, was associated with significantly lower AP activities. Commercial fortifiers widely used in Europe are incompletely adapted to the nutritional needs of preterm infants weighing less than 1500 g.
The authors thank the participating parents and the the staff of the neonatal units, F. Hochhaus, MD; U. Felderhoff, MD; Ms. Prause for their assistance, and Ms. Sahm and Mr. B. Berger for expert laboratory work. The authors thank Ms. T. Schink, Institute of Medical Statistics and Biometrics, Charité, Humboldt University Berlin for their statistical work.
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Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
Human milk fortifier; Very low-birth-weight infants; Trace elements; Minerals; Weight gain