Early and late Iron supplementation for low birth weight infants: a meta-analysis
© Jin et al.; licensee BioMed Central. 2015
Received: 18 November 2014
Accepted: 18 February 2015
Published: 14 March 2015
Iron deficiency in infancy is associated with a range of clinical and developmentally important issues. Currently, it is unclear what is the optimal timing to administer prophylactic enteral iron supplementation in preterm and very low birth weight infants. The objective of this meta-analysis was to evaluate early compared with late iron supplementation in low birth weight infants.
PubMed and Cochrane Library databases were searched up to May 10, 2014 for studies that compared the benefit of early and late iron supplementation in infants of low birth weight. Sensitivity analysis was carried out using the leave one-out approach and the quality of the included data was assessed.
The data base search and detailed review identified four studies that were included in the meta-analysis. The number of included patients was 246 (n = 121 for early supplementation and n = 125 for late supplementation) and the majority were premature infants. Across studies, early supplementation ranged from as early as enteral feeding was tolerated to 3 weeks, and late supplementation ranged from 4 weeks to about 60 days. Early treatment was associated with significantly smaller decreases in serum ferritin and hemoglobin levels (P < 0.001). In addition, the rate of blood transfusions was lower with early compared with late iron supplementation (P = 0.022). There was no difference between early and late supplementation in the number of patients with nectorizing enteroclitis (>bell stage 2) (P = 0.646). Sensitivity analysis indicated no one study overly influenced the findings and that the data was reliable.
In conclusion, early iron supplementation resulted in less a decrease in serum ferritin and hemoglobin levels in infants with low birth rate. However, caution should be used when treating infants with iron so as not to result in iron overload and possibly negative long-term effects on neurodevelopment.
KeywordsIron Supplementation Low birth weight Infant Meta-analysis
Iron is an essential nutrient and plays a key role in many processes including growth and development. Iron deficiency in infancy is associated with a range of clinical and developmentally important issues including neurodevelopmental deficits, delayed maturation of the auditory brainstem response, and abnormalities of memory and behavior [1,2]. Iron deficiency is estimated to range between 25% and 80% in preterms during infancy [3,4]. Low birth weight infants are particularly susceptible to developing iron deficiency anemia since they typically have small iron stores at birth and a greater need for iron due to the rapid increase in red cell mass [5-7]. Other factors that may impact development of iron deficiency anemia in low birth weight infants are preterm birth, maternal conditions (such as diabetes mellitus, hypertension, smoking, etc.) increased hemolysis, reduced red blood cell life span, low circulating erythropoietin levels, blood sampling, and loss of blood due to surgery [1,3,8].
A number of studies have found that iron supplementation increases the levels of hematologic indicators or iron status and reduces the frequency of anemia or iron deficiency in low birth weight or premature infants [8,9]. One concern with iron supplementation is that free ferrous iron may increase oxidative stress via the production of free radicals . Hence, it is important to prevent not only iron deficiency but also iron overload. Currently, it is unclear at what time to administer prophylactic iron supplementation in preterm very low birth weight infants . In fact, the different international associations recommend different timings for initiation of iron supplementation for these babies . European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition recommends prophylactic enteral iron supplementation (given as a separate iron supplement, in preterm formula or in fortified human milk) should be started at 2 to 6 weeks of age (2–4 weeks in extremely-low-birth weight infants) . The Canadian Pediatric Society suggests for infants with low birth weight (<1000 g) they should receive a total intake of 3–4 mg/kg per day starting at 6–8 weeks after birth . The American Academy of Pediatric recommend that that a preterm infant who is fed milk should receive a supplement of elemental iron at 2 mg/kg per day starting by 1 month of age and extending through 12 months of age . The objective was to gain insight into the importance of timing of iron supplementation by evaluating early compared with late iron supplementation in low birth weight infants.
PubMed and Cochrane Library databases were searched up to May 10, 2014 for studies that compared the benefit of early and late iron supplementation in infants of low birth weight. Search terms included premature birth, preterm birth, premature infant, preterm infant, low birth weight infant, iron supplementation, early, and late. The search also included: (premature birth OR preterm birth OR low birth weight) AND (iron deficiency OR iron supplement OR iron). Included studies were randomized controlled prospective trials whose patient population were low birth weight infants (<2500 g) or premature infants (gestational age <37 weeks). Eligible studies used an intervention that involved iron supplementation (any kind), and had to compare the effect of early and late iron supplementation. Early supplementation was considered between 2–3 weeks postnatal age and late supplementation was defined as >4 weeks postnatal age. Studies were included if they evaluated infants who could tolerate enteral feeding (usually >2 weeks of age). Studies were excluded if they were single arm and did not evaluate serum ferritin and hemoglobin levels. Studies were also excluded if the intervention was combined with erythropoietin treatment, andif they were non-English, case reports, letters, or comments.
The following data was extracted: author’s first name, study design, inclusion criteria, iron source, early or late supplementation, dosing route, number of subjects, gestational age, birth weight, gender, and time of evaluation. Also the level of serum ferritin (ng/mL) and hemoglobin before and after treatment was extracted as was the percent of subjects requiring blood transfusions and necrotizing enterocolitis (>bell stage 2). Two reviewers extracted the studies, and a third reviewer was consulted to resolve any disagreements.
Quality assessment of the included studies was based on Cochrane handbook version 5.1.0 Chapter 8 “Assessing risk of bias in included studies” table for validity assessment of eligible trials .
The changes in serum ferritin and hemoglobin levels, blood transfusion rate, and necrotizing enterocolitis rate were compared between participants who received early supplementation and participants who received late supplementation. For the continuous data, changes in serum ferritin levels and hemoglobin levels, the data were represented as mean ± standard deviation (SD) or mean (range: min, max) for a given group in each study. The effect size was calculated as difference in means of outcomes after iron supplementation between early and late groups with estimated 95% confidence intervals (95% CI) and corresponding P values. For those data with mean (range), the SD was utilized according to the equation SD = Range/4before analysis . The difference in means of outcomes greater than 0 indicated the late group was favored. The difference in means of outcomes lower than 0 indicated the early group was favored. If the means difference was zero than both the early and late groups had similar change in outcomes. For blood transfusion and necrotizing enterocolitis rates, data were represented as events/total participants for a given group in each study.
The effect size was calculated as odd ratio (OR) of outcomes after iron supplementation with estimated 95% CI between early and late groups and corresponding P values. OR >1 indicates late group had higher rate than early group; OR <1 indicates late group had lower rate than early group; OR = 0 indicated both groups had similar rate. A χ2 based test of homogeneity was performed using Cochran’s Q statistic and I2. I2 indicates the percentage of the total variability in effect estimates among trials due to heterogeneity rather than chance. Random-effects model of analysis (DerSimonian–Laird method) was used if heterogeneity was detected (I2 >50% or P-value <0.05). Otherwise, fixed-effects model (Mantel-Haenszel method) was used. For evaluation, a combined difference in mean with 95% CI for continuous outcomes and OR (95% CI) for categorical variables were calculated for the pooled study results. A two-sided P value <.05 was taken to indicate statistical significance for one comparison group over the other. Sensitivity analysis was carried out for the outcomes using the leave-one-out approach. Publication bias was not performed because more than five studies are required to detect funnel plot asymmetry . All analyses were performed using Comprehensive Meta-Analysis statistical software, version 2.0 (Biostat, Englewood, NJ).
Summary of basic characteristics of selected studies
1st AU (year)
Medical iron source
Route ; dose
Number of subject
Gestation age (weeks)
Birth weight (kg)
Evaluated time point
Intramural preterm (<37 weeks gestational age) VLBW infants (birth weight 1000–1500 g) who reached full enteral feeds of 180 mL/kg/day by 2 weeks postnatal age
colloidal ferric hydroxide
PO; 2 mg/kg/day start at 2 weeks postnatal age
32.4 ± 1.7
1.35 ± 0.15
PO; 2 mg/kg/day start at 6 weeks postnatal age
32.4 ± 1.6
1.33 ± 0.14
Preterm VLBW (<1500 g) infants who reached at least 100 mL/kg/day of oral feeds by day 14
PO; 3–4 mg/kg/d at 2 weeks
32.4 ± 1.8
1.189 ± 0.228
PO; no iron until 60 days
31.5 ± 2.6
1.213 ± 0.196
All infants with a gestational age of 32 weeks who were fed human milk and reached enteral intake of 100 mL/kg/d
Iron trivalent (III)– hydroxide polymaltose complex
PO; 5 mg/kg/d enteral iron polymaltose complex at 2 weeks
30 (27, 32)†
1.248 (0.859, 1.960)†
PO; 5 mg/kg/d enteral iron polymaltose complex at 4 weeks
29 (27, 32)†
1.072 (0.830, 2.173)†
All inborn infants with a birth weight of < 1301 g
PO; 2–4 mg/kg/d oral iron once enteral feeding was tolerated
26.7 (23, 33)*
0.868 (0.380, 1.300)*
PO; started at 61 days of life at a dose of 2 mg/kg/day.
26.9 (23, 35)*
0.872 (0.370, 1.300)*
LBW infants with a birth weight ≦2000 g and/or a gestational age of ≦35 weeks
PO; 2–3 mg/kg/day from 3 weeks of age
All: 34 (29–37)*
1.855 ± 0.430
1-2 days; 8–10 weeks; 6 months
PO; 2–3 mg/kg/day from 2 months of age
1.779 ± 0.327
Summary of outcomes of selected studies
Serum ferritin (ng/mL)
1st AU (year)
number of evaluated subject
Blood transfusion (%)
Necrotizing enterocolitis (>bell stage 2)
112 ± 5 at 2 weeks of age
82 ± 5
12.9 ± 0.8 at 2 weeks of age
10.1 ± 0.4
113 ± 6 at 2 weeks of age
63 ± 3
13.1 ± 0.6 at 2 weeks of age
9.2 ± 0.4
55.7 ± 12.1 at enrollment
50.8 ± 11.5
59.0 ± 12.1 at enrollment
45.3 ± 11.9
94 ± 27 at 2 weeks of age
46 ± 20 at 8 weeks of age
12.5 ± 0.9 at 2 weeks of age
9.0 ± 1 at 8 weeks of age
90 ± 21 at 2 weeks of age
30 ± 12 at 8 weeks of age
11.9 ± 1.3 at 2 weeks of age
7.4 ± 0.7 at 8 weeks of age
85.5 (18, 282) *at birth
87.8 (9, 478)*
77.9 (13, 354)*at birth
74.2 (9, 682)*
102 (34–220)*at 1–2 days of age
56 (16–175)* at 8–10 weeks of age 26 (18–45)* at 6 months of age
20.0 ± 2.7 at birth
10.3 ± 1.0 at 8–10 weeks of age; 11.5 ± 0.7 at 6 monthsof age
1-2 days: 100 (45–200)*at 1–2 days of age
72 (21–170)* at 8–10 weeks of age 28 (10–115)* at 6 months of age
19.1 ± 2.9 at birth
9.7 ± 1.0 at 8–10 weeks of age 11.5 ± 0.5
at 6 months of age
1st AU (year)
Random sequence generation
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Did the analysis include an intention-to-treat analysis?
Serum ferritin level
Three studies had complete hemoglobin data and were included in the analysis A fixed effects analysis was applied because there was no evidence of heterogeneity among the studies (Q statistic = 0.817, I2 = 0%, P = .665). Similar to ferritin levels, the summarized difference in means of change of hemoglobin levels after iron supplementation favored the early iron supplementation group (difference in means = −1.07, 95% CI = −1.29 to −0.85, P < .001) (Figure 2B). The decrease in hemoglobin levels was smaller in the early compared with the late iron supplementation group.
Three studies were included in the analysis since they had complete data for the frequency of blood transfusions. A fixed effects analysis was used because there was no evidence of heterogeneity among the studies (Q statistic = 1.625, I2 = 0%, P = .444). The summarized OR = 0.287 with a 95% CI = 0.099 to 0.834 indicating that early iron supplementation lowered the frequency of blood transfusion rate compared with late supplementation (P = .022) (Figure 2C).
Necrotizing enterocolitis (> bell stage 2)
Three studies that had complete necrotizing enterocolitis data were included in the analysis. A fixed effects analysis was applied as there was no evidence of heterogeneity among the studies (Q statistic = 1.242, I2 = 0%, P = .537). The summarized OR = 0.755 with a 95% CI = 0.227 to 2.506 indicated there was no difference between early and late supplementation in the frequency of necrotizing enterocolitis(P = .646) (Figure 2D).
Our analysis investigated the relative benefit of early versus late iron supplementation in low birth weight infants including premature infants. Early treatment was associated with significantly smaller decreases in serum ferritin and hemoglobin levels (P <.001). In addition, the rate of blood transfusions was lower with early compared with late iron supplementation (P = .022). There was no difference between early and late supplementation in the number of patients with nectorizing enteroclitis (P = .646). Sensitivity analysis indicated no one study overly influenced the findings and that the data was reliable.
Our study is consistent with findings that suggest early compared with later iron supplementation may benefit infants with low birth weights. The study of Lundstrom et al.  found that in low birth weight infants (1,000 to 2,000 gm) (N = 117) that those infants who did not receive iron supplementation (2 mg of iron/kg/day starting at 2 weeks of age) had a higher tendency (about 80% of infants by 6 months) to develop iron deficiency compared to those infants who did receive iron supplementation (about 5-10% by 6 months) . Hall et al.  performed a randomized controlled study that compared iron nutritional status in premature infants with birth weight <1800 g (N = 20) who received iron (1.7 mg/L, 3 mg/L or 15 mg/L) added to premature formula that was fed to the infants during initial hospitalization. They found that the higher iron supplementation (3 mg/L and 15 mg/L) added at this early timepoint resulted in a reduced frequency of anemia and low transferrin saturation compared with the infants who were given the 1.7 mg/L iron supplementation . A study by Miller at al.  found that there was no difference in conventional measures of iron status in preterm babies (24–32 weeks of gestation) who either did or did not receive iron supplementation (3–12 mg/kg/day) when the supplementation occurred relatively late (ie, 7- to 60-days after birth).
Iron deficiency in infancy is associated with growth and neurodevelopmental deficits. Steinmacher et al.  in a follow-up study of a prior randomized trial examined whether early compared with late iron supplementation improved neurocognitive and motor development in preterm infants (<1301 gm) . The original study found that early enteral iron supplementation (as early at enteral feeding was possible) compared with late supplementation (Day 61 of life) reduced the frequency of blood transfusions and the incidence of iron deficiency in low birth weight infants . In the follow-up study, they used the Kaufmann Assessment Battery for Children and the Gross Motor Function Classification Scale to evaluate neurocognitive and psychomotor development in children at 5.3 years’ corrected age who had been treated with early or late iron supplementation in the original study. The Kaufman Assessment Battery for Children is a standardized test that assesses intelligence and achievement in children aged two years, six months to 12 years, six months. The Gross Motor Function Classification Scale is a scale from 0 to 5 that classifies the severity of motor involvement of children on the basis of their functional abilities and their need for assistive technology. Steinmacher et al. found that early enteral iron supplementation compared with late supplementation was associated with a trend for better long-term neurocognitive and psychomotor development; about 19% of the early and 35% of the late supplementation group had abnormal neurological development and approximately 66% and 54%, respectively, were without disability. Gross Motor Function Classification Scale score >1 was found in 2% of patients for the early and 7% of patients in the late iron supplementation group. A limitation of the study was that the original study was not powered to evaluate neurocognitive development.
Two other studies also evaluated the use of iron supplementation in low birth weight infants on cognitive and neurodevelopment outcomes [25,26]. Friel et al.  investigated the effect of increased iron intake on hematologic and cognitive status in infants with low birth rate (N = 58). They evaluated two levels of iron supplementation: 13.4 mg iron/L and 20.7 mg iron/L. They found that hemoglobin and Griffith’s Developmental Assessment were not different between treatment groups (P values <.05). They did find that the number of respiratory tract infections was higher in the high compared with low iron groups, possibly indicating a detriment for administering high levels of iron. These findings suggest there is no advantage to administering elevated iron to infants with low birth weights.
Ohls et al.  assessed the effect of supplementing erythropoietin and iron compared with iron alone on long-term developmental outcomes in extremely low birth weight infants (≤1000-gm birth weight) (N = 172). Approximately 5 mg/kg of iron was included in both treatment groups. The study evaluated the need for transfusions, anthropometric measurements, post-discharge events, and developmental outcomes at 18 to 22 months’ corrected age. They found no significant difference in weight, length, or head circumferance between the erythropoietin plus iron compared with iron alone groups. There was also no difference between groups in rate or rehospitalization, transfusions after discharge, the percentage of patients with Bayley-II Mental Developmental Index <70 (34% for erythropoietin plus iron and 36% for iron alone) or other neurodevelopmental and cognitive functions. The authors conclude that early treatment with erythropoietin plus iron was not of greater developmental benefit than iron alone.
Our meta-analysis only included four studies and the studies were heterogenous with respect to dosage and timing of iron supplementation. For example, the definition of “early” and “late” supplementation varied across studies. Heterogeneity in studies investigating the effect of iron supplementation in low birth infants has been noted before  and indicates the need for more consistent designs among studies that investigate this issue. In addition, the iron sources used across the studies differed and had different oral absorption and gastrointestinal tolerance , which may have confounded our findings. We also did not evaluate the effect of early versus late iron supplementation on neurodevelopment, cognitive function, or growth. Further studies are required to address these important medical questions. Our findings showed that the early group had a better iron status than late group, which suggest that the prevalence of iron deficiency and iron deficiency anemia may be lower in early supplement group. However, only one included study  evaluated iron deficiency, hence, we were not able to analyze this directly. In addition, we did not assess how dose and a more precise evaluation of timing affected the results. This was not possible as the doses across the studies overlapped and the timing was variables. Moreover, only five studies were included in the analysis making it not practical to do subgroup analysis.
In conclusion, early iron supplementation improved serum ferritin and hemoglobin levels in infants with low birth rate. However, caution should be used when treating infants with iron so as not to result in iron overload and possibly negative long-term effects on neurodevelopment .
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