IRON ABSORPTION FROM INFANT MILK FORMULA AND THE OPTIMAL LEVEL OF IRON SUPPLEMENTATION

Abstract. Thirty healthy infants, aged 11–13 months, were studied with regard to the iron absorption from proprietary milk formula. The infants were divided into three groups (I-III) depending on the concentration of iron in the formula: 0.8 (I), 6.8 (II), and 12.8 (III) mg/1, respectively. The calculated amount of iron absorbed per test dose of SO ml of milk averaged 5 μg (I), 32 μg (II), and 43 μg (III). Group I differed significantly from groups II and III. No correlation was found between iron absorption and hemoglobin, MCV, serum transferrin saturation or serum ferritin within the range of normal values. Our findings suggest that at least 7 mg of iron as ferrous sulphate per litre of formula is required to prevent iron deficiency.     

The influence of feeding regimens on endogenous digoxin-like immunoreactive substance concentrations in infants

The aim of this study was to investigate serum digoxin-like immunoreactive substance (DLIS) levels in 60 healthy term infants when they reached 1–6 months of age with regard to feeding regimen. Group I consisted of 30 infants fed exclusively on breast milk. Groups II and III each consisted of 15 infants fed on formula and cow's milk, and on formula and cow's milk supplemented by breast milk, respectively. Mean serum DLIS concentrations were 0.03 ± 0.05, 0.18 ± 0.09 and 0.15 ± 0.09 ng/ml in groups I-III, respectively. The difference between the DLIS levels in groups II and III was not significant. Serum DLIS levels of infants in groups II and III, on the other hand, were significantly higher than in group I ( p < 0.05). These findings were interpreted to suggest that artificial nutrients may cause volume expansion and an increase in endogenous DLIS levels. The latter response is possibly a protective mechanism to decrease volume expansion in groups II and III.     

Bioavailability of iron in soy-based formula and its effect on iron nutriture in infancy

Soy products have been reported to inhibit absorption of nonheme food iron and fortification iron. Iron bioavailability from a soy formula (Prosobee-PP 710) (iron added as ferrous sulfate: 12 mg/L; ascorbic acid: 54 mg/L) was examined in 16 adult women using the extrinsic radioactive tag method. The geometric mean absorption from the soy formula was only 1.7%. The effect of this formula on iron nutrition in infants was studied in 47 healthy term infants weaned spontaneously before 2 months of age and who received the formula ad libitum until 9 months of age. For control, 45 infants received a cow's milk formula fortified with ferrous sulfate (iron: 15 mg/L; ascorbic acid: 100 mg/L), which has been shown to be effective in preventing iron deficiency, and 49 additional breast-fed infants were also followed. All babies received solid foods (vegetables and meat) starting at 4 months of age. Iron nutritional status was determined at 9 months. Infants fed soy formula and iron-fortified cow's milk had similar mean values of hemoglobin, mean corpuscular volume, transferrin saturation, free erythrocyte protoporphyrin, and serum ferritin; both formula groups differed significantly (P less than .05) from the breast-fed group in all measurements except free erythrocyte protoporphyrin. Anemia (hemoglobin less than 11 g/dL) was present in only 4.3% and 2.2% of infants receiving the soy and the fortified formulas, respectively, v 27.3% in the breast-fed group. These results indicate that soy formula, in spite of the lower iron bioavailability when measured in adults, is essentially as effective as iron-fortified cow's milk in preventing iron deficiency in infants.     

Vitamin E status in preterm infants fed human milk or infant formula

Vitamin E status was assessed in 36 infants with birth weights less than 1500 gm who were assigned randomly to receive one of three sources of nutrition: milk obtained from mothers of preterm infants (preterm milk), mature human milk, or infant formula. Infants in each dietary group were further assigned randomly to receive iron supplementation (2 mg/kg/day) beginning at 2 weeks or to receive no iron supplementation. All infants received a standard multivitamin, providing 4.1 mg alpha-tocopherol daily. Serum vitamin E concentrations at 6 weeks were significantly related both to type of milk (P less than 0.0001) and to iron supplementation (P less than 0.05). Infants fed preterm milk had significantly higher serum vitamin E levels than did infants fed mature human milk, and both groups had significantly higher levels than did those fed formula. Ratios of serum vitamin E/total lipid were also significantly greater for infants fed human milks than for those fed formula. The addition of iron to all three diets resulted in significantly lower serum vitamin E levels at 6 weeks (P less than 0.05); however, only in the group fed formula was there evidence of vitamin E deficiency. Preterm milk with routine multivitamin supplementation uniformly resulted in vitamin E sufficiency in VLBW infants whether or not iron was administered.     

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 infant's own mother's 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.     

Iron gain in low-birthweight infants: role of milk feeding

The availability of iron is critical in low-birthweight infants. We followed a group of small preterm infants without iron supplementation who were either exclusively breast-fed or weaned early to industrial infant milk formula or home-prepared cow's milk formula. The gain of iron was compared within the milk groups on the basis of hemoglobin and serum ferritin concentrations at the ages of 3 and 4 mth when only trace amounts of solid foods had been given. Contrary to the reports on term infants we found unsupplemented proprietary infant milk formula and breast milk similar as a source of iron. It is possible that there is no major inhibition of iron absorption from any milk during the time of simultaneously occurring accelerated erythropoiesis and exhaustion of iron stores in preterm infants. The apparent inferiority of cow's milk could be due to increased intestinal loss of blood.     

The effect of iron in formula milk after 6 months of age

Ninety two normal birthweight infants aged 6 months entered a double blind controlled trial which compared a follow on formula milk with no added iron against the same formula milk containing 1.2 mg of iron per 100 ml. There was no significant difference in the social class or demographic characteristics of the two treatment groups or in the proportion of each group completing the trial. There was no difference between the two groups in the quantity of milk taken but the amounts taken lessened between 6 and 18 months of age. There was no difference between the two groups with respect to mean haemoglobin and median serum ferritin at 6, 9, 12, 15, and 18 months of age. Very few infants developed iron deficiency anaemia in either group but there was a tendency for serum ferritin levels to fall between 6 and 18 months of age in both groups. The results suggest that iron added to follow on milk was not an important source of dietary iron in the infants studied.     

The effect of iron in formula milk after 6 months of age.

Ninety two normal birthweight infants aged 6 months entered a double blind controlled trial which compared a follow on formula milk with no added iron against the same formula milk containing 1.2 mg of iron per 100 ml. There was no significant difference in the social class or demographic characteristics of the two treatment groups or in the proportion of each group completing the trial. There was no difference between the two groups in the quantity of milk taken but the amounts taken lessened between 6 and 18 months of age. There was no difference between the two groups with respect to mean haemoglobin and median serum ferritin at 6, 9, 12, 15, and 18 months of age. Very few infants developed iron deficiency anaemia in either group but there was a tendency for serum ferritin levels to fall between 6 and 18 months of age in both groups. The results suggest that iron added to follow on milk was not an important source of dietary iron in the infants studied.     

Nutrient intakes of formula-fed infants and infants fed cow's milk

Twenty-four-hour dietary intake data from the second National Health and Nutrition Examination Survey (NHANES II), 1976-1980, were analyzed to compare nutrient intakes among infants 7 to 12 months of age who were fed mixed diets containing solid foods and either infant formula or cow's milk. Solid foods fed to the infants in both groups were low in iron and linoleic acid, and high in sodium, potassium, and protein, relative to Recommended Dietary Allowances. Infants who were fed cow's milk received lower median intakes of iron (7.8 mg v 14.9 mg), linoleic acid (1.8 g v 6.1 g), and vitamin C (39 mg v 64 mg), and higher median intakes of protein (41 g v 25 g), sodium (1,000 mg v 580 mg), and potassium (1,630 mg v 1,020 mg) than formula-fed infants. Seventy-five percent of the infants fed cow's milk had iron intakes below the Recommended Dietary Allowance; 69% had sodium intakes above the range of estimated safe and adequate daily dietary intake. Linoleic acid provided less than 3% of energy intake for 74% of the infants fed cow's milk. Differences in nutrient intakes were due not only to different concentrations of nutrients in each of the milk feedings but also to the different amounts and types of solid foods fed to the two groups of infants.     

强化乳铁蛋白配方奶粉对人乳喂养婴儿生长发育和铁代谢影响的前瞻性多中心非随机对照研究

目的 了解添加强化乳铁蛋白(LF)配方奶粉对婴儿生长发育和铁代谢的影响。方法 本研究为前瞻性多中心非随机对照试验,生后以人乳喂养的4~6月龄健康足月儿自愿添加配方奶粉者纳入本研究,按门诊顺序分别纳入强化组(LF 38 mg·100 g-1 ,铁元素4 mg·100 g-1)和对照组(LF 0,铁元素4.2 mg·100 g-1,其余成分与强化组相同)。两组干预时间均为3个月。两组婴儿在干预前后分别测定身长、体重、头围、Hb、血清铁蛋白(SF)、血清转铁蛋白受体(sTfR);同时计算TFR-F指数、机体总铁含量(TBIC)、年龄别身高Z评分(HAZ)、年龄别体重Z评分(WAZ)、身高别体重Z评分(WHZ),比较上述指标的干预前后和组间差异。结果 213名婴儿完成了研究,强化组115名,对照组98名。强化组和对照组婴儿人均日摄入配方奶粉量(94.3±9.8) vs (88.2±8.7) g, P>0.05;人均日铁剂摄入量(3.8±0.4) vs (3.7±0.6) mg, P>0.05。强化组人均日LF摄入量为(35.8±3.7) mg。强化组与对照组干预后各指标改变值比较,体重：(2 213±82) vs (2 033±77) g, WAZ: (0.82±0.22) vs (-0.05±0.01), WHZ: (0.74±0.32) vs (0.20±0.06), Hb: (13.9±4.1) vs (7.2±1.8) g·L-1, SF: (1.37±0.08) vs (0.55±0.04) μg·L-1, TFR-F指数：(0.86±0.11) vs (0.39±0.05),TBIC: (19.4±8.8) vs (9.1±3.4) mg·kg-1, P均<0.05。同时干预后强化组贫血、铁缺乏和缺铁性贫血检出率均显著低于对照组,贫血： 4.1% vs 7.5%,铁缺乏：13.9% vs 24.4%,缺铁性贫血：1.7% vs 8.2%,P均<0.05。结论 添加强化LF配方奶粉干预可以显著改善人乳喂养婴儿生长发育以及铁营养状况     

Follow-on formula in the prevention of iron deficiency: a multicentre study

Abstract Six-month-old infants were recruited at 21 centres in the UK and Ireland and randomly assigned to receive matching iron-fortified (12.3 mg/l iron) or non-fortified (1.4 mg/l iron) formula for 9 months. Infants already receiving cow's milk continued this feed. Haematological indices and iron status were evaluated at age 6 months, 9–10 months and 15 months. Four hundred and six infants entered and 302 completed the study. There were no differences between the groups for increases in weight, head circumference or length. Significant differences between the groups were observed at 15 months for haemoglobin, serum ferritin, serum iron and total iron binding capacity. Haemoglobin levels were < 110 g/l in 33% of infants fed cow's milk compared with 13% and 11% in those receiving non-iron-fortified and iron-fortified formula respectively. The corresponding figures for serum ferritin < 10 µg/l were 43%, 22% and 6%. Follow-on formula provides an acceptable vehicle for preventing iron deficiency in this vulnerable group.     

Oral iron absorption in infantile protein-energy malnutrition.

The ability of infants with protein-energy malnutrition to absorb iron was assessed using the serum iron response to a dose of ferrous sulfate providing 3 mg elemental iron per kg body weight. Responses were grouped as flat (delta serum Fe less than 30 microgram/dl), intermediate (30 to 100 microgram/dl), and normal (greater the 100 microgram/dl). Of 25 consecutively admitted children studied, seven had a flat, five an intermediate, and 13 a normal curve (mean delta serum Fe: 10 microgram/dl, 66 microgram/dl, and 175 microgram/dl, respectively). There were no differences among the three groups in hematocrit, fasting serum iron or transferrin saturation, severity of malnutrition, or evidence of other malabsorption sufficient to explain these differences. Although hematocrits, fasting serum iron, and transferrin saturations did not change appreciably during nutritional rehabilitation, all children with initially abnormal responses subsequently had normal tests.     

Serum glucagon-like peptide-2 levels in neonates: Comparison between extremely low-birthweight infants and normal-term infants

BACKGROUND: Glucagon-like peptide-2 (GLP-2) arises from proglucagon within enteroendocrine L cells of the small and large intestines, and its physiological roles have been gradually elucidated. However, the circulating GLP-2 levels in human neonates are still unknown. The aim of the present study was to measure serum GLP-2 levels in extremely low-birthweight (ELBW) infants and normal-term infants, and to compare these values between the two groups. METHODS: Blood samples were collected and serum GLP-2 concentrations measured, from 15 ELBW infants at three stages (stage I, before initial feeding after birth; stage II, point at which milk intake reached 100 mL/kg per day; stage III, corrected 40 weeks of gestation), and from 30 normal-term infants at two stages (stages I and II). RESULTS: No significant difference in basal GLP-2 values at stage I (before initial feeding) was found between ELBW infants and normal-term infants (7.37 +/- 0.95 ng/mL vs 9.47 +/- 0.94 ng/mL). However, in ELBW infants, serum GLP-2 concentrations at stage II were significantly increased, compared with those at stage I (P < 0.0001). In normal-term infants, serum GLP-2 concentrations at stage II were also significantly increased compared with those at stage I (P < 0.001). CONCLUSION: The results suggest that initial feeding stimulates secretion of serum GLP-2 in neonates. In addition, the secretion mechanism of GLP-2 is considered to be established at 24 weeks of gestation at the latest.     

Changes in growth and metabolism in very low birthweight infants fed with fortified breast milk

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.     

Improved Bone Mineral Status in Very Low Birthweight Infants Fed Human Milk Mixed with Preterm Formula

The bone mineral status of very low birthweight (VLBW) infants fed exclusively their own mother's milk (group I) was compared with that of VLBW infants fed mother's milk in the initial 4 weeks followed by a 1:1 mixture of mother's milk and preterm formula containing high phosphorus (P) and calcium (Ca) (group II). In both groups, most infants showed a biochemical picture characteristic of phosphorus deficiency syndrome by the fourth week. Thereafter, serum alkaline phosphatase activity (ALP) decreased and serum P increased in all group II infants. Conversely, serum ALP rose and hypophosphatemia persisted in most group I infants. Group II had a significantly higher serum P at weeks 8 and 12 and a significantly lower ALP at week 12 than group I. Furthermore, group II had a lower incidence of severe radiographic abnormalities than group I at week 12. We confumed previous observations that VLBW infants fed exclusively human milk require P and Ca supplementation to prevent metabolic bone disease of prematurity.     

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

By photon absorptiometry, extrauterine bone mineralization was evaluated in preterm infants (less than 1,600 g birth weight) fed either a commercial premature formula containing 117 mg calcium, 58.5 mg phosphorus/100 kcal, the same formula containing higher phosphorus (82 mg/100 kcal), the same formula with higher calcium (140 mg Ca) and phosphorus (82 mg/100 kcal), or their own mother's milk. All infants had serum protein, albumin, calcium, phosphorus, bicarbonate, 25-hydroxyvitamin 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.     

Manganese absorption from human milk, cow's milk, and infant formulas in humans

Manganese absorption from human milk, cow's milk, and infant formulas was studied in humans by using extrinsic labeling of the diets with manganese 54 or manganese 52 and whole-body retention measurements. The fractional manganese absorption from human milk (8.2% +/- 2.9%) was significantly different when compared with cow's milk (2.4% +/- 1.7%), soy formula (0.7% +/- 0.2%), and whey-preponderant cow's milk formula with 12 mg/L of iron (1.7% +/- 1.0%) and without iron fortification (2 mg/L of iron) (3.1% +/- 2.8%), while no significant difference was observed between a whey-preponderant cow's milk formula with 7 mg/L of iron (5.9% +/- 4.8%) and human milk. The total amount of absorbed manganese was significantly higher from the non--iron-fortified cow's milk formula (2 mg/L of iron) as compared with human milk, while no significant differences were observed for the other milks and formulas.     

Iron, zinc, copper and selenium status of breast-fed infants and infants fed trace element fortified milk-based infant formula

Infants were fed cow's milk-based formulas containing 4 mg of iron/I from 1.5 to 6 months of age and their hematological status was compared to infants receiving the same formula but with 7 mg of iron/l and with breast-fed infants. One formula with 4 mg of iron/l contained iron as ferrous sulfate, in another, part of the iron was provided as bovine lactoferrin. We also studied the effect of selenium (10 μg/l) and copper (0.4 mg/l) supplementation on selenium and copper status. There were no significant differences in hematological indices among the groups at 6 months of age; all infants had satisfactory iron status. Serum transferrin receptor levels, a potential novel indicator of iron status, were highest in breast-fed infants, suggesting a cellular need for iron, and lowest in infants receiving formula with 7 mg of iron/l. Selenium status, as assessed by serum glutathione peroxidase activity, was similar at 6 months of age in breast-fed infants and infants fed formula fortified with selenium but lower in infants fed unfortified formula. The lowest levels of glutathione peroxidase activity were found in infants fed the highest concentration of iron (7 mg/l). Serum copper concentrations were similar in all groups, but the lowest levels were found in infants fed the highest concentration of iron. These results suggest that 4 mg of iron/l is adequate for infants up to 6 months of age and that higher levels may have some negative effects.     

Supplementation of an adapted formula with bovine lactoferrin. 2. Effects on serum iron, ferritin and zinc levels

Breast milk provides an excellent supply of most nutrients for newborn infants. Infant formulae should be nutritionally comparable to breast milk especially with regard to critical nutrients like iron and other trace elements. Infant formulae supplemented with various amounts of bovine lactoferrin were given to two groups of infants. These infants were compared with infants receiving unsupplemented formula and breast-fed infants. The effects of these diets on levels of haemoglobin, haematocrit, serum iron, ferritin and zinc were examined for a study period of 150 days. At birth, concentrations of iron, haemoglobin, haematocrit and zinc were comparable in all four feeding groups. The fact that the serum zinc level was not altered by lactoferrin supplementation appears to rule out an in-vivo effect of lactoferrin on zinc nutrition of infants. Ferritin levels of breast-fed infants were significantly higher than in non-supplemented formula-fed infants at day 30 and day 90. This difference was seen only at day 30, when comparing breast-fed infants to lactoferrin-supplemented formula-fed infants. Comparing the infants receiving formulae, the formula supplemented with the higher amount of bovine lactoferrin induced significantly higher serum ferritin levels compared to the unsupplemented formula at day 90 and day 150. These observations favour the idea that lactoferrin may be involved in iron absorption. Since this effect was pronounced only after 90 days, it has to be discussed as to whether this effect is a convincing argument for supplementing infant formulae with bovine lactoferrin.     

Iron fortification of infant milk formula: the effect on iron status and immune function.

We conducted a randomized double-blind trial of a cow's milk infant formula with increased iron fortification in order to confirm its safety and to measure its effects on iron status and immune function. A group of full-term, well nourished and healthy infants was followed from the age of 3 months to 1 year. A control group of 74 infants was given a commercially available infant formula containing 8.3 mg Fe/100g. The test group of 75 infants received a similar formula with 40 mg Fe/100 g. The formula with the extra iron proved to be safe and, when compared with the control group, the children in the test group had significantly improved iron status as reflected by the proportion of children classed as normal (25 of 61 cf. 44 of 65; p less than 0.003), and by the mean values of the haemoglobin concentration (11.5 cf. 11.9 g/dl; p = 0.04), red cell distribution width (15.5% cf. 14.4%; p = 0.0005), red cell zinc protoporphyrin (3.4 cf. 4.0 micrograms/g Hb; p = 0.04) and ferritin (29 cf. 17.3 micrograms/l; p = 0.004). The extra iron fortification depressed zinc concentration in plasma (90.6 cf. 83.5 micrograms/l; p = 0.05). There was no significant difference between the two groups for laboratory measures of immune function or for incidence of infection. No adverse effects such as infection could be attributed to the increased iron. We conclude that iron fortification of cow's milk infant formula may be safely increased to 40 mg/100 g (i.e. by a factor of 4.8 over the common concentration of 8.3 mg/100 g), but that this has less than the expected effect on iron status. Further studies are required to define (a) the long-term role of facilitators of iron absorption such as ascorbic acid, (b) the interaction of iron with absorption of divalent trace elements such as zinc, and (c) the effect of iron status on immune function and susceptibility to infection.