Meeting the Iron Needs of Low and Very Low Birth Weight Infants

Key Messages

- Infants with low birth weight (<2,500 g) are at high risk of iron deficiency and poor health outcomes.
- Delayed umbilical cord clamping and improved iron intake in low birth weight infants improve long-term health outcomes. 

Keywords 
Iron · Low birth weight · Preterm 

Abstract 
Low birth weight (LBW), defined as a birth weight of <2,500 g, affects 16% of all newborns and is a risk factor for impaired neurodevelopment as well as adverse cardiovascular and metabolic outcomes, including hypertension. LBW infants include both term, small for gestational age infants and pre-term infants. Most LBW infants have only marginally LBW (2,000–2,500 g). Recent advances in neonatal care have sig­nificantly improved the survival of very LBW (VLBW) infants (<1,500 g). LBW infants are at high risk of iron deficiency due to low iron stores at birth and higher iron requirements due to rapid growth. Using a factorial approach, iron require­ments of LBW infants have been estimated to be 1–2 mg/kg/ day, which is much higher than the requirements of term, normal birth weight infants, who need almost no dietary iron during the first 6 months of life. In VLBW infants, blood losses and blood transfusions related to neonatal intensive care, as well as erythropoietin treatment, will greatly influ­ence iron status and iron requirements. The timing of um­bilical cord clamping at birth is of great importance for the amount of blood transfused from the placenta to the new­born and thereby total body iron. Delayed cord clamping of LBW infants is associated with less need for blood transfu­sion, less intraventricular hemorrhage, and less necrotizing enterocolitis. Randomized controlled trials have shown that an iron intake of 1–3 mg/kg/day (1–2 mg for marginally LBW and 2–3 mg for VLBW) is needed to effectively prevent iron deficiency. There is some recent evidence that these levels of iron intake will prevent some of the negative health con­sequences associated with LBW, especially behavioral prob­lems and other neurodevelopmental outcomes and possibly even hypertension. However, it is also important to avoid excessive iron intakes which have been associated with ad­verse effects in LBW infants. 

Background
Low birth weight (LBW), defined as a weight of <2,500 g at birth, regardless of gestational age, is a major risk factor for poor short- and long-term health outcomes. Accord­ing to the World Health Organization, the global preva­lence of LBW is 15.5%, which means that 20 million LBW infants are born each year [1] . The prevalence of LBW is higher in low-income countries and ranges from 4–9% in Europe to 28% in South Asia [2]. 

LBW is the leading cause of neonatal mortality world­wide and survivors are at high risk of impaired health later in life, including poor neurodevelopment and ad­verse cardiovascular/metabolic outcomes. Observed ad­verse health outcomes in children born with LBW are outlined in Table 1. 

LBW infants include both term, small for gestational age infants and preterm infants. Most LBW infants have only marginally LBW (2,000–2,500 g). Recent advances in neonatal care have significantly improved the survival of very LBW (VLBW) infants (<1,500 g). 

Recent data suggests that early nutrition may be one of the most important factors that can be modified in clini­cal practice in order to minimize later morbidity in LBW infants and iron is a critical nutrient in this context.

Iron 
Iron is an essential nutrient which is required for heme synthesis, oxygen transport, and many enzyme functions, especially cellular energy metabolism. LBW infants are at high risk of iron deficiency (ID) due to low iron stores at birth, higher iron requirements due to rapid growth, and in the case of VLBW infants, iron losses due to fre­quent blood samplings during neonatal intensive care. ID should be avoided since it may have adverse effects on brain development. However, in contrast to most other nutrients, there is no mechanism for iron excretion from the human body and iron is a highly reactive pro-oxidant as well as an important substrate for pathogens, so exces­sive iron supplementation of infants may have adverse effects [3] . 

The combination of hemoglobin and ferritin is often used as a measure of iron status in children. Age-specific cutoffs for iron status indicators, including hemoglobin and ferritin, should be used for LBW infants since major physiological changes occur in iron status and red cell morphology during early development (Table 2). 

The main public health problem associated with ID in childhood is the risk of poor neurodevelopment. Animal experiments have determined that iron is essential for several aspects of brain development including myelin formation, monoamine synthesis and function, neuronal and glial energy metabolism as well as neuronal growth and arborization [4] . A number of case-control studies in children have shown a consistent association between iron deficiency anemia (IDA) in infancy and long-lasting poor cognitive and behavioral performance up to adoles­cence [5] . A meta-analysis of 17 randomized controlled clinical trials in children of various ages showed that iron supplementation had a positive effect on mental develop­ment indices [6] . However, there is no convincing evi­dence that iron supplements improve motor or mental development in young children with IDA [7] , suggesting that prevention is a more effective strategy. A meta-anal­ysis based on a very small number of studies showed that preventive iron supplements in infancy (starting at 0–6 months of life) had a positive effect, at least on motor de­velopment [8]. 

Table 1. Adverse health outcomes associated with low birth weight 


On the other hand, unnecessary iron supplementation of iron-replete infants may have adverse effects, including increased risk of infections and impaired growth [9] . Iron is an essential nutrient not only for humans but also for almost all living organisms, including pathogenic bacte­ria and parasites. It has been shown that iron supplemen­tation of young children in malarious regions can in­crease malaria-related morbidity and mortality if not accompanied by active anti-malaria measures [10, 11] . A possible mechanism for adverse effects of dietary iron may be changes in the gut microbiota. A recent trial in infants showed that iron-fortified porridge resulted in in­creased abundance of Firmicutes and Escherichia/Shi­gella, while bifidobacteria decreased [12] . 

Since iron cannot be extracted from the body, intesti­nal iron absorption is strictly regulated. Preterm VLBW infants with a low postnatal iron intake have a capacity for a relatively high fractional iron absorption: 25–40% from iron supplements given between feedings [13, 14] and 11–27% from iron-fortified formula [15, 16] , sug­gesting that they are able to upregulate intestinal iron ab­sorption when needed. It is less clear whether infants are capable of downregulating iron absorption enough when they are iron sufficient, and one study suggested that this might not be the case in infants up to 6 months of age [17] . Studies are lacking on iron bioavailability from multinu­trient-fortified human milk but it may be higher than from preterm formula since, in term infants, iron absorp­tion is significantly higher from human milk than from infant formula [18] .

Table 2. Recommended cutoffs for the diagnosis of iron overload, iron deficiency, and anemia in low birth weight infants at different ages [46] 




Fig. 1. Body iron compartments and total body iron in a term infant with a birth weight of 3,500 g.
  
Estimated Iron Requirements 
Total body iron at birth is about 75 mg/kg [19] , most of which is found in hemoglobin, and a healthy, term newborn also has some iron stores, corresponding to about 25% of total body iron ( Fig. 1 ). The newborn has a high hemoglobin concentration in blood (average 170 g/L), which is an adaptation to the hypoxic intrauterine environment. Oxygen saturation increases sharply from birth and, consequently, erythropoiesis is downregulated and the hemoglobin level falls to about 120 g/L during the first 6 postnatal weeks [20] . During this period, iron from senescent erythrocytes is transferred from hemoglobin to iron stores, which thereby increase in size. During the fol­lowing months, as the baby grows and expands its blood volume, iron is gradually transferred back to the hemo­globin compartment until the iron stores are depleted. This means that the normal, term newborn has virtually no need of dietary iron during the first 6 months of life ( Fig. 1 ), which is fortunate since breast milk has a very low concentration of iron (0.3 mg/L) [21, 22].

Two approaches can be used to estimate iron require­ments of LBW infants. The first is the factorial approach, i.e., calculating the theoretical iron requirements based on expected growth rate and the iron content of the dif­ferent body compartments. The second approach is to make recommendations based on interventional trials that have been performed in LBW infants (see Effects of Interventions section). 

LBW infants have lower iron stores at birth due to their lower birth weight. As shown in Figure 2 , a LBW infant with a birth weight of 2,000 g has higher iron require­ments during the first months of life due to more rapid postnatal growth. The factorial approach, assuming an average body weight of 7.5 kg at 6 months, a blood volume of 80 mL/kg and tissue iron of 7 mg/kg indicate that iron stores of an infant with a birth weight of 2,000 g would be depleted within 6–12 weeks after birth and that the re­quirement of absorbed iron from 6 weeks to 6 months is 0.12 mg/kg/day. Assuming an average bioavailability of 10%, this corresponds to an enteral iron intake of 1.2 mg/ kg/day. 

Using a factorial approach, the iron requirements of a VLBW infant with a birth weight of 1 kg have been esti­mated to reach a maximum of 0.37 mg/kg/day at around term age [16] . This corresponds to an enteral intake of 1.4–2 mg/kg/day assuming 20–27% absorption. Howev­er, such estimations of iron requirements have not con­sidered blood losses, blood transfusions, or erythropoie-tin treatment. 

In VLBW infants, blood losses and blood transfusions related to neonatal intensive care, as well as erythropoi­etin treatment, will greatly influence iron status and iron requirements. Phlebotomy losses commonly amount to 6 mg/kg of iron per week [23] and in some cases much more. Each red blood cell transfusion typically adds 8 mg/ kg of iron and hepatic iron stores as well as serum ferritin concentrations in preterm infants are highly correlated to the number of blood transfusions received [24]. 

Erythropoietin therapy has been advocated as a way to reduce the need for red blood cell transfusions in VLBW infants and is used in some centers. However, this treat­ment greatly increases iron requirements and high doses of oral or parenteral iron are therefore recommended as an adjunct to this therapy. Factorial calculations suggest that parenteral iron requirements of VLBW infants would be 0.2–0.37 mg/kg/day [16].

However, parenteral iron has been given in much higher doses, up to 3 mg/kg/day, in erythropoietin trials. Some studies showed that 6 mg/kg/ day of enteral iron supplements is as effective as paren­teral iron in this context [25] . There are insufficient data on safety of high doses of iron in combination with eryth­ropoietin, but a Cochrane meta-analysis showed that ear­ly erythropoietin treatment, which includes supplemental iron, increases the risk of retinopathy of prematurity [26].

The timing of umbilical cord clamping at birth is of great importance for the amount of blood transfused from the placenta to the newborn and thereby total body iron. We and others have shown that delayed cord clamp­ing increases iron stores and prevents ID at 3–6 months of age in normal birth weight infants [27, 28] . Delayed cord clamping may be even more important in LBW in­fants. A Cochrane review concluded that delayed cord clamping of preterm infants is associated with less need for blood transfusion, less intraventricular hemorrhage, and less necrotizing enterocolitis [29] .

Effects of Interventions 
The risk for LBW infants to develop IDA during the first 6 months of life, without additional dietary iron, is as high as 77% [30] . Intervention studies from the 1970s and 1980s showed that prophylactic iron, in most studies at a dose of 2 mg/kg/day, effectively prevents anemia up to 6 months of age in LBW infants with birth weights ranging from 1,500 to 2,500 g [31] . 

There are relatively few randomized intervention trials in LBW infants comparing the effects of different doses of iron supplements or fortification of human milk or in­fant formula. 


Fig. 2. Body iron compartments and total body iron in a low birth
weight infant with a birth weight of 2,000 g.

In a study by Friel et al. [32] , 58 infants with an average birth weight of 1,500 g were randomized to different in­fant formulas resulting in iron intakes of 3–6 versus 2– 3 mg/kg/day up to 9 months of age. There was no differ­ence in anemia or neurodevelopment at 12 months be­tween the two groups. However, the group that received the higher amount of iron had higher glutathione per­oxidase concentrations (a marker of oxidative stress), lower plasma zinc and copper levels, and a higher inci­dence of respiratory tract infections, suggesting possible adverse effects of the higher iron intake. 

Similarly, Barclay et al. [33] found no effect on hemo­globin of an iron intake of 3.6–6.8 mg/kg/day as com­pared to 1.0–1.6 mg/kg/day from 2 to 30 weeks postnatal age in infants with an average birth weight of 2,000 g. However, there was a lower erythrocyte superoxide dis-mutase activity in the high iron group, suggesting altered copper metabolism – a possible adverse effect of iron [33]. 

Taylor and Kennedy [34] randomized 150 VLBW in­fants to receive 2 mg/kg/day of iron (from fortified breast milk or preterm formula) or an additional 2 mg/kg/day of iron supplements, yielding a total of 4 mg/kg/day, from 2 to 3 weeks of age until 36 weeks postmenstrual age or discharge. No significant effect was observed with regard to the main outcome (hematocrit at 36 weeks) or the number of blood transfusions. Nor was there any signifi­cant difference in neonatal morbidity, reticulocyte count, or weight up to 36 weeks. Unfortunately, this study did not include measurements of ferritin or follow-up after discharge. 

Griffin et al. [35] randomized 78 mostly VLBW in­fants (mean birth weight 1,360 g) to receive infant for­mulas with differing iron contents from hospital dis­charge until 6 months’ corrected age. The regimens pro­vided iron intakes ranging from 0.8 to 1.2 mg/kg/day. No significant effects were observed between groups with regard to hemoglobin concentrations, ferritin, or the in­cidence of ID, and hemoglobin concentrations were sim­ilar to those of term infants of the same postmenstrual age. 

Berglund et al. [36] randomized 285 marginally LBW Swedish infants (2,000–2,500 g) to iron supplements at the following doses: 0 (placebo), 1, or 2 mg/kg/day. The intervention lasted from 6 weeks to 6 months of age. In this population, iron supplements at a dose of 2 mg/kg/ day, compared with placebo, significantly reduced the risk of IDA at 6 months [36] . In the placebo group, 36% developed ID and 10% developed IDA, as compared with 4 and 0%, respectively, in the 2-mg group. Iron supple­mentation at a rate of 1 or 2 mg/kg/day resulted in differ­ences in iron status, but there was no difference between the two groups in the proportion of infants who devel­oped ID or IDA. Iron supplements did not adversely af­fect infant growth, infections, or other morbidity in this study. Considering compliance to the intervention as well as iron intakes from other sources (about half of the in­fants were formula-fed), the investigators found that an actual iron intake of 0.25 mg/kg/day was sufficient to prevent IDA and that an intake of 1 mg/kg/day prevent­ed ID [36] . 

Timing of Iron Supplementation of LBW Infants 
In order to have a preventive effect on ID, iron supple­ments should be started before iron stores are depleted, which as a rule of thumb is when the infant has doubled its birth weight, which can be as early as 6 weeks after birth in a moderately LBW infant. 

It is generally not recommended to give iron before 2 weeks of age to newborns since there are data suggesting that antioxidant systems are not fully active until that age 
[37]. In most studies of iron supplementation of moder­ately or marginally LBW infants, iron supplementation has been initiated at 4–6 weeks of age. 

Two randomized controlled studies in VLBW infants have suggested that an early (2 weeks of age) as compared to late (6–8 weeks) start of iron supplementation results in less need for blood transfusions [38, 39] . 

Effects of Early Iron Intake on Neurodevelopment and Health in LBW Infants 
There is a severe paucity of studies investigating the effects of early iron intake on neurodevelopment and oth­er long-term health outcomes in LBW infants. 

In the small study by Friel et al. [32] (see above), LBW infants were randomized to a normal or high dose of iron and no effect was observed on neurodevelopment at 12 months. 

In 2007, Steinmacher et al. [40] published a follow-up study of the VLBW infants in the study by Franz et al. [38] (see above), who were randomized to early versus late iron supplementation. In this follow-up study, children who received early enteral iron supplementation had a significantly lower risk of having abnormal findings on neurological examination at 5 years of age [40] . However, there were no significant differences between groups in test scores for motor or cognitive development. Further­more, the fact that the infants in the late iron group re­ceived more blood transfusions during the neonatal pe­riod makes the groups difficult to compare. 

A Cochrane review in 2012 investigated the effects of enteral iron supplementation in preterm and LBW in­fants and found a total of 26 intervention studies. Of the 21 studies comparing iron supplementation with con­trols, none evaluated neurodevelopmental status as an outcome [41]. 

Since the Cochrane review, there has been only one new publication on this topic, providing the best current evidence [42] . This was a follow-up of the randomized controlled trial by Berglund et al. [36] , described above, where 385 marginally LBW infants were randomized to receive 0, 1, or 2 mg/kg/day of iron supplements from 6 weeks to 6 months of age. At 3½ years of age, the infants from the original intervention as well as 95 normal birth weight reference children were assessed with a psycho­metric test (Wechsler Preschool and Primary Scale of Intelligence) and a validated behavioral instrument (the Child Behavior Checklist). There was no difference in cognitive scores between groups, but children in the pla­cebo group had significantly more behavioral problems: 13% compared to 3% in the two iron supplemented groups (p = 0.027) and also compared to 3% in the refer­ence group [42]. 

An interesting result from the follow-up of this inter­vention study was that LBW children who received early iron supplementation (1 or 2 mg/kg/day) had lower sys­tolic blood pressure at 7 years (mean difference 2.2 mm Hg, 95% CI 0.3–3.2) as well as a lower risk of having sys­tolic blood pressure within the hypertensive range (OR 0.32; 95% CI 0.11–0.96) [43]. This suggests that the in­creased risk of hypertension that is observed in children and adults who are born with LBW might at least partly be due to ID and that iron supplementation may reduce this risk. There is a well-known association between ID and pulmonary hypertension in adults and iron has been suggested as a therapy for pul­monary hypertension [44]. A possible mechanism for this blood pressure-lowering ef­fect of iron is an effect on nitric oxide synthesis, which has been observed in a rat model [45]. 

Conclusions 
LBW infants (16% of all newborns globally) are at high risk of ID. Ensuring an adequate iron intake in these in­fants should be a high priority since it will reduce the risk of ID and IDA and may prevent some of the negative health consequences associated with LBW, especially be­havioral problems and other neurodevelopmental out­comes and possibly even hypertension. However, it is also important to avoid excessive iron intakes which have been associated with adverse effects in LBW infants such as an increased risk of infections, impaired zinc and cop­per status, and increased oxidative stress. 

Marginally LBW infants (preterm or term infants with birth weights 2,000–2,500 g) should receive iron supple­ments of 1–2 mg/kg/day, starting at 2 to 6 weeks of age and continuing to 6 months of age [22] . This dose can safely be recommended for both breastfed and formula-fed infants. In malarious regions, iron supplementation should be combined with anti-malaria measures.

The recommended iron intake of LBW infants with a birth weight of 1,500–2,000 g is 2 mg/kg/day [46] from 2 to 4 weeks of life and this can be achieved initially by us­ing iron-containing human milk fortifier or preterm for­mula and later (or initially) using iron supplements which should be continued to 6 months of age or possibly longer depending on infant diet. 

For VLBW infants, the standard recommendation is a daily iron intake of 2–3 mg/kg/day starting at 2 weeks of age [46] . Infants who receive erythropoietin treatment need a higher dose (up to 6 mg/kg/day) during the treat­ment period. However, since individual iron status in VLBW infants is highly variable, depending on the number of received blood transfusions and blood losses from phle­botomy, it is recommended to follow these infants with repeated measurements of serum ferritin during the hospital stay. The normal range of ferritin in preterm infants is 35–300 µg/L (Table 2). If ferritin is <35 µg/L, the iron dose should be increased up to 3–4 (or maximum 6) mg/ kg/day may during a limited period. A prolonged dietary iron intake of >3 mg/kg/day should be avoided in most cases because of possible ad­verse effects. If ferritin is >300 µg/L, which usually is the re­sult of multiple blood transfu­sions, iron supplementation and fortification should be dis­continued until serum ferritin falls below this level. Iron supplements or intake of iron-fortified formula in the rec­ommended doses should be continued also after discharge, at least until 6–12 months of age, depending on diet. He­moglobin and serum ferritin should be checked at follow-up visits. 

Like all infants, LBW infants should receive iron-rich complementary foods from 6 months of age [22] . In ad­dition, delayed umbilical cord clamping, whenever fea­sible, is recommended for all LBW infants. 

These recommendations are based on data from a rel­atively small number of intervention studies and very few of them investigated the effect on neurodevelopment or other long-term outcomes. More randomized controlled trials with a long-term follow-up are needed to firmly es­tablish the specific iron intakes which will lead to the best health outcomes in this vulnerable group of infants.

Disclosure Statement 
The author has no conflicts of interest to report. The writing of this article was supported by Nestlé Nutrition Institute.

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