Research Notes: Iron

Am Fam Physician. 2002 Oct 1.
Prevention of iron deficiency in infants and toddlers.
Kazal LA Jr.
Navajo Health Foundation/Sage Memorial Hospital, Ganado, Arizona, USA.

The prevalence of nutritional iron deficiency anemia in infants and toddlers has declined dramatically since 1960. However, satisfaction with this achievement must be tempered because iron deficiency anemia in infants and toddlers is associated with long-lasting diminished mental, motor, and behavioral functioning. Additionally, the prevalence of iron deficiency anemia in one- to three-year-old children seems to be increasing. The exact relationship between iron deficiency anemia and the developmental effects is not well understood, but these effects do not occur until iron deficiency becomes severe and chronic enough to produce anemia. At that point, treatment with iron can reverse the anemia and restore iron sufficiency, yet the poorer developmental functioning appears to persist. Therefore, intervention should focus on the primary prevention of iron deficiency. In the first year of life, measures to prevent iron deficiency include completely avoiding cow's milk, starting iron supplementation at four to six months of age in breastfed infants, and using iron-fortified formula when not breastfeeding. Low-iron formula should not be used. In the second year of life, iron deficiency can be prevented by use of a diversified diet that is rich in sources of iron and vitamin C, limiting cow's milk consumption to less than 24 oz per day, and providing a daily iron-fortified vitamin. All infants and toddlers who did not receive primary prevention should be screened for iron deficiency. Screening is performed at nine to 12 months, six months later, and at 24 months of age. The hemoglobin/hematocrit level alone detects only patients with enough iron deficiency to be anemic. Screening by erythrocyte protoporphyrin or red-cell distribution width identifies earlier stages of iron deficiency. A positive screening test is an indication for a therapeutic trial of iron, which remains the definitive method of establishing a diagnosis of iron deficiency.

J Trop Pediatr. 2002 Aug;48(4):204-9.
Reversal of iron deficiency anemia-induced peripheral neuropathy by iron treatment in children with iron deficiency anemia.
Kabakus N, Ayar A, Yoldas TK, Ulvi H, Dogan Y, Yilmaz B, Kilic N.
Department of Pediatric Neurology, Firat University, Faculty of Medicine, Elazig, Turkey.

The effects of iron deficiency anemia (IDA) on nerve conduction and efficiency of iron therapy were investigated by peripheral nerve-electrophysiological measurements. Eighteen children (10 boys, eight girls; mean age 31 +/- 1.3 months) with IDA and 12 healthy children (six boys, six girls; mean age 29 +/- 1.3 months) were enrolled into the study. Nerve conduction velocity was measured in the median and posterior tibial nerve. After nerve conduction values were determined in the patients and controls, 6 mg/kg/24 h ferrous sulphate was given orally to the patients for 3 months and nerve conduction velocity tests were performed again. Median/motor and sensory nerve conduction velocity and tibial/motor nerve distal-amplitute values of children with IDA were lower than for the control group (p < 0.05, p < 0.01 and p < 0.001 respectively). With iron supplementation these values increased to the normal levels and even higher than control levels for some parameters. In correlation studies between whole blood parameters and nerve conduction velocity results, there was a correlation between median/sensory nerve conduction velocity values and serum iron levels. Additionally there was a correlation between some nerve conduction velocity values and age. In conclusion, the evidence from this preliminary study suggests that peripheral neuropathy may develop in children with IDA. Peripheral neuropathy symptoms in these patients may be improved by iron therapy.

Am J Clin Nutr. 2002 Jun.
Nutritional effect of including egg yolk in the weaning diet of breast-fed and formula-fed infants: a randomized controlled trial.
Makrides M, Hawkes JS, Neumann MA, Gibson RA.
Child Nutrition Research Centre, Child Health Research Institute, Women's & Children's Hospital, North Adelaide, Australia.
[ Free full text ]

Background: Egg yolks can be a source of docosahexaenoic acid (DHA) and iron but are often associated with adverse consequences on plasma cholesterol. Objective: Our goal was to investigate the effect of consumption of 4 egg yolks/wk on infant DHA status and hemoglobin, ferritin, and plasma cholesterol concentrations. Secondary outcomes included plasma iron, transferrin, and transferrin saturation. Design: This was a randomized controlled trial comparing no dietary intervention, consumption of 4 regular egg yolks/wk, and consumption of 4 n-3 fatty acid-enriched egg yolks/wk in breast-fed and formula-fed infants from 6 to 12 mo of age. Erythrocyte DHA concentrations, cholesterol, and iron status were assessed at 6 and 12 mo of age. Results: Of the 82 breast-fed infants recruited, 23 of 28 (no intervention), 23 of 27 (regular eggs), and 24 of 27 (n-3 eggs) completed the trial. Of the 79 formula-fed infants enrolled, 23 of 27 (no intervention), 24 of 26 (regular eggs), and 20 of 26 (n-3 eggs) completed the trial. Erythrocyte DHA concentrations were 30-40% higher after the n-3 egg intervention than after treatment with regular eggs or no eggs in both breast-fed and formula-fed infants. Egg treatment had no significant effect on plasma cholesterol, hemoglobin, ferritin, and transferrin but did result in improvements in plasma iron and transferrin saturation compared with no egg treatment. Conclusions: n-3 Fatty acid-enriched eggs may provide a means of increasing dietary DHA during the second 6 mo of life. Egg yolks may also be a useful source of iron during the weaning period and can be safely included in the weaning diet with no perturbations in plasma cholesterol.

Excerpts from the full text article:

Weaning of both breast-fed and formula-fed infants is usually recommended from 4 to 6 mo of age. Although it is common to introduce iron-fortified cereals as a first food, this contrasts with more traditional weaning practices in which egg yolks and brains were used as first foods. Iron stores in breast-fed infants become depleted by 6 mo. Because breast milk is not a good source of iron, iron-rich weaning foods are considered important to avoid iron deficiency. Like meat, egg yolks contain both heme and nonheme iron. Heme iron refers to the iron in hemoglobin, myoglobin, and heme-containing enzymes; nonheme iron includes all other forms of iron. Heme iron is absorbed more efficiently than is nonheme iron and its absorption is not significantly influenced by iron status or other constituents of the diet. Conversely, the absorption of nonheme iron, mainly from iron salts, can be modified by different dietary factors, and studies investigating the addition of whole eggs to meals containing nonheme iron show a reduction in iron absorption. These observations are supported by other studies showing that egg white inhibits nonheme iron absorption. However, iron absorption from egg yolk alone has not been investigated. Given that egg yolks contain some heme iron, are small in volume, and have a soft texture suitable for weaning infants, an investigation of whether egg yolk in the weaning diet can influence iron status is warranted.

The n-3 long-chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA; 22:6n-3) is an integral component of breast milk and until recently was not added to infant formulas. Randomized controlled trials of infant formula supplemented with DHA compared with formula containing only precursor fatty acids have consistently shown short-term improvements in visual and neural development of preterm infants. Trials involving term infants have reported neutral or positive outcomes. Although the potential long-term benefits of DHA are still being explored, biochemical data indicate that breast-fed infants accumulate DHA in the brain until 12 mo of age and at a greater rate than do infants fed formula without DHA. To our knowledge, no trials have addressed whether weaning foods high in n-3 fatty acids, such as n-3 fatty acid–enriched egg yolks, can improve infant DHA status during late infancy.

The most commonly cited reason for delaying the introduction of whole eggs to infants is to avoid sensitizing infants to egg white proteins and hence the development of egg-related allergies. Furthermore, although dietary recommendations for adults to reduce their intake of eggs to limit the cholesterol content of the diet have little relevance to young children, such guidelines may influence a parent's food choices for his or her child. The purpose of our trial was to investigate the nutritional role of egg yolks in the weaning diets of breast-fed and formula-fed infants. Primary outcome measures included erythrocyte DHA concentrations, infant iron status, and plasma cholesterol concentrations. Secondary outcomes included growth and plasma indexes of allergy.

Protocol

Healthy 6-mo-old infants born at term (>37 wk gestation) with birth weights >2500 g were eligible for the trial. Infants were excluded if they had known protein intolerances or allergies. Infants were eligible for entry into the breast-fed cohort if they received <120 mL formula (or cow milk)/wk and were eligible for entry into the formula-fed cohort if they were receiving all their nutrition as formula feeds by 4 wk after birth and were subsequently formula fed. All formulas consumed by infants did not contain LCPUFAs and were fortified with iron.

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Dietary intervention

The aim of the dietary intervention was to include 4 egg yolks/wk in the diet of weaning infants between 6 and 12 mo of age without significantly altering intake from other foods. The dietary intervention with n-3 eggs was designed to match the amount of DHA a breast-fed infant would normally receive, ie, 100 mg/d. The fatty acid and nutrient compositions of the eggs are shown in Tables 1and 2. The eggs were enriched with DHA by feeding hens diets rich in n-3 fatty acids, including DHA (11). Eggs (weighing 60–65 g each) were purchased from South Coast Eggs (Myponga, South Australia) and were supplied in plain cartons coded A or B. The regular and n-3 eggs were similar in appearance, taste, and smell. Both the study participants and the research personnel were unaware of the type of eggs provided.

Compliance was encouraged by providing the family with 2 dozen eggs per fortnight, delivered by courier to the home of each infant allocated to an egg group. All mothers received advice regarding preparation, received instruction about separating the egg yolk from the egg white, and were supplied with plastic egg separators and a recipe booklet compiled by a dietitian.

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The normal reference ranges used in this study for the iron status of infants (6 mo to 2 y) are as follows: hemoglobin, 105–135 g/L; ferritin, 10–250 µg/L; iron, 8–30 µmol/L; transferrin, 2.0–3.6 g/L; and transferrin saturation, 10–60%. Infants whose hemoglobin and plasma iron markers fell within these limits were considered iron sufficient. All infants with a hemoglobin concentration <105 g/L were classified as having anemia. Infants who had plasma ferritin concentrations 10 mg/L were classified as having iron deficiency. Infants with iron deficiency who also had hemoglobin concentrations < 105 g/L were classified as having iron deficiency anemia.

Study sample

A total of 251 eligible mother-infant pairs were approached to enter the trial, and 161 gave written, informed consent to participate (Figure 1). Of these, 82 were breast-fed and 79 were formula-fed. Of the 82 breast-fed infants recruited, 23 of 28 (control group), 23 of 27 (regular egg group), and 24 of 27 (n-3 egg group) completed the trial. Twelve breast-fed infants were withdrawn for the following reasons: anemia at trial entry (n = 8), failure to attend the initial appointment (n = 2), ceased breast-feeding before 9 mo (n = 1), and perceived adverse reaction to eggs by the parents (n = 1). Of the 79 formula-fed infants recruited, 23 of 27 (control group), 24 of 26 (regular egg group), and 20 of 26 (n-3 egg group) completed the trial. Twelve formula-fed infants were withdrawn for the following reasons: failure to attend the initial appointment (n = 9), loss to follow-up (n = 1), perceived adverse reaction to eggs by the parents (n = 1), and unknown reason (n = 1).

The dietary intervention resulted in mothers reporting increased use of egg yolks in both the breast-fed and formula-fed cohorts (Table 4). Reported consumption of 4 egg yolks/wk did not affect the frequency of consumption of other foods, such as meats and cereals, that are likely to contribute iron or LCPUFAs to infant diets. The formula-fed infants consumed more adult cereal, meat, chicken, and fish than did the breast-fed infants, whereas the breast-fed infants consumed more baby cereal.

Compliance with the dietary intervention is highlighted by the fact that erythrocyte DHA concentrations were 30% higher after treatment with n-3 eggs than after treatment with regular eggs in both the breast-fed and formula-fed infants at 12 mo of age (Table 5). Note that adding 4 n-3 egg yolks/wk to the diets of infants fed formula without LCPUFAs resulted in erythrocyte DHA concentrations that were not significantly different from those in the breast-fed infants in the control group at 12 mo of age. Erythrocyte AA concentrations were <10% lower after treatment with n-3 eggs than after the control or treatment with regular eggs in both the breast-fed and formula-fed cohorts at 12 mo of age.

Increasing egg yolk consumption from 1 to 4/wk did not alter mean plasma cholesterol concentrations in either the breast-fed or formula-fed infants (Table 5). The breast-fed infants did, however, have higher cholesterol concentrations than the formula-fed infants at 6 mo of age [4.3 ± 0.8 (n = 70) compared with 3.8 ± 0.7 (n = 67) mmol/L; P < 0.001]. This difference disappeared by 12 mo of age [4.3 ± 0.7 (n = 70) compared with 4.1 ± 0.7 (n = 67) mmol/L], when all infants were consuming a greater variety of foods.

Hemoglobin, ferritin, and transferrin values did not differ significantly between the combined egg treatment groups and the control group within both the breast-fed and formula-fed cohorts (Table 6). At 12 mo, however, plasma iron and transferrin saturation were higher in the egg-treated breast-fed and formula-fed infants than in the respective control groups. Only one breast-fed infant receiving regular eggs had iron deficiency anemia at 12 mo of age. Iron status did not differ significantly between the breast-fed and formula-fed infants, except that plasma ferritin concentrations tended to be lower in the breast-fed infants (P = 0.06). At 12 mo of age, more breast-fed infants (17.1%, 12 of 70) than formula-fed infants (7.5%, 5 of 67) were iron deficient (NS). The frequency of positive values for antibodies specific to egg yolk and egg white did not differ significantly between the combined egg treatment group and the control group within both cohorts or between the breast-fed and formula-fed cohorts (Table 7).

Weight, length, and head circumferences were not significantly different between the dietary groups nor were there any significant interactions between diet and time (data not shown). However, the breast-fed infants were consistently lighter [at 6 mo, 7575 ± 892 (breast-fed, n = 70) compared with 7942 ± 943 (formula-fed, n = 67) g; at 9 mo, 8584 ± 999 compared with 9081 ± 1043 g; and at 12 mo, 9626 ± 1060 compared with 10121 ± 1130 g; P < 0.01] and shorter [at 6 mo, 67.1 ± 2.6 (breast-fed, n = 70) compared with 67.6 ± 2.3 (formula-fed, n = 67) cm; at 9 mo, 70.9 ± 2.4 compared with 72.1 ± 2.5 cm; and at 12 mo, 75.1 ± 2.5 compared with 75.9 ± 3.5 cm; P < 0.05] than the formula-fed infants. There was no significant difference in head circumference between the breast-fed and formula-fed infants.

Discussion

Our trial was a systematic study of the nutritional value of including egg yolk in the weaning diet of breast-fed and formula-fed infants. With the separate random assignment of the breast-fed and formula-fed infants, the trial was structured to answer current nutritional issues pertinent to all infants. For example, although formula-fed infants are generally iron sufficient, the issue of improving their LCPUFA status remains topical. Conversely, breast-fed infants have an ample supply of dietary LCPUFAs but have been reported to be at risk of depleted iron stores during late infancy. Our trial addressed whether egg yolk, which can be a good source of both LCPUFAs and iron, is beneficial for all infants regardless of whether they are breast-fed or fed formula, without adverse consequences on plasma cholesterol concentrations or plasma indexes of allergy.

A major finding of the current trial was that infants fed formulas without DHA but who consumed 4 n-3 egg yolks/wk had erythrocyte DHA percentages that were not significantly different from those of the breast-fed infants. We showed in an earlier study that weaning diets are very low in LCPUFAs, such that formula-fed infants have little chance in the normal course of events to achieve LCPUFA status similar to that seen in breast-fed infants. In that earlier study, we calculated that it could take 14 regular egg yolks/wk to provide an infant with the same amount of DHA that breast-fed infants receive. The results of the present trial, which showed that 4 regular egg yolks/wk in the weaning diet had no significant effect on erythrocyte DHA status, add credibility to this calculation. However, the addition of 4 n-3 egg yolks/wk, which provided 100 mg additional DHA/d in the weaning diets of the formula-fed infants, resulted in erythrocyte DHA amounts not significantly different from those of the breast-fed infants, who also obtained 100 mg DHA/d.

It is also interesting to note that erythrocyte DHA concentrations decreased with age in the breast-fed infants in the control group, whereas there was no significant change in DHA status with time in the formula-fed infants in the control group. Although breast milk remains the main dietary source of DHA in 6–12-mo-old infants, the increasing consumption of weaning foods low in DHA and the reduction in breast milk volume consumed during this age bracket probably explain the reduction in DHA status of the breast-fed infants in the control group. On the other hand, DHA status remains low in infants consuming formulas without DHA and DHA-poor weaning foods and does not alter with age. Our data indicate that n-3 egg yolks can be a useful dietary source of DHA for both breast-fed and formula-fed infants, and show for the first time that egg yolks can be incorporated into the weaning diet for a sustained period of time. The implications of these findings remain to be determined because no trials have specifically addressed changes in physiologic functions or clinical outcomes of infants supplemented with DHA during the second 6 mo of life.

Our trial showed no significant effect of egg yolk intervention on hemoglobin and ferritin, the major determinants of iron status, although there was a positive effect of egg treatment on transferrin saturation and plasma iron. This is perhaps not surprising because the infants studied were largely iron sufficient and had adequate hemoglobin and iron stores (as measured by ferritin). The improvements in plasma iron and transferrin saturation with egg treatment reflect increases in iron transportation. Given that the additional amount of iron supplied by the egg yolk intervention was 0.5 mg/d, it is possible that either a greater dose or a longer treatment period would be necessary before improvements in iron stores could be observed.

Other comparable trials involving largely iron-sufficient infants that investigated the effect of different iron-containing weaning foods on infant iron status had different results. Engelmann et al showed that partially breast-fed infants randomly allocated to a high-meat (27 g/d) diet had improved iron status compared with infants allocated to a low-meat (10 g/d) weaning diet. Note that the iron contribution from meat in the high-meat group is similar to the amount of iron received from the egg yolk treatment in the current trial. Conversely, one of our earlier trials showed that infants fed a high-iron weaning diet (8.2 ± 2.9 mg/d), in which the iron was derived largely from iron-fortified cereal, had iron status that was not different from that of a control group (5.2 ± 3.4 mg/d) at 12 mo of age. The infants in the intervention group of this earlier trial received an extra 3 mg Fe/d compared with an extra 0.5 mg Fe from egg yolk in the current trial. Collectively, these data suggest that foods such as egg yolks and meat may make a useful contribution to the weaning diet and that interventions aimed at increasing the intake of such foods in iron-deplete infants deserve to be tested in a large, community-based trial.

Although an egg yolk typically contains 200 mg cholesterol and 6 g fat (2 g of which is saturated fat), introducing 4 eggs/wk to the diets of weaning infants did not significantly alter plasma cholesterol concentrations in either breast-fed or formula-fed infants. This finding parallels observations from a trial involving adults in which the intake of 4 regular or 4 n-3 eggs/wk resulted in no increase in blood lipids. One of the largest randomized intervention trials that investigated early diet and lifestyle counseling to reduce atherosclerosis risk factors showed that intervention to reduce fat intake and replace saturated fat with monounsaturated and polyunsaturated fat in the weaning diet of infants resulted in no effect on blood lipids when infants were 13 mo of age. On the other hand, breast-fed infants are consistently reported to have higher plasma cholesterol concentrations than formula-fed infants. Various randomized trials of cholesterol-supplemented formula have been undertaken with the aim of investigating the effect of cholesterol supplementation on blood lipids and lipid metabolism. Although both trials reported increases in plasma cholesterol with cholesterol supplementation of infant formula, cholesterol synthesis remained lower in breast-fed infants than in cholesterol-supplemented, formula-fed infants. Few data exists regarding the implications of these findings for physiologic functions and clinical outcomes, and these remain controversial. It has been suggested that cholesterol consumption in human milk may promote the delivery of adequate substrate for brain lipids, but other work suggests that the rat brain synthesizes its cholesterol de novo.

Egg allergy and intolerance are among the most common food allergies and intolerances. In our group of healthy infants with no known protein allergies or intolerances, only 1 of 82 breast-fed and 1 of 79 formula-fed infants were withdrawn from the trial because the parents perceived that the infants had an adverse reaction to the egg yolk intervention. Both of these infants were ingesting egg protein as part of their usual weaning diet, however, and we did not have the opportunity to confirm egg intolerance by using a double-blind, placebo-controlled challenge. The presence of antigen-specific antibodies to egg yolk and egg white were used as indexes of egg intolerance, although IgE antibody responses to food proteins can appear in healthy infants with no clinical manifestations of allergy or intolerance. The results of our trial confirm this because none of the infants had overt signs of egg intolerance, but 4% and 8% of the egg-treated infants had specific antibody responses to egg yolk and egg white, respectively, compared with 2% and 15% of the control infants, respectively. Within the limits of our trial there were no significant differences in specific antibody responses between the treated and control infants. However, given the relatively low rates of positive responses, hundreds of infants per treatment group would have been required to detect differences. Further studies should be conducted to better define the clinical and plasma markers of allergy in response to egg intervention.

In summary, the results of our trial indicate that it is possible and practical for weaning infants to consume 4 egg yolks/wk without affects on the intake of other foods such as cereals and meats. The egg yolk intervention resulted in modest improvements in iron status that may be most beneficial to infants who are iron deplete, and this deserves further investigation. Eggs fortified with n-3 fatty acids provide a means of increasing dietary DHA during the second 6 mo of life without altering plasma cholesterol. The emerging work in the field of dietary DHA and infant outcomes will determine whether there are any physiologic or clinical benefits to improved DHA status during the second half of infancy.

Pediatr Hematol Oncol. 2001 Dec.
Low serum carnitine concentrations in healthy children with iron deficiency anemia.
Cemeroglu AP, Kocabas CN, Coskun T, Gurgey A.
Dokuz Eylul University Faculty of Medicine, Department of Pediatric Endocrinology, Inciralti, Izmir, Turkey.

Carnitine is not only obtained from animal-derived foods but also synthesized in the body. It plays an important role in the energy metabolism of many tissues, including heart and skeletal muscles. Iron is known to be essential for the biosynthesis of carnitine. Although many conditions are well known to cause secondary carnitine deficiency, iron deficiency, which is a very common condition in children, is not well studied as a cause of secondary carnitine deficiency in humans. This study demonstrates the coexistence of iron deficiency and low carnitine levels in otherwise healthy children. The mean carnitine concentration of 18 otherwise healthy children with iron deficiency anemia was significantly lower compared to the mean carnitine concentration of healthy children without iron deficiency anemia. Based on the evidence about the effect of low iron on carnitine stores in experimental animals, we proposed that low serum carnitine levels in these children may be secondary to iron deficiency. However, further studies need to be done to further clarify this relationship.

Nutrition. 2001 May.
Effectiveness of treatment of iron-deficiency anemia in infants and young children with ferrous bis-glycinate chelate.
Pineda O, Ashmead HD.
Latin American Center for Nutrition and Metabolic Studies, Antigua, Guatemala.

Forty infants, 6 to 36 mo old, with iron-deficiency anemia (hemoglobin < 11 g/dL) were matched and assigned to two groups. One group received FeS0(4) and the other received ferrous bis-glycinate chelate at a dose of 5 mg of Fe daily per kilogram of body weight for 28 d. Both groups had significant hemoglobin increases (P < 0.001), but only the group treated with ferrous bis-glycinate chelate had significant increases (P < 0.005) in plasma ferritin. Apparent iron bioavailabilities were calculated at 26.7% for FeS0(4) and 90.9% for ferrous bis-glycinate chelate. Regression analysis indicated that absorption of both sources of iron were similarly regulated by the body according to changes in hemoglobin. We concluded that ferrous bis-glycinate chelate is the iron of choice for the treatment of infants with iron-deficiency anemia because of its high bioavailability and good regulation.

Arch Latinoam Nutr. 2001 Mar.
Relative effectiveness of iron bis-glycinate chelate (Ferrochel) and ferrous sulfate in the control of iron deficiency in pregnant women.
Szarfarc SC, de Cassana LM, Fujimori E, Guerra-Shinohara EM, de Oliveira IM.
Sao Paulo University, Sao Paulo, Brazil.

The relative effectiveness of daily supplementation of iron deficiency during pregnancy using 15 mg/day of iron from iron-bis-glycinate chelate (71 pregnant women), or 40 mg iron from ferrous sulfate (74 pregnant women) was evaluated by measuring hemoglobin, transferrin saturation and serum ferritin, at the beginning of the study (< 20 weeks of pregnancy) and at 20-30 weeks and 30-40 weeks thereafter. Ingestion for 13 weeks or more was considered adequate. Seventy three percent of the Ferrochel consuming group and 35% of the ferrous sulfate consuming group were considered to have taken the treatment adequately. The decrease in levels of all the measured parameters was significantly less pronounced in the group that consumed Ferrochel in spite of the lower treatment dose. Iron depletion was found in 30.8% of the women treated with Ferrochel and in 54.5% of the women than consumed ferrous sulfate. Of the factors responsible for non-compliance, taste was reported in 29.8% of the ferrous sulfate consumers and none in the groups that consumed Ferrochel. It is concluded that daily supplementation with Ferrochel was significantly more effective, in spite of the lower dose, than supplementation with ferrous sulfate.

Food Chem Toxicol. 1999 Jul.
Safety evaluation of ferrous bisglycinate chelate.
Jeppsen RB, Borzelleca JF.
Technical Services, Albion Laboratories, Inc., Clearfield, UT, USA.

Ferrous bisglycinate chelate (Ferrochel) is a highly stable chelate that can be added to most foods. Data from human and animal studies indicate that the ferrous iron is readily bioavailable with fewer side-effects than the more commonly used iron salts. The acute oral LD50 for male and female Sprague-Dawley (S-D) rats is 2800 mg/kg body weight (560 mg/kg body weight iron [confidence limit (CL) 399-786] as the active ingredient). Male and female CD (Sprague Dawley-derived) rats were fed ferrous bisglycinate as a dietary admixture at doses of 0, 100, 250 and 500 mg/kg body weight/day. There were no biologically or statistically significant dose-related differences between the control and treated animals with respect to body weight gain, food consumption, food efficiency, behavioural effects, clinical chemistries, haematology, absolute and relative organ weights, or gross and microscopic findings. Hepatic non-heme iron concentrations were elevated, indicating that the ferrous iron had been absorbed. The no-observed-adverse-effect level (NOAEL) was 500 mg/kg body weight/day, the highest dose tested.

Child Dev. 1998 Feb.
Behavior of infants with iron-deficiency anemia.
Lozoff B, Klein NK, Nelson EC, McClish DK, Manuel M, Chacon ME.
Center for Human Growth and Development, University of Michigan, Ann Arbor, USA.

This study tested the hypothesis that infants with iron-deficiency anemia show behaviors, such as increased proximity to caregivers, increased wariness or hesitance, and decreased activity, that could contribute to "functional isolation." The behavior of 52 Costa Rican 12- to 23-month-old infants with iron-deficiency anemia was contrasted with that of 139 comparison group infants with better iron status during free play and mental and motor testing and in the home. Infants with iron-deficiency anemia maintained closer contact with caregivers; showed less pleasure and delight; were more wary, hesitant, and easily tired; made fewer attempts at test items; were less attentive to instructions and demonstrations; and were less playful. Adult behavior also differed. The results indicate that iron-deficiency anemia in infancy is associated with alterations in affect and activity, suggesting that functional isolation is a useful framework for understanding poorer developmental outcome in iron-deficiency anemia, the world's most common single nutrient deficiency.

J Nutr. 1997 Jul.
Milk inhibits and ascorbic acid favors ferrous bis-glycine chelate bioavailability in humans.
Olivares M, Pizarro F, Pineda O, Name JJ, Hertrampf E, Walter T.
Hematology Unit, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile.

The chemical properties of ferrous bis-glycine chelate allow for its use as a fortificant in fluid, high fat vehicles. This chemical form may also protect iron from the inhibitory or enhancing effects of the diet on iron absorption. Alternatively, iron bis-glycine chelate may be absorbed by a mechanism independent of an individual's iron stores. To test these hypotheses, the bioavailability of iron bis-glycine chelate added to water and milk was studied using a double-isotopic method in two groups of 14 women. Iron absorption from aqueous solutions of 0.27 mmol/L (15 mg/L) of elemental iron as either iron bis-glycine or ferrous ascorbate was not significantly different (34.6 and 29.9%, respectively). There were significant correlations between (log) iron absorption of iron bis-glycine with (log) serum ferritin (r = -0.60, P < 0.03) and with (log) iron absorption from ferrous ascorbate (r = 0.71, P < 0.006), suggesting that iron bis-glycine chelate bioavailability is indeed affected by iron stores. Iron absorption of iron bis-glycine given in milk was significantly lower (P < 0.002) than when given in water, with values of 11.1 and 46.3%, respectively (standardized to 40% absorption of the reference dose). With the addition of 0.57 mmol/L ascorbic acid (100 mg/L), iron absorption of iron bis-glycine given in milk increased significantly from 11.1 to 15.4% (P < 0.05). These findings show that milk and ascorbic acid affect iron bis-glycine chelate bioavailability and also demonstrate that iron stores may influence its bioavailability as well. The good bioavailability of iron bis-glycine makes this compound a suitable alternative to be considered in iron fortification programs.