Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Enteral iron supplementation in preterm and low birth weight infants

Enteral iron supplementation in preterm and low birth weight infants

Skip sharing on social media links
Share this:

Authors

Ryan John Mills1, Mark W Davies2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Paediatrics, Logan Hospital and University of Queensland, Loganholme DC, Australia [top]
2Grantley Stable Neonatal Unit, Royal Brisbane and Women's Hospital, Department of Paediatrics & Child Health, The University of Queensland, Brisbane, Australia [top]

Citation example: Mills RJ, Davies MW. Enteral iron supplementation in preterm and low birth weight infants. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD005095. DOI: 10.1002/14651858.CD005095.pub2.

Contact person

Ryan John Mills

Department of Paediatrics
Logan Hospital and University of Queensland
P.O. Box 4096
Loganholme DC
Queensland
4129
Australia

E-mail: Ryan_Mills@health.qld.gov.au

Dates

Assessed as Up-to-date: 12 August 2011
Date of Search: 12 August 2011
Next Stage Expected: 12 August 2013
Protocol First Published: Issue 1, 2005
Review First Published: Issue 3, 2012
Last Citation Issue: Issue 3, 2012

What's new

Date / Event Description
17 April 2012
Amended

Table 1 'Summary of results by study' linked to text.

History

Date / Event Description
04 February 2010
Amended

Converted to new review format

04 December 2007
New citation: conclusions changed

Substantive amendment

Abstract

Background

Preterm infants are at risk of exhausting their body iron stores much earlier than healthy term newborns. It is widespread practice to give enteral iron supplementation to preterm and low birth weight infants to prevent iron deficiency anaemia. However, it is unclear whether supplementing preterm and low birth weight infants with iron improves growth and neurodevelopment. It is suspected that excess exogenous iron can contribute to oxidative injury in preterm babies, causing or exacerbating conditions such as necrotising enterocolitis and retinopathy of prematurity. Additionally, the optimal dose and timing of commencement and cessation of iron supplementation are uncertain.

Objectives

To evaluate the effect of prophylactic enteral iron supplementation on growth and neurodevelopmental outcomes in preterm and low birth weight infants. The secondary objectives were to determine whether iron supplementation results in improved haematological parameters and prevents other causes of morbidity and mortality.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group. We searched Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8), MEDLINE (1951 to August 2011), CINAHL (1982 to August 2011) and conference proceedings and previous reviews.

Selection criteria

Randomised controlled trials (RCTs) and quasi-randomised trials that compared enteral iron supplementation with no iron supplementation, or different regimens of enteral iron supplementation in preterm or low birth weight infants or both.

Data collection and analysis

We extracted data using the standard methods of the Cochrane Neonatal Review Group. Both review authors separately evaluated trial quality and data extraction. We synthesised data using risk ratios (RRs), risk differences (RDs) and weighted mean differences (WMDs). Where data about the methodology and results or both were lacking, we made an attempt to contact the study authors for further information.

Results

We included twenty-six studies (2726 infants) in the analysis. The heterogeneity of participants, methods and results precluded an extensive quantitative synthesis. Of the 21 studies comparing iron supplementation with controls, none evaluated neurodevelopmental status as an outcome. Of thirteen studies reporting at least one growth parameter as an outcome, only one study of poor quality found a significant benefit of iron supplementation. Regarding haematological outcomes, no benefit for iron supplementation was demonstrated within the first 8.5 weeks of postnatal life (16 trials), except by two poor quality studies. After this age, most studies reported a higher mean haemoglobin in iron-supplemented infants. We were only able to include a limited number of studies in a quantitative meta-analysis, which suggested the haemoglobin concentration in iron-supplemented infants was higher by about 6 g/L at six to nine months. One study comparing high dose and low dose iron supplementation monitored neurodevelopmental outcome for one year, without finding any significant difference between the groups. One study comparing early versus late commencement of iron supplementation found no difference in cognitive outcome, but an increased rate of abnormal neurological examination in the late iron group at five years of age. The studies comparing high and low doses of iron indicated that there was no discernible haematological benefit in exceeding 'standard' doses of iron (i.e. 2 mg/kg/day to 3 mg/kg/day).

Authors' conclusions

The available data suggest that infants who receive iron supplementation have a slightly higher haemoglobin level, improved iron stores and a lower risk of developing iron deficiency anaemia when compared with those who are unsupplemented. However, it is unclear whether iron supplementation in preterm and low birth weight infants has long term benefits in terms of neurodevelopmental outcome and growth. The optimum timing and duration of iron supplementation remains unclear.

Plain language summary

Enteral iron supplementation in preterm and low birth weight infants

This review examined whether providing iron supplementation is beneficial for preterm and low birth weight infants. The potential benefits included improvements in the level of red blood cells and stored iron in their blood. In the longer term, it was thought that iron supplementation might improve the babies' growth and development. We identified 25 randomised controlled trials (RCTs) which were relevant to this topic. We concluded that the long term benefits of iron supplementation for preterm and low birth weight babies remain uncertain. Regarding red blood cell and iron levels, it was found that in the first year of life, after two months of age, iron supplementation may result in slightly higher iron stores and red blood cell levels, and lower rates of iron deficiency anaemia. However, there was a lot of variability between different studies. More RCTs are needed, using well defined patient groups.

[top]

Background

Description of the condition

Most of the healthy term newborn's iron stores have been laid down during the third trimester. Therefore, this important acquisition of iron stores is reduced in preterm infants. The preterm infant has a higher requirement for iron due to proportionally more rapid postnatal growth than that of the term infant. This exacerbates the total body iron deficit of the preterm infant, as iron stores decrease over the first three months of postnatal life. While non-iron supplemented term infants have not been shown to develop biochemical or haematological iron deficiency before six months of age, there is a high rate of iron deficiency anaemia before this age in preterm infants fed only breast milk (Doyle 1992).

Human milk contains about 0.5 mg/L of elemental iron, while iron fortified formulas contain at least ten times that amount of iron. Despite their limited erythropoiesis, breast fed preterm infants are in negative iron balance for at least the first 30 days after birth, due to obligatory intestinal and insensible skin loss of iron (Shaw 1982).

For these reasons, the American Academy of Pediatrics (AAP) recommends supplementation of preterm neonates with 2 mg/kg/day of enteral iron, either as an iron mixture, or in the form of iron-fortified formula. It is recommended that this supplementation commence within two months of birth, and be continued until 12 months of age (Baker 2010).

Description of the intervention

Several studies have demonstrated higher haemoglobin or ferritin levels in low or very low birth weight infants who were supplemented with enteral iron compared with breast milk or unfortified cow milk formula (Hall 1993; Lundstrom 1977). However, the evidence is unclear as to whether this improvement in biochemical and haematological parameters is associated with a difference in neurodevelopmental outcomes or growth parameters in preterm and low birth weight infants.

How the intervention might work

Studies in term infants have demonstrated a correlation between iron deficiency anaemia and reduced performance in developmental testing (Lozoff 1987; Walter 1989). It is hypothesised that the provision of enteral iron supplementation to preterm and low birth weight infants, who are at particular risk of iron deficiency, will result in improved neurodevelopmental outcomes by avoiding iron deficiency.

Why it is important to do this review

The potential risks of iron supplementation need to be considered. Iron overload can occur in the setting of multiple blood transfusions (Ng 2001). High transfusion requirements early in life have been shown to be associated with a greater risk of retinopathy of prematurity (Dani 2001; Hesse 1997; Inder 1997). Increased body iron load has also been hypothesised to increase the risk of chronic lung disease (Cooke 1997). Putative risks have been suggested related to iron's ability to cause oxidative injury. In addition to the direct oxidative property of iron, large iron doses decrease the absorption of the anti-oxidant vitamin E, thus exacerbating anaemia in vitamin E deficient neonates (Doyle 1992).

Iron fortification of formulas has been suspected, but not proven, to cause a range of gastrointestinal symptoms in infants (Hyams 1995). While necrotising enterocolitis (NEC) has not been explicitly linked to enteral iron supplementation, it is recognised that human milk is protective against NEC (McGuire 2003).

If enteral iron supplementation is accepted as being a beneficial intervention, the optimum dose, time of initiation and duration of treatment need to be defined.

Objectives

The primary objective of this systematic review was to evaluate the effect of prophylactic enteral iron supplementation on growth and neurodevelopmental outcomes of preterm and low birth weight infants. The secondary objectives were to determine whether iron supplementation results in improved haematological parameters and prevents other causes of morbidity and mortality.

We planned separate comparisons of:

  1. trials that compared enteral iron supplementation versus no supplementation; and
  2. trials that compared different regimens of enteral iron supplementation (dose, duration and timing of initiation).

Data permitting, the following subgroup analyses were planned.

  1. Type of milk feeding: trials involving exclusively formula-fed infants and those involving exclusively or partially breast fed infants.
  2. Postnatal age of commencement of iron supplementation: 'early commencement' (less than 28 days postnatal) and 'late commencement' (28 days or more postnatal).
  3. Daily dose of supplemental iron administered: 'low dose' (2 mg/kg/day or less) and 'high dose' (more than 2 mg/kg/day).
  4. Duration of iron supplementation: 'short duration' (six months or less) and 'long duration' (more than six months).
  5. Gestational age and birth weight of participants, or both: less than or equal to 33 completed weeks' or less than 1500 g and more than 33 completed weeks' or 1500 g or more.

[top]

Methods

Criteria for considering studies for this review

Types of studies

RCTs and some non-RCTs (quasi-randomised) in which individual infants were either:

  1. allocated to receive enteral iron supplementation (of at least 1 mg/kg/day), and compared with a control group (placebo or no drug or < 1 mg/kg/day of iron); or
  2. allocated to different regimens of enteral iron supplementation (in regard to dosage, duration and timing of initiation).

We excluded cross-over studies.

Types of participants

Infants born preterm (before 37 weeks' completed gestation), or of low birth weight (< 2500 g).

Types of interventions

  1. Enteral iron supplement of at least 1 mg/kg/day versus no supplementation (i.e. < 1 mg/kg/day).
  2. Comparison of different regimens of enteral iron supplementation, in regard to the dose, duration, and timing of initiation of iron supplementation.

We specifically excluded studies in which the subject infants were receiving concurrent treatment with erythropoietin.

Types of outcome measures

Primary outcomes
  1. Standardised measures of neurodevelopmental outcome (e.g. Bayley MDI and PDI), at 12 months or less, two years or less and five years or less.
  2. Length, weight and head circumference at 12 months or less, two years or less and five years or less.
Secondary outcomes
  1. Blood haemoglobin concentration and mean corpuscular volume (MCV), at six to eight weeks, three to four months, six to nine months and 12 months.
  2. Serum ferritin concentration, transferrin saturation and total iron binding capacity (TIBC), at six to eight weeks, three to four months, six to nine months and 12 months.
  3. Severe anaemia (haemoglobin level < 8 g/dL or hematocrit < 0.25).
  4. Mortality (during primary hospitalisation and before two years of life).
  5. Chronic lung disease (persisting oxygen requirement at 36 weeks postmenstrual age).
  6. Retinopathy of prematurity (Stage 3 and above, and all stages).
  7. NEC (Bell's stage 2 or above).
  8. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, urine or from a normally sterile body space.
  9. Feed intolerance defined as a requirement to cease enteral feeds and commence parenteral nutrition.
  10. Total duration of primary hospitalisation.
  11. Requirement for readmission to hospital in the first year of life.

Search methods for identification of studies

Electronic searches

We used the standard search method of the Cochrane Neonatal Review Group.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8 ), 'Old Medline' (1951 to 1965), MEDLINE (1966 to August 2011), CINAHL (1982 to August 2011) and the Oxford Database of Perinatal Trials. We used the following search strategy.

MeSH search terms 'Iron/tu [Therapeutic use]', 'Iron/ad [Administration and dosage]', 'Iron, Dietary', 'Ferrous compounds/tu [Therapeutic use]', or text words 'ferrous sulphate', 'ferrous sulfate', 'ferrous gluconate'
AND
MeSH search term 'infant', or text words 'preterm', 'premature', 'low birth weight'

We also searched clinical trials registries for ongoing or recently completed trials (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Searching other resources

In addition, we included previous reviews (including cross references), abstracts, conference and symposia proceedings published in Pediatric research. We did not restrict searches by language of publication. We contacted lead investigators of included studies, where possible, to clarify methods and results and identify other published or unpublished studies which fulfil the inclusion criteria.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

Selection of studies

We screened the title and abstract of all studies identified by the above search strategy. We obtained the full articles for all potentially relevant trials. We re-assessed the full text of any potentially eligible reports and excluded those studies that did not meet all of the inclusion criteria. We resolved any disagreements by consensus.

Data extraction and management

We used a data collection form to aid extraction of relevant information from each included study. Both review authors extracted the data separately. We discussed any disagreements until consensus was achieved. We contacted the trialists for further information if data from the trial reports were insufficient.

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Review Group to independently assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents or caregivers and assessors to intervention, and completeness of assessment in all randomised individuals. We requested additional information from the trial authors to clarify methodology and results as necessary.

We included this information in the Characteristics of Included Studies and Risk of Bias tables. We used the following criteria to complete the Risk of Bias table:

  1. Random sequence generation (checking for possible selection bias). For each included study, we categorised the method used to generate the allocation sequence as:
    1. low risk (any truly random process e.g. random number table; computer random number generator);
    2. high risk (any non-random process e.g. odd or even date of birth; hospital or clinic record number); or
    3. unclear risk of bias.
  2. Allocation concealment (checking for possible selection bias). For each included study, we categorised the method used to conceal the allocation sequence as:
    1. low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    2. high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or
    3. unclear risk of bias.
  3. Blinding (checking for possible performance bias). For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes. We categorised the methods as:
    1. low risk, high risk or unclear risk for participants;
    2. low risk, high risk or unclear risk for personnel; and
    3. low risk, high risk or unclear risk for outcome assessors.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts or protocol deviations). For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised the methods as:
    1. low risk (< 20% missing data);
    2. high risk (greater than/or equal to 20% missing data); or
    3. unclear risk of bias.
  5. Selective reporting bias. For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:
    1. low risk (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
    2. high risk (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcome(s) were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; and the study fails to include results of a key outcome that would have been expected to have been reported); or
    3. unclear risk of bias.
  6. Other sources of bias. For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at a:
    1. low risk;
    2. high risk; or
    3. unclear risk of bias.

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

We used the standard methods of the Cochrane Neonatal Review Group. We performed statistical analyses using Review Manager software (RevMan 2011). We analysed continuous data using weighted mean difference (WMD). Where appropriate data were available, we analysed categorical data using risk ratio (RR), risk difference (RD) and the number needed to benefit or harm (NNTB/NNTH). We reported the 95% Confidence interval (CI) on all estimates.

Unit of analysis issues

Where studies presented data in non-SI units, we performed conversion to SI units (International System of Units) when extracting the data. Overall, difference in units of analysis was not a significant obstacle in this review.

Dealing with missing data

Where studies published data with insufficient detail to permit their inclusion in quantitative meta-analysis, we contacted the authors to provide additional detail. If no further detail was received, the studies remained eligible for inclusion in the review, but were not included in the pooled quantitative analysis.

Assessment of heterogeneity

If meta-analysis was possible, we examined the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We assessed the impact of heterogeneity in the meta-analysis using a measure of the degree of inconsistency in the studies' results (I2 statistic). If we found statistical heterogeneity, we explored the possible causes (for example, differences in study quality, participants, intervention regimens or outcome assessments) using post hoc subgroup analyses. We used a fixed-effect model for meta-analyses.

Assessment of reporting biases

Where possible, we asked the authors of the included studies to notify us of relevant unpublished data. This would permit an assessment of the likelihood of reporting biases.

Data synthesis

The meta-analysis was performed using Review Manager software (RevMan 2011), supplied by the Cochrane Collaboration. For estimates of typical RR and RD, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. We used the fixed-effect model for all meta-analyses.

Subgroup analysis and investigation of heterogeneity

We planned separate comparisons of:

  1. trials that compared iron supplementation versus no supplementation; and
  2. trials that compared different regimens of iron supplementation (dose, duration and timing of initiation).

Data permitting, we had planned to conduct the following subgroup analyses.

  1. Type of milk feeding: trials involving exclusively formula-fed infants and those involving exclusively or partially breast-fed infants.
  2. Postnatal age of commencement of iron supplementation: 'early commencement' (less than 28 days postnatal) and 'late commencement' (28 days or more postnatal).
  3. Daily dose of supplemental iron administered: 'low dose' (2 mg/kg/day or less) and 'high dose' (more than 2 mg/kg/day).
  4. Duration of iron supplementation: 'short duration' (six months or less) and 'long duration' (more than six months).
  5. Gestational age and birth weight of participants, or both: less than or equal to 33 completed weeks' or less than 1500 g and more than 33 completed weeks' or 1500 g or more.

[top]

Results

Description of studies

Results of the search

We identified 64 studies for detailed assessment.

Included studies

We included twenty-six trials (see table Characteristics of Included Studies). Twenty-one trials compared enteral iron supplementation with no supplement or minimal supplementation (less than 1 mg/kg/day). Four trials specifically compared early versus late commencement of iron supplementation (Arnon 2009; Halliday 1983; Jansson 1979; Steinmacher 2007); Arnon 2009 also tested iron versus no or minimal iron. Three studies compared high dose iron supplementation with "standard" dose iron supplementation (Barclay 1991, which also tested iron versus no or minimal iron; Friel 2001; Groh-Wargo 1990). In addition to comparing with placebo, Berglund 2010 compared a low dose (2 mg/kg/day) with a very low dose (1 mg/kg/day). None of the trials compared the effect of longer duration iron supplementation with shorter duration.

Twelve of the trials were conducted in North America (Berseth 2004; Diamond 1958; Friel 2001; Gorten 1964; Groh-Wargo 1990; Gross 1985; Hall 1993; Melhorn 1971; Melnick 1988; Quilligan 1954; Reedy 1952; Rudolph 1981) and the remainder in a variety of countries including the United Kingdom (Barclay 1991; Coles 1954; Griffin 1999; Halliday 1983), Germany (Franz 2000; Steinmacher 2007), India (Aggarwal 2005; Sankar 2009), Finland (Hanninen 1961; Lundstrom 1977), Sweden (Berglund 2010; Jansson 1979), Brazil (Ferlin 1998) and Israel (Arnon 2009). The span of publication dates was wide, from 1952 to 2010. The spread of dates was very even, with four from the 1950s, two from the 1960s, three from the 1970s, four from the 1980s, five from the 1990s and eight from 2000 onwards.

Participants

A total of 2726 infants were enrolled in the 26 trials. Some 21 trials involved only preterm infants (Arnon 2009; Berseth 2004; Coles 1954; Diamond 1958; Ferlin 1998; Franz 2000; Gorten 1964; Griffin 1999; Gross 1985; Halliday 1983; Hall 1993; Hanninen 1961; Jansson 1979; Lundstrom 1977; Melhorn 1971; Melnick 1988; Quilligan 1954; Reedy 1952; Rudolph 1981; Sankar 2009; Steinmacher 2007). Another study (Groh-Wargo 1990) only specified a birth weight cut-off (< 1500 g), but most of the infants included were likely to have been premature. Three other studies (Barclay 1991; Berglund 2010; Friel 2001) specifically studied low birth weight (< 2500 g) infants of any gestation. A number of the older trials simply recorded their subject infants as 'premature' without specifying the gestation or birth weight cut-off (Coles 1954; Diamond 1958; Quilligan 1954; Reedy 1952). One trial exclusively enrolled term, low birth weight infants (Aggarwal 2005).

In five trials participating infants were exclusively formula fed (Gorten 1964; Griffin 1999; Hall 1993; Melhorn 1971; Rudolph 1981). In four studies, the feeding method was not stated (Diamond 1958; Hanninen 1961; Melnick 1988; Quilligan 1954). In the remainder, the infants were either fully breast milk fed, or given a combination of breast milk and formula.

Interventions

Most of the studies assessed the effect of iron supplementation (generally between 2 mg/kg/day and 4 mg/kg/day of elemental iron) versus placebo or no supplement. A number of the trials undertaken before the mid-1960s prescribed much higher doses of iron: Coles 1954, Diamond 1958, Hanninen 1961 and Quilligan 1954 all used more than 10 mg/kg/day, and in one trial up to 44 mg/kg/day (Coles 1954). Iron supplementation was usually commenced between four and six weeks postnatally, although the time of commencement was often defined by the establishment of enteral feeding, such that the target or mean postnatal age of commencement was not published. Four trials compared earlier (from about two to three postnatal weeks) versus later (about eight weeks) introduction of iron supplements (Arnon 2009; Halliday 1983; Jansson 1979; Steinmacher 2007). Three trials compared "high" doses versus "standard" doses of iron supplementation but there was variation in the definition of dose. Specifically, Friel 2001 compared 3.4 mg/kg/day versus 2.1 mg/kg/day; Groh-Wargo 1990 compared 4 mg/kg/day versus 2 mg/kg/day; and Barclay 1991 compared 7.1 mg/kg/day of iron versus 3.6 mg/kg/day. Berglund 2010 compared a low dose (2 mg/kg/day) with a very low dose (1 mg/kg/day).

For the purpose of comparison between trials, we converted all doses of iron into a dose per kilogram body weight per day. The body weight used for this calculation was the published mean birth weight. If a mean birth weight was not provided, we made an estimate based on the reported weights and gestational ages or both, of the infants in the study. For studies of iron fortified infant formulas, we often had to make an estimate of the daily intake of formula; we applied the estimate of 160 ml/kg/day to all the relevant studies.

Outcomes

Only two of the trials assessed neurodevelopmental outcomes (Friel 2001; Steinmacher 2007). Eight reported anthropometric data, usually weight gain, as an outcome measure (Aggarwal 2005; Barclay 1991; Berglund 2010; Berseth 2004; Ferlin 1998; Hall 1993; Quilligan 1954; Reedy 1952). Most trials reported only short term (up to four to six months corrected age) haematological parameters as the primary outcomes. None of the trials reported neonatal mortality, and quantitative measures of other neonatal morbidities were not reported by most studies.

Excluded studies

We excluded thirty-six studies because they were not randomised or quasi-randomised trials, or because the study population was inappropriate (see table, Characteristics of excluded studies). Two studies are awaiting foreign language translation (Hurgoiu 1986; Neimann 1957).

Risk of bias in included studies

Overall, the methodological quality of the studies identified as qualifying for inclusion was fair to poor (see table, Characteristics of Included Studies). This is partly due to the age of many of the studies. However, several more recent studies continued to use less rigorous methodologies, such as quasi-randomisation.

Allocation (selection bias)

Of the 26 included studies, only eight are known to have an adequate method of allocation concealment (Aggarwal 2005; Berseth 2004; Friel 2001; Gorten 1964; Griffin 1999; Halliday 1983; Rudolph 1981; Sankar 2009), and in most of these studies we only ascertained the adequacy of allocation concealment by direct communication with the authors. Six of the studies were quasi-randomised (Diamond 1958; Ferlin 1998; Hanninen 1961; Lundstrom 1977; Quilligan 1954; Reedy 1952). In three cases, the authors admitted to a lack of blinding of the allocation process (Franz 2000; Melnick 1988; Steinmacher 2007). In the remaining studies, a method of allocation concealment is not described.

Blinding (performance bias and detection bias)

Most of the studies used placebo controls, or at least were comparing two formulas or preparations to which the participants and study personnel were blind. Blinding of the outcome assessors is vitally important for the primary outcomes of this review, namely neurodevelopmental outcome and growth parameters. For the secondary outcomes such as haematological parameters, a natural blinding is likely to have been inherent in the laboratory basis of the tests, even in studies for which we have not been able to confirm blinding of outcome assessment with the authors. Overall, this review did not detect any significant likelihood of systematic bias related to blinding in the included studies.

Incomplete outcome data (attrition bias)

Loss to follow-up, usually due to failure to attend appointments, or due to illness, was a significant problem for many of the included studies. Of the 26 included studies, only eight had documented completion rates of 80% or more (Arnon 2009; Barclay 1991; Berglund 2010; Griffin 1999; Gross 1985; Jansson 1979; Sankar 2009; Steinmacher 2007). Documentation of the recruitment rate of eligible subjects was lacking from all the included studies except Arnon 2009 and Sankar 2009. A number of studies implied complete follow-up without explicitly stating the number enrolled (Ferlin 1998; Groh-Wargo 1990; Halliday 1983; Melnick 1988). While the follow-up was suboptimal in most studies, this review did not detect any significant likelihood of systematic bias in attrition in the included studies.

Selective reporting (reporting bias)

If any unpublished data had been received, we would have made an assessment as to the existence of reporting bias in this topic. As we did not receive any unpublished data, there is currently no evidence of reporting biases.

Effects of interventions

Comparison 1: Enteral iron supplementation versus no iron supplementation
Primary outcomes
  • Neurodevelopmental outcome

None of the trials reported the neurodevelopmental outcome of the participants.

  • Growth

Thirteen trials reported at least one of the growth parameters (weight, length or head circumference) as an outcome, but often without providing the numerical data. The duration of follow-up varied from just six weeks postnatal age (Berseth 2004; Melnick 1988), up to 18 months (Gorten 1964). Most trials only monitored growth outcomes until about two months postnatal age. Twelve studies did not find a statistically significant difference in weight gain between the groups (Aggarwal 2005; Barclay 1991; Berglund 2010; Berseth 2004; Coles 1954; Ferlin 1998; Gorten 1964; Hall 1993; Melhorn 1971; Melnick 1988; Quilligan 1954; Sankar 2009). None of the six trials that assessed linear and head growth found a significant difference between the groups (Aggarwal 2005; Barclay 1991; Berseth 2004; Ferlin 1998; Gorten 1964; Hall 1993).

One study found a difference in weight gain between the iron-treated group and the untreated group. Reedy 1952 reported that the treated infants with birth weight 1000 g to 1500 g had a greater weight gain than the controls at 12 months (mean difference (MD) 1.4 kg; no significance measure was provided). A smaller trend in the same direction was seen in the 1500 g to 2000 g group (MD 794 g; no significance statistic), and the 2000 g to 2250 g group (MD 1.4 kg; no significance statistic). The data from Reedy 1952 is severely limited by the small sample analysed at 12 months (four treated and two untreated patients). We could not conduct a meta-analysis of the growth outcomes due to a lack of appropriately detailed numerical data (i.e. to enable calculation of means and standard deviations (SDs)).

Secondary outcomes
  • Blood haemoglobin concentration and mean corpuscular volume (MCV)

Six to eight weeks: a total of 16 trials reported haemoglobin with or without MCV at approximately six to eight weeks postnatal (Barclay 1991; Coles 1954; Diamond 1958; Ferlin 1998; Franz 2000; Gorten 1964; Griffin 1999; Hall 1993; Halliday 1983; Lundstrom 1977; Melhorn 1971; Melnick 1988; Quilligan 1954; Reedy 1952; Rudolph 1981; Sankar 2009). Only Quilligan 1954 and Gorten 1964 reported a significant benefit for the iron supplementation group. Melhorn 1971 found a lower haemoglobin in the iron supplementation group which was maximal at six weeks (MD 6 g/L in 1000 g to 1500 g birth weight; MD 7 g/L in 1501 g to 2000 g birth weight; P < 0.01 for both). This apparent effect of iron was ameliorated by supplementation with vitamin E.

Only nine trials (n = 526) had data which were able to be pooled for meta-analysis (Barclay 1991; Ferlin 1998; Gorten 1964; Griffin 1999; Hall 1993; Melhorn 1971; Quilligan 1954; Rudolph 1981; Sankar 2009). On meta-analysis, there was no statistically significant difference in haemoglobin concentration: (WMD 1.4 g/L; 95% CI -0.2 to 3.1) (Outcome 1.4). The lack of a statistically significant difference in haemoglobin concentration at six to eight weeks remained in subgroup meta-analyses of trials of formula-fed infants (n = 389) (WMD 0.7 g/L; 95% CI -1.1 to 2.6). In trials of partially or fully breast fed babies (n = 137) a statistically significant difference in favour of iron supplementation was noted: (WMD 4.1 g/L; 95% CI 0.6 to 7.7). However, there was statistical heterogeneity in all meta-analyses, most likely due to differences in the participants between the trials. For example, Barclay 1991 included term and preterm infants, while the other studies only included preterm infants.

Three to four months: a total of 11 trials reported haemoglobin with or without MCV at approximately three to four months postnatal (Aggarwal 2005; Barclay 1991; Coles 1954; Diamond 1958; Gorten 1964; Griffin 1999; Hall 1993; Halliday 1983; Hanninen 1961; Lundstrom 1977; Reedy 1952). Four trials reported that iron supplementation resulted in a statistically significant higher haemoglobin concentration (Aggarwal 2005; Coles 1954; Hanninen 1961; Lundstrom 1977). Data from five trials were able to be pooled (Aggarwal 2005; Barclay 1991; Gorten 1964; Griffin 1999; Hall 1993). Meta-analysis found a borderline statistically significant difference in haemoglobin concentration (WMD 2.5 g/L; 95% CI -0.04 to 4.95) (Outcome 1.5). There were no statistically significant differences in subgroup meta-analyses of trials in formula-fed (WMD 2.4 g/L; 95% CI -0.42 to 5.2) or breast fed infants (WMD 2.7 g/L; 95% CI -2.7 to 8.1). There was statistical heterogeneity in all meta-analyses.

Six to nine months: a total of nine trials reported haemoglobin with or without MCV at approximately six to nine months postnatal (Berglund 2010; Coles 1954; Diamond 1958; Gorten 1964; Griffin 1999; Halliday 1983; Hanninen 1961; Lundstrom 1977; Reedy 1952). Six trials (Berglund 2010; Coles 1954; Gorten 1964; Hanninen 1961; Lundstrom 1977; Reedy 1952) reported a higher haemoglobin in the iron supplementation group at six months; Diamond 1958, Griffin 1999 and Halliday 1983 found no statistically significant difference. Gorten 1964 and Griffin 1999 had data available to pool. Both these studies were of formula-fed babies. Meta-analysis showed a statistically significantly higher haemoglobin concentration in the iron supplemented group (WMD 6.6 g/L; 95% CI 3.1 to 10.1) (Outcome 1.6.1), but with significant heterogeneity between the trial estimates of effect. Berglund 2010 was a good quality study that found higher haemoglobin when compared to placebo for both 2 mg/kg/day of elemental iron (MD 8.0g/L; 95% CI 5.2 to 10.8) (Outcome 1.6.2) and 1 mg/kg/day of elemental iron (MD 3.8 g/L; 95% CI 1.2 to 6.4) (Outcome 1.6.3).

Twelve months: a total of three trials reported haemoglobin with or without MCV at approximately 12 months postnatal (Gorten 1964; Halliday 1983; Reedy 1952). Gorten 1964 reported a statistically significant difference in haemoglobin concentration (WMD 16.0 g/L; 95% CI 10.7 to 21.3) (Outcome 1.7). Halliday 1983 did not find a statistically significant difference. Although Reedy 1952 reported a large difference in haemoglobin between the iron supplementation and no iron supplementation groups (MD 59 g/L in the 1000 g to 1500 g group), the finding should be interpreted with caution due to extremely significant loss to follow-up (n = 6 at 12 months in this birth weight group, but n = 16 at birth).

MCV was reported as an outcome by Berglund 2010, Hall 1993 and Lundstrom 1977, but not by the other studies. At six to eight weeks, Lundstrom 1977 found no significant difference in MCV, but at three to four months (P < 0.01) and six to nine months (P < 0.05) there was a statistically significant difference in favour of the iron supplementation group (the results were presented graphically rather than numerically). Berglund 2010 also found an increase in MCV compared to placebo at six months for both 2 mg/kg/day of iron (MD 2.5 fL; 95% CI 1.3 to 3.7) (Outcome 1.11.1) and 1 mg/kg/day (MD 1.7 fL; 95% CI 0.5 to 2.9) (Outcome 1.11.2). At six to eight weeks, Hall 1993 found a higher MCV in the iron supplementation group (MD 4 fL; P < 0.05) and likewise at three to four months (MD 6 fL; P < 0.01).

  • Serum ferritin concentration, transferrin saturation, total iron binding capacity (TIBC)

Six to eight weeks: (eight trials: Barclay 1991; Franz 2000; Griffin 1999; Hall 1993; Halliday 1983; Lundstrom 1977; Melnick 1988; Sankar 2009). Three trials reported a higher ferritin level in the iron supplementation group (Hall 1993; Lundstrom 1977; Melnick 1988). The other trials did not find any statistically significant difference. Data on serum ferritin concentration suitable for pooling was reported by Barclay 1991 and Hall 1993. Meta-analysis did not detect a statistically significant difference (WMD 26.9 mcg/L; 95% CI -0.83 to 54.6 mcg/L).

Three trials reported the transferrin saturation at six to eight weeks. Only Hall 1993 reported a statistically significantly difference (MD 7.00%; 95% CI 0.05% to 13.95%) (Outcome 1.12) in favour of iron supplementation.

Three to four months: data on serum ferritin concentration at three to four months postnatal and suitable for pooling was provided by Aggarwal 2005, Barclay 1991 and Hall 1993. The pooled results showed a very small benefit in favour of the no iron supplementation group (WMD -4.14 mcg/L; 95% CI -5.9 to -2.38). A higher ferritin level at three to four months postnatal in the iron supplementation group was found by Lundstrom 1977. No difference in ferritin at three to four months was found by Griffin 1999 and Halliday 1983.

Two trials reported the transferrin saturation at two to four months. Hall 1993 did not detect a statistically significantly difference (MD -4.00%; 95% CI -9.21 to 1.21) (Outcome 1.13). Halliday 1983 found no difference at three to four months (MD 1% in favour of no iron supplementation, no significance calculation).

Six to nine months: (three trials: Berglund 2010; Griffin 1999; Halliday 1983). Neither Griffin 1999 nor Halliday 1983 found a statistically significant difference in serum ferritin levels. Halliday 1983 reported the data graphically, as did Griffin 1999. Berglund 2010 found a higher serum ferritin at six months compared with placebo for both 2 mg/kg/day elemental iron (MD 30.7 mcg/L; 95% CI 30.0 to 31.4) (Outcome 1.10.1) and 1 mg/kg/day (MD 15.4 mcg/L; 95% CI 14.8 to 16.0) (Outcome 1.10.2).

Halliday 1983 reported transferrin saturation at six to nine months, finding no difference (MD 1% in favour of no iron supplementation, no significance calculation). Berglund 2010 found a difference in favour of both 2 mg/kg/day of iron (MD 9.1%; 95% CI 6.0 to 12.2) (Outcome 1.14.1) and 1 mg/kg/day of iron (MD 5.9%; 95% CI 3.4 to 8.4) (Outcome 1.14.2).

Twelve months: (one trial: Halliday 1983). Halliday 1983 did not find a statistically significant difference in serum ferritin levels (data presented graphically rather than numerically).

Only Halliday 1983 reported transferrin saturation at 12 months, finding no significant difference (MD 4% in favour of no iron supplementation; no significance calculation).

No trials reported TIBC.

  • Severe anaemia (haemoglobin level < 8 g/dL or hematocrit level < 0.25)

Three studies reported the development of anaemia as an outcome measure (Coles 1954; Gorten 1964; Hall 1993). However, only Coles 1954 used a definition which was within the prespecified range of < 8 g/dL; Gorten 1964 defined anaemia as haemoglobin concentration below 9.0 g/dL on two successive tests; and Hall 1993 assessed as an outcome the prevalence of a haemoglobin concentration < 9.0 g/dL at discharge from hospital. Therefore, we did not pool the results for further analysis.

Coles 1954 defined anaemia as haemoglobin concentration below 7 g/dL once (or less than 7.5 g/dL for two consecutive months). No infants (out of 22) in the iron supplementation group developed anaemia, but 3 of 29 in the no iron supplementation group developed anaemia.

  • Mortality: not reported by any trials.
  • Chronic lung disease (one trial): Sankar 2009 did not find a statistically significant difference (one occurrence in each group).
  • Retinopathy of prematurity (one trial): Sankar 2009 did not find a statistically significant difference.
  • Necrotising enterocolitis (two trials): neither Berseth 2004 nor Sankar 2009 found a statistically significant difference in the incidence of NEC.
  • Invasive infection (two trials): neither Berseth 2004 nor Sankar 2009 found a statistically significant difference in the incidence of sepsis.
  • Enteral feed intolerance (four trials: Aggarwal 2005; Berseth 2004; Franz 2000; Melnick 1988).None of the trials reported a statistically significant difference in the incidence of feed intolerance. Aggarwal 2005 reported vomiting in 6% of the iron supplementation group and 0% of the no iron supplementation group at three to four months. Berseth 2004 compared a number of related outcomes (daily residuals, abdominal distention, guaiac-positive stools, withholding of feeds due to intolerance and clinically significant emesis) and there were no statistically significant differences on any measure. Franz 2000 reported a 16% incidence of feed intolerance in the iron supplementation group, which was said to be similar to that in the no iron supplementation group. Melnick 1988 did not provide numerical data.
  • Total duration of primary hospitalisation: not reported by any trials.
  • Requirement for readmission to hospital in the first year of life (1 trial): Sankar 2009 found no significant difference in rehospitalisation rate.
Subgroup analyses

Type of milk feeding: trials involving exclusively formula-fed infants and those involving exclusively or partially breast fed infants: details provided above.

Postnatal age of commencement of iron supplementation: 'early commencement' (less than 28 days postnatal) and 'late commencement' (28 days or more postnatal). Of the 21 studies, only Aggarwal 2005, Berglund 2010, Coles 1954 and Griffin 1999 had a 'late commencement' of iron supplementation. Diamond 1958 and Reedy 1952 did not state the time of commencement. The other 15 studies commenced 'early'. Quantitative meta-analysis of haemoglobin at six to eight weeks: 'early commencement' (WMD 1.55 g/L; 95% CI -0.12 to 3.2), 'late commencement' (WMD -1.1 g/L; 95% CI -8.8 to 6.6) (Outcome 1.16.4); and haemoglobin at three to four months: 'early' (WMD 0.75 g/L; 95% CI -2.4 to 3.9) (Outcome 1.17.3), 'late' (WMD 5.6 g/L; 95% CI 1.4 to 9.8) (Outcome 1.17.4).

Daily dose of supplemental iron administered: 'low dose' (2 mg/kg/day or less) and 'high dose' (more than 2 mg/kg/day). The studies using a low dose of iron were Berglund 2010 (including doses of both 2 mg/kg/day and 1 mg/kg/day), Franz 2000, Gorten 1964, Griffin 1999, Gross 1985, Lundstrom 1977 and Rudolph 1981. Reedy 1952 gave a low dose until discharge, followed by a high dose; the other studies used a high dose. Quantitative meta-analysis of haemoglobin at six to eight weeks: 'low dose' (WMD 3.9 g/L; 95% CI 1.5 to 6.3) (Outcome 1.16.5), 'high dose' (WMD -0.76 g/L; 95% CI -3.0 to 1.5) (Outcome 1.16.6); and haemoglobin at three to four months: 'low dose' (WMD 4.0 g/L; 95% CI 0.85 to 7.2) (Outcome 1.17.5), 'high dose' (WMD -0.15 g/L; 95% CI -4.2 to 3.9) (Outcome 1.17.6).

Duration of iron supplementation: 'short duration' (six months or less) and 'long duration' (more than six months). Two studies only administered iron for a short period, Coles 1954 ceasing at eight weeks and Melhorn 1971 at six weeks. No numerical data was available for quantitative meta-analysis after six to eight weeks. Two other studies contained a comparison group ceasing iron early (Griffin 1999 and Reedy 1952) - see Characteristics of Included Studies tables for description. The remaining 15 studies continued iron supplementation until at least the final outcome measurement.

Gestational age or birth weight of participants, or both: less than or equal to 33 completed weeks' or less than 1500 g and more than 33 completed weeks' or 1500 g or more. Only two studies dealt specifically with low birth weight infants (Aggarwal 2005 term LBW infants and Berglund 2010 marginally LBW infants, irrespective of gestation). For a number of studies, mean birth weights could not be obtained, but a reasonable estimate could be made from the provided data. Studies in which the infants had a published or estimated mean birth weight of less than 1500 g were Berseth 2004, Ferlin 1998, Franz 2000, Griffin 1999, Gross 1985, Hall 1993, Melnick 1988, Rudolph 1981 and Sankar 2009. Studies with a published or estimated mean birth weight of over 1500 g were Aggarwal 2005, Barclay 1991, Coles 1954, Gorten 1964, Halliday 1983, Lundstrom 1977. Melhorn 1971 and Reedy 1952. Three studies did not provide enough information to estimate the mean birth weight (Diamond 1958; Hanninen 1961; Quilligan 1954). On quantitative meta-analysis for haemoglobin at six to eight weeks (8 trials), neither subgroup showed a significant difference: 'under 1500 g' (WMD -0.42 g/L; 95% CI -4.3 to 3.4) (Outcome 1.16.7); '1500 g or over' (WMD 0.77 g/L; 95% CI -1.2 to 2.7) (Outcome 1.16.8). At three to four months (5 trials), the '1500 g or over' subgroup had a slight but statistically significant benefit for haemoglobin in favour of iron supplementation: (WMD 3.5 g/L; 95% CI 0.3 to 6.8) (Outcome 1.17.8). However, the 'under 1500 g' subgroup had no significant difference: (WMD 1.0 g/L; 95% CI -2.9 to 4.8) (Outcome 1.17.7).

We could not perform subgroup analyses at later ages than three to four months and for outcomes other than haemoglobin due to the small number of studies with available data.

Comparison 2: Early versus late commencement of iron supplementation - different regimens of iron supplementation (dose, duration and timing of initiation)

(4 trials: Arnon 2009; Halliday 1983; Jansson 1979; Steinmacher 2007).

Primary outcomes
  • Neurodevelopmental outcome

Steinmacher 2007 reported neurodevelopmental outcome at five years of age; there was no significant difference in cognitive function testing at five years of age. There was an increased proportion of children with abnormal clinical neurological examination in the late iron group (35% versus 17%; P = 0.02).

  • Growth

Steinmacher 2007 reported no significant difference in weight, length and head circumference at five years of age.

Secondary outcomes

Six to eight weeks : we pooled data from Arnon 2009 and Jansson 1979. Haemoglobin concentration was higher in the early iron group: (WMD 1.7 g/L; 95% CI 1.4 to 2.0). Halliday 1983 reported that there was not a statistically significant difference in haemoglobin concentration between the early and late supplementation groups, but the data were presented graphically rather than numerically.

Three to four months: Jansson 1979 did not report at three to four months. Halliday 1983 reported that there was not a statistically significant difference in haemoglobin concentration between the early and late supplementation groups, but numerical data were not supplied.

Six to nine months: Jansson 1979 did not detect a statistically significant difference in the haemoglobin concentration: (WMD 0 g/L; 95% CI -5.43 to 5.43) (Outcome 2.3). Halliday 1983 reported that there was not a statistically significant difference in haemoglobin concentration between the early and late supplementation groups, but numerical data were not supplied.

Twelve months: Jansson 1979 did not report at 12 months. Halliday 1983 reported that there was not a statistically significant difference in haemoglobin concentration between the early and late supplementation groups, but numerical data were not supplied. Neither study reported MCV.

Six to eight weeks: Arnon 2009 found a higher serum ferritin in the early iron group (WMD 25.0 mcg/L; 95% CI 16.9 to 33.1) (Outcome 2.4). Jansson 1979 found no statistically significant difference in serum ferritin (MD -16 mcg/L; no significance calculation due to unreported SD). Halliday 1983 reported that there was no statistically significant difference in transferrin saturation, but numerical data were not supplied. Therefore, we were unable to pool the data.

Three to four months: Jansson 1979 did not report at three to four months. Halliday 1983 reported that there was no statistically significant difference in transferrin saturation, but numerical data were not supplied.

Six to nine months: Jansson 1979 found no statistically significant difference in serum ferritin (MD -2 mcg/L; no significance calculation). Halliday 1983 reported that there was no statistically significant difference in transferrin saturation, but numerical data were not supplied.

Twelve months: Jansson 1979 did not report at 12 months. Halliday 1983 reported that there was no statistically significant difference in transferrin saturation, but numerical data were not supplied.

  • Severe anaemia: not reported by any trials.
  • Mortality: not reported by any trials.
  • Chronic lung disease: no difference (Arnon 2009).
  • Retinopathy of prematurity: no difference (Arnon 2009).
  • Necrotising enterocolitis: no difference (Arnon 2009).
  • Invasive infection: no difference (Arnon 2009).
  • Enteral feed intolerance: not reported by any trials.
  • Total duration of primary hospitalisation: not reported by any trials.
  • Requirement for readmission to hospital in the first year of life: not reported by any trials.
Comparison 3: High versus low dose iron supplementation

(Three trials: Barclay 1991; Friel 2001; Groh-Wargo 1990).

Primary outcomes
  • Neurodevelopmental outcome (one trial)

Friel 2001 did not find a statistically significant difference in the Griffiths Developmental Assessment score at 12 months: 118 in both groups (WMD 0.000; 95% CI -6.38 to 6.38) (Outcome 3.1).

  • Growth (three trials)

None of the trials found any statistically significant differences in growth parameters up to about 20 weeks postnatal age. Numerical data were only provided by Friel 2001, who documented no significant difference in weight and height z scores at approximately 12 months postnatally (z score difference of 0 and 0.1 respectively).

Secondary outcomes
  • Blood haemoglobin concentration and MCV

Six to eight weeks: (two trials: Barclay 1991; Friel 2001). (Groh-Wargo 1990 did not supply data for six to eight weeks). Neither individual trial, nor meta-analysis of both trials, found a statistically significant difference between the groups: (WMD -1.4 g/L; 95% confidence interval -8.2 to 5.4) (Outcome 3.2.1).

Three to four months: (two trials: Barclay 1991; Friel 2001; Groh-Wargo 1990). None of the individual trials found a statistically significant difference between the groups. However, meta-analysis suggested a slight benefit in favour of the higher iron dose: (WMD 4.49 g/L; 95% CI 0.84 to 8.13) (Outcome 3.3). Groh-Wargo 1990 reported that the MCV was statistically significantly higher in the high dose group: (WMD 3.30 units; 95% CI 0.06 to 6.54) (Outcome 3.6).

Six to nine months : (one trial: Friel 2001). The trial did not find a statistically significant difference in mean haemoglobin concentration between the groups: (MD 4.0 g/L; 95% CI -1.6 to 9.6) (Outcome 3.4).

Twelve months: (one trial Friel 2001). The trial did not find a statistically significant difference between the groups: (MD -2.0 g/L; (95% CI -7.2 to 3.2) (Outcome 3.5).

Six to eight weeks: Friel 2001 did not detect a statistically significant difference in ferritin concentration between the two groups: (MD -5.00; 95% CI -33.1 to 23.1) (Outcome 3.7). The transferrin saturation level was statistically significantly lower in the high dose group: (MD -10.0%; 95% CI -17.7 to -2.27) (Outcome 3.11).

Three to four months: neither study detected a statistically significant difference in ferritin concentration. On meta-analysis, (WMD 4.2; 95% CI -3.7 to 12.0). Neither Friel 2001 nor Groh-Wargo 1990 found a significant difference in transferrin saturation: on meta-analysis, (WMD 1.74; 95% CI -1.2 to 4.7) (Outcome 3.12).

Six to nine months: Friel 2001 reported a statistically significant higher mean ferritin concentration in the high dose group: (MD 4.00; 95% CI 0.12 to 7.88) (Outcome 3.9). The transferrin saturation level was not statistically significantly different: (MD 2.00%; 95% CI -2.95 to 6.95) (Outcome 3.13).

Twelve months: Friel 2001 did not detect a statistically significant difference in ferritin concentration (MD -2.00; 95% CI -7.67 to 3.67) (Outcome 3.10).

  • Severe anaemia: not reported by any trials.
  • Mortality: not reported by any trials.
  • Chronic lung disease: not reported by any trials.
  • Retinopathy of prematurity: not reported by any trials.
  • Necrotising enterocolitis: not reported by any trials.
  • Invasive infection: not reported by any trials.
  • Enteral feed intolerance: not reported by any trials.
  • Total duration of primary hospitalisation: not reported by any trials.
  • Requirement for readmission to hospital in the first year of life: not reported by any trials.
Comparison 4: Duration of iron supplementation

(Two trials: Griffin 1999 and Reedy 1952)

  • Blood haemoglobin concentration and MCV

Six to eight weeks: Griffin 1999 found no difference in haemoglobin (MD 3.7; 95% CI -3.8 to 11.2) (Outcome 4.1). Reedy 1952 found a MD of 6 g/L in favour of short duration in the 1000 g to 1500 g group (no significance calculation possible), and 3 g/L in favour of short duration in the 1500 g to 2000 g group (no comparison available for the 2000 g to 2250 g group). This result is severely limited by the large loss to follow-up.

Three to four months: Griffin 1999 found no difference in haemoglobin (MD 1.5 g/L; 95% CI -3.9 to 6.9 g/L) (Outcome 4.2). Reedy 1952 found a MD of 10 g/L in favour of long duration in the 1000 g to1500 g group (no significance calculation possible), but no difference in the larger birth weight groups. This result is severely limited by the large loss to follow-up.

Six to nine months: Griffin 1999 found a slight benefit for the longer duration of iron supplementation (MD 5.7 g/L; 95% CI 0.5 to 10.9) (Outcome 4.3). Reedy 1952 found a MD of 5 g/L in favour of short duration in the 1000 g to 1500 g group (no significance calculation possible), 2 g/L in favour of long duration in the 1500 g to 2000 g group and 3 g/L in favour of short duration in the 2000 g to 2250 g group. The results of Reedy 1952 are severely limited by the large loss to follow-up.

Twelve months: Reedy 1952 found a MD of 28 g/L in the 1000 g to 1500 g group (no significance calculation possible), and of 10 g/L in the 2000 g to 2250 g group (no comparison available for the 1501 g to 2000 g group). The results of Reedy 1952 are severely limited by the large loss to follow-up.

See Table 1 for summary of results by study.

Discussion

Summary of main results

There is insufficient evidence regarding the effect of enteral iron supplementation on the neurodevelopmental and long term growth outcomes for preterm and low birth weight infants. No RCT comparing enteral iron supplementation with no iron supplementation examined the comparative neurodevelopmental outcomes.

Enteral iron supplementation of both preterm and term low birth weight infants appears to confer a slight improvement in haemoglobin and ferritin levels after eight weeks postnatal age, and reduces the risk of infants developing anaemia. However, there is significant heterogeneity in the outcomes of the included RCTs, which is likely due to a number of methodological issues outlined below.

This review did not identify any benefit in providing more than 2 mg/kg/day to 3 mg/kg/day of elemental iron. Some recent evidence supports provision of iron supplementation to all low birth weight infants, whether they are born term or preterm (Berglund 2010).

Overall completeness and applicability of evidence

One study compared early commencement of iron supplementation with later commencement, finding no difference in cognitive development at five years of age, but an increase in the rate of abnormal clinical neurological examination in the late commencement group (Steinmacher 2007). One further study comparing a standard dose of iron supplementation with a higher dose examined the neurodevelopmental outcome of infants, and did not find any difference up to 12 months of age (Friel 2001). A number of studies measured weight and/or length and head circumference, but in all cases this was only done for the duration of monitoring of haematological parameters, which for most studies was well under a year postnatally.

Most studies were concerned primarily with assessing the effects of iron supplementation on haematological parameters such as haemoglobin and serum ferritin levels. However, only a small number of studies were able to be quantitatively synthesised, because appropriate data was not available, despite attempting to contact the authors for further data. The studies included were very heterogeneous, in relation to the population, the intervention used, the outcomes measured and the results themselves. Qualitatively, the evidence to date indicates that the provision of enteral iron supplementation to premature and term, low birth weight infants probably confers a slight benefit for the haemoglobin level from approximately two months postnatally. Iron stores, reflected in the serum ferritin, are also slightly benefited by iron supplementation. One recent, relatively large RCT has suggested that an early (two weeks postnatal) commencement of iron supplementation results in improved haematological parameters compared with later (four weeks) introduction of iron (Arnon 2009).

Quality of the evidence

The methodological quality of most of the RCTs was fair at best. For example, only eight of the 26 studies are known to have used allocation concealment of adequate quality. Most failed to report adequate blinding of intervention and outcome measurement, and only eight of 26 had documented follow-up rates of more than 80% for the key outcomes at the end of the study. Other methodological weaknesses were contamination of non iron-supplemented groups by iron-fortified formulas (Barclay 1991; Franz 2000; Jansson 1979) and removal of anaemic infants from analysis (Coles 1954; Gorten 1964; Lundstrom 1977; Melhorn 1971). Since most of these removals came from the control (unsupplemented) groups, this is likely to have resulted in an underestimation of the effect of iron supplementation on haemoglobin levels.

There was also a paucity of outcome data reported for possible morbidity associated with iron supplementation, such as necrotising enterocolitis, retinopathy of prematurity, and chronic neonatal lung disease. Rather, the studies looking at adverse effects of iron supplementation concentrated on haematological measures such as evidence of red cell fragility or haemolysis.

Of the studies comparing enteral iron supplementation versus no iron supplementation, there was some variation in the doses of iron administered. The most common dose of iron (either as a medicinal supplement or as formula fortification) was 2 mg/kg/day to 3 mg/kg/day of elemental iron, which was the dose administered in 11 of those 21 studies. This review did not find any evidence that a dose greater than that recommended by the AAP (2 mg/kg/day) results in improvement of outcomes. This is reflected both in the results of studies that specifically addressed this question (Barclay 1991; Friel 2001; Groh-Wargo 1990) and in the subgroup analysis of trials using doses of iron of 2 mg/kg/day or less compared with those using a higher dose, meta-analysis of which actually indicated a small but statistically significant benefit for haemoglobin at six to eight weeks and three to four months in the 'low iron' but not the 'high iron' group.

A few features of the heterogeneity of study methods are worthy of further comment. First, studies varied greatly in their approach to blood transfusion. For example, among the 21 studies comparing enteral iron supplementation with no (or minimal) iron supplementation, four permitted blood transfusions among the participants before and during the study period (Berseth 2004; Franz 2000; Hall 1993; Sankar 2009). Two studies permitted transfusions before, but not after study entry (Barclay 1991; Griffin 1999). The other studies either excluded all infants who required transfusion (7 studies), or did not state any policy (eight studies). The effect of this heterogeneity could be important, given the iron content of blood, and previous research which has suggested that premature babies who receive multiple transfusions are at risk of iron overload (Ng 2001). It is feasible that extremely preterm infants who receive one or more blood transfusions may not receive as much benefit from iron supplementation as more mature infants who do not receive any transfusions (Ng 2001; Rao 2002).

One author suggests that the measurement of ferritin levels in preterm neonates who have received transfusions may be useful to guide the initiation of iron therapy, but again this remains untested (Brown 1996). Of the nine studies comparing iron with no iron that were known or estimated to have a mean birth weight of less than 1500 g (Aggarwal 2005; Berseth 2004; Ferlin 1998; Franz 2000; Griffin 1999; Hall 1993; Melnick 1988; Rudolph 1981; Sankar 2009), five of these studies Berseth 2004; Franz 2000; Griffin 1999; Hall 1993; Sankar 2009) included infants who had received blood transfusions prior to commencement of the intervention and two studies did not state the policy on transfusions (Melnick 1988; Rudolph 1981).

Second, the provision or otherwise of vitamin E supplementation varied between the studies. Apart from the two studies which investigated the supplementation of vitamin E as a controlled intervention (Ferlin 1998; Melhorn 1971), five other studies reported vitamin E supplementation of both the intervention and control groups, ranging from 2 IU/kg/day to 20 IU/kg/day (Barclay 1991; Berseth 2004; Gross 1985; Lundstrom 1977; Rudolph 1981; Sankar 2009). The heterogeneity and uncertainty around the provision or otherwise of vitamin E in these studies is unlikely to have resulted in a significant adverse impact on the review's validity. For example, the finding by Melhorn 1971 that iron supplementation exacerbates the 'early' anaemia of prematurity (i.e. at six to eight weeks postnatally) was not supported by the other trials in this review. In the studies in which the presence or absence of vitamin E supplementation was not documented, it is unlikely, particularly in the studies from the 1950s and 1960s, that it had been given. In most modern neonatal units, a small vitamin E supplement is routinely given to preterm infants, in accordance with AAP recommendations of 5 IU to 25 IU per day (AAP 1985). In Melhorn 1971, the apparent deleterious effect of iron supplementation was ameliorated by vitamin E supplementation. Therefore, any residual concern that iron might exacerbate the early anaemia of pregnancy in non-vitamin E supplemented infants is unlikely to be relevant today.

Third, the provision of enteral cobalt was examined in three studies from the 1950s. No clear picture of its utility for haematological outcome emerged. The study by Coles 1954 suggested the conferring of a slight benefit for haemoglobin level by the addition of cobalt supplementation at two months, but this was smaller in magnitude, duration and statistical significance than that given by iron supplementation. The study of Diamond 1958 appeared to show a slight benefit also, but was of poor quality. In Quilligan 1954 there was no comparison with iron alone, and so no conclusion can be drawn about the additive effect of cobalt.

Authors' conclusions

Implications for practice

There is a paucity of evidence from RCTs about how enteral iron supplementation of preterm and low birth weight infants affects growth and neurodevelopmental outcomes. However, there appear to be slight haematological benefits after eight weeks postnatal age. Doses of more than 2 mg/kg/day to 3 mg/kg/day of iron do not appear to confer extra benefit. One recent trial suggests that commencing iron early (at two weeks of age) results in improved haematological parameters from as early as eight weeks of age. The RCT evidence to date does not suggest a particular threshold of birth weight or gestational age at which iron supplementation becomes beneficial, and two of the more recent and methodologically sound trials suggest a benefit even for marginally low birth weight infants, whether term or preterm.

Implications for research

There is a need for new RCTs of enteral iron supplementation in preterm infants that stratify according to birth weight and gestation, feeding method (breast milk or formula) and prior blood transfusion. This is because it remains unclear from RCT evidence to date whether enteral iron supplementation is required, or indeed might cause harm, in the very low birth weight or extremely low birth weight preterm infant who has already received a blood transfusion. There are strong arguments on a physiological basis that supplementation might only be required in non-transfused infants, but this has not been satisfactorily tested to date.

Acknowledgements

Dr William Maguire edited a draft of the review and provided invaluable advice.
The following researchers kindly provided further information regarding aspects of their publications which are included in this review: Prof H.P.S. Sachdev, Cheryl Harris, M.L.S. Ferlin MD, Dr Axel Franz, Dr James Friel, Dr Ian Griffin, Prof Henry Halliday, Greg Melnick MD, Prof H. Devlieger, Nathan Rudolph MD and Shmuel Arnon MD.

Contributions of authors

Ryan Mills: Background, search strategy and search, data extraction and assessment of methodological quality. Initial write-up of methods, description of studies, results and discussion.

Mark Davies: Review question, search strategy and search, data extraction and assessment of methodological quality.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Aggarwal 2005

Methods

Blinding of randomisation: yes (author correspondence)
Blinding of intervention: yes
Complete follow-up: 4 weeks - yes (85%); 8 weeks - no (36%)
Blinding of outcome measurement: yes

Participants

Gestation: term
Birth weight: low birth weight (< 2500 g)
Feeding: breast fed
Age of enrolment: 50 to 80 days
Exclusion criteria: twinning, congenital malformations, > 10 mL of blood sampling in the past, those already on iron supplementation, significant morbidity and maternal antepartum haemorrhage
Blood transfusions: excluded if previously received

Interventions

Iron supplementation group: 3 mg/kg/day as ferric ammonium citrate drops (n = 37), commencing at 50 to 80 days of age
No iron supplementation group: indistinguishable placebo mixture (n = 36)

Outcomes

Primary: haemoglobin concentration
Secondary: peripheral smear, serum ferritin, weight, length, head circumference
Timing: baseline (7 to 11weeks postnatal), 4 weeks (11 to 15 weeks postnatal) and 8 weeks (15 to 19 weeks postnatal)

Notes

73 infants were randomised
Randomisation was performed using computer generated random numbers
Protocol for treatment of anaemia: not stated

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generation

Allocation concealment (selection bias) Low risk

Adequate allocation concealment (author correspondence)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) High risk

8 week follow-up 36%

Selective reporting (reporting bias) Unclear risk

No evidence of selectivity

Other bias Low risk

No other risk of bias identified

Arnon 2009

Methods

Blinding of randomisation: unclear
Blinding of intervention: no (author communication)
Complete follow-up: Yes (87%)
Blinding of outcome measurement: Yes (author communication)

Participants

Gestation: less than/or equal to 32 weeks
Birth weight: no limits (mean < 1300 g)
Feeding: breast milk
Exclusion criteria: major anomalies, haemolytic disease, twin-twin transfusion syndrome, illness requiring cessation of supplementation for over 3 days
Blood transfusions: permitted prior to study entry (when enteral intake less than/or equal to 100 mL/kg/day); excluded if requiring transfusion during study period. Restrictive transfusion policy

Interventions

Early iron group: Iron polymaltose complex, 5mg/kg/day, from 2 weeks of age
Late iron group: Iron polymaltose complex, 5mg/kg/day, from 4 weeks of age (after receiving placebo from 2 weeks)
Both groups received 25 IU of vitamin E from 2 to 8 weeks of age

Outcomes

Primary outcome: vitamin E (alpha-tocopherol) levels at 2, 4 and 8 weeks of age
Secondary outcomes: serum iron, serum ferritin, haemoglobin level and reticulocyte count at 2, 4 and 8 weeks of age
Not published for full cohort, but received from author: requirement for transfusion and soluble transfusion receptor level (at 2, 4 and 8 weeks of age)

Notes

Requirement for transfusion and soluble transfusion receptor level (at 2, 4 and 8 weeks of age) were also reported in Arnon 2007 in a subset of this cohort

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generation

Allocation concealment (selection bias) Unclear risk

Allocation known to pharmacist but concealed from treating staff using envelopes (author communication).

Blinding (performance bias and detection bias) High risk

Blinding of intervention: No (author communication)

Blinding of outcome measurement: Yes (author communication)

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: Yes (87%)

Selective reporting (reporting bias) Unclear risk

No evidence of selectivity

Other bias Low risk

No other risk of bias identified

Barclay 1991

Methods

Blinding of randomisation: not known
Blinding of intervention: not known
Complete follow-up: yes (89%)
Blinding of outcome measurement: not known

Participants

Gestation: term or preterm
Birth weight: less than 2500 g
Feeding: 11 infants were exclusively fed breast milk, and the remainder received infant formula containing 5 to 6.7 mg/l (0.8 mg/kg/day) of iron
Exclusion criteria: congenital or chromosomal abnormalities, haemolytic disease, gastrointestinal disorders and intravenous nutrition for more than 5 days
Blood transfusion: excluded if occurring after day 14

Interventions

High iron group (HiFe): approximately 7.1 mg/kg/day (13.8 mg of iron daily as iron edetate) (n = 20)
Low iron group (MidFe): approximately 3.6 mg/kg/day (7 mg iron daily as iron edetate) (n = 16) (this group used as iron supplementation group for comparison with no iron supplementation)
No iron supplementation group (NatFe): no additional iron (n = 19)
All supplements began at 28 days postnatally

Outcomes

Primary: erythrocyte superoxide dismutase levels
Secondary: haemoglobin concentration, reticulocyte count; plasma copper, zinc and ferritin levels; weight, length and head circumference
Timing: baseline (27 days), 8 weeks, 12 weeks and 20 weeks postnatal age

Notes

62 infants were randomised
Infants were randomised within each stratum of gestational age (< 32 weeks, 33 to 35 weeks and > 36 weeks)
The infants received different vitamin regimens based on their birth weight, which did not necessarily correlate strictly with the gestational age groups
The data for those who failed to attend follow-up visits were not included in the analysis
Treatment of anaemia: not stated

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not stated

Allocation concealment (selection bias) Unclear risk

Blinding of randomisation: not known

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Blinding of outcome measurement: not known

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes (89%)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Berglund 2010

Methods

Blinding of randomisation: yes

Blinding of intervention: yes

Complete follow-up: yes (91%)

Blinding of outcome measure: yes

Participants

Gestation: term or preterm, enrolment at 6 weeks postnatal age

Birth weight: 2000 g to 2500 g

Feeding: breast milk or iron-fortified formula

Exclusion criteria: disease symptoms at 6 weeks postnatal, chronic disease, previous blood transfusion, previous iron supplementation and anaemia or other haematological disorder at 6 weeks postnatal

Blood transfusions: excluded

Interventions

High iron group (HiFe): 2 mg/kg/day of elemental iron (as ferrous succinate) from 6 weeks to 6 months postnatal age

Low iron group (MidFe): 1 mg/kg/day of elemental iron (as ferrous succinate) from 6 weeks to 6 months postnatal age

No iron group: placebo mixture from 6 weeks to 6 months postnatal age

Outcomes

Haematological: at baseline (6 weeks), 12 weeks and 6 months - complete blood count, haemoglobin level, mean cell volume, serum ferritin, serum transferrin, serum iron, C-reactive protein, transferrin saturation, transferrin receptor concentration

Growth: at baseline (6 weeks), 12 weeks, 19 weeks and 6 months - weight, length, head circumference, knee-heel length

Notes

Infants were randomised within stratification for gender and study centre

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generated randomisation

Allocation concealment (selection bias) Low risk

Blinding of treatment assignment was reported

Blinding (performance bias and detection bias) Low risk

As reported

Incomplete outcome data (attrition bias) Low risk

Follow up 91%

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Berseth 2004

Methods

Blinding of randomisation: yes (author communication)
Blinding of intervention: yes
Complete follow-up: no (52%)
Blinding of outcome measurement: yes

Participants

Gestation: less than 33 weeks
Birth weight: less than 1500 g
Feeding: breast milk (fortified)
Exclusion criteria: conditions expected to affect growth or feed tolerance; 5-minute Apgar score < 4; major surgery; IVH of grade 3 or 4; 4 or more days of steroid therapy before or within 72 hours of day 0; had received any HMF before day 0; had received EPO, vitamin D, minerals or iron by day 0; still mechanically ventilated by day 0
Blood transfusion: permitted

Interventions

Iron supplementation group: approximately 2.4 mg/kg/day of iron (in powdered fortifier which providing 15.3 mg/L of iron (n = 96), commencing when enteral intake > 100 mL/kg/day
No iron supplementation group: approximately 0.64 mg/kg/day of iron (in another fortifier providing 4.4 mg/L of iron (n = 85)
The first day of fortification was at half strength, and from the second day at full strength

Outcomes

Primary outcome: weight gain
Secondary outcomes:
Length and head circumference; hematocrit, albumin, transthyretin, alkaline phosphatase, BUN, triglycerides, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, zinc, copper, ferritin and vitamin D
Incidence of feed intolerance (gastric residuals, abdominal distention and emesis), respiratory outcomes (supplemental oxygen, mechanical ventilation), and incidence of NEC. Need for blood transfusion

Notes

185 infants were randomised
Infants were randomised when they had achieved an enteral intake of 100 ml/kg/day of unfortified human milk
Randomisation occurred within predetermined stratification groups (by gender and birth weight above or below 1000 g)
Blinding was achieved by otherwise identical, coded labels

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generated (author communication)

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes (author communication).

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) High risk

52% follow-up to completion

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other identified bias

Coles 1954

Methods

Blinding of randomisation: not known
Blinding of intervention: not known
Complete follow-up: no (58.7% at 6 months)
Blinding of outcome measurement: not known

Participants

Gestation: premature (specific gestation not specified)
Birth weight: not stated
Feeding: breast or formula fed
Exclusion criteria: severe haemorrhage, death
Blood transfusion policy: not stated

Interventions

Iron supplementation group (Group IV): Approx 44 mg/kg/day of iron (as 4.5 grains of ferrous sulphate) and cobalt sulphate 20 mg daily (n = 22) from 4 to 8 weeks of life
No iron supplementation group (Group III): Cobalt sulphate orally, 20 mg daily from 4 to 8 weeks (n = 29)
Other groups not included in systematic review:
Group I: controls (n = 53)
Group II: cobalt sulphate orally, 10 mg daily from day 1 to 12 of life (n = 22)

Outcomes

Primary outcomes: haemoglobin concentration and red blood cell count
Timing: birth, 1 week, 2 weeks, 1 month, monthly to 6 months, at 9 months and 1 year postnatal

Notes

51 infants were randomised to the groups included in this review (groups IV and III)
Iron and cobalt supplements or both were administered from 4 to 8 weeks postnatally
Management of anaemia: ferrous sulphate 4.5 grains (approximately 44 mg/kg/day) when haemoglobin < 70 g/L (< 6 months), or < 75 g/L (> 6 months) and cobalt sulphate 20 mg if RCC < 2.5 m/cmm and haemoglobin < 70 g/L
Vitamin supplementation: vitamins A, D and C

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not stated

Allocation concealment (selection bias) Unclear risk

Blinding of randomisation: not known

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Blinding of outcome measurement: not known

Incomplete outcome data (attrition bias) High risk

Complete follow-up: no (58.7% at 6 months)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Diamond 1958

Methods

Blinding of randomisation: no (quasi-randomised)
Blinding of intervention: not known
Complete follow-up: not known (100% implied)
Outcome assessment blind: not known

Participants

Gestation: not stated
Birth weight: not stated
Feeding: not stated

Interventions

Iron supplementation group (Group 2): approximately 12 mg/kg/day of iron (as 75 mg per day of ferrous sulfate) (n = 12)
No iron supplementation group (Group 3): no supplement (n = 16)
Time of commencement of supplementation is not stated
Additional study group not included in systematic review:
Group 1: approximately 12 mg/kg/day of iron (as 75 mg per day of ferrous sulfate) and 2 mg/kg/day of cobalt chloride (n = 16)

Outcomes

Primary outcome: haemoglobin level
Timing of outcome measurement: monthly, up to 6 months postnatal

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Quasi-randomised

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (quasi-randomised)

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Outcome assessment blind: not known

Incomplete outcome data (attrition bias) Unclear risk

Complete follow-up: not known (100% implied)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other known bias

Ferlin 1998

Methods

Blinding of randomisation: no (author communication - quasi-randomised)
Blinding of intervention: yes (placebo used)
Complete follow-up: not known (100% implied)
Blinding of outcome measurement: yes (author communication)

Participants

Gestation: up to 35 weeks gestation
Birth weight: less than 1600 g birth weight
Feeding: all started on breast milk, then changed to a non-iron supplemented formula at unspecified intervals
Exclusions: those who failed to attend follow-up
Blood transfusion policy: excluded from study

Interventions

Iron supplementation group: iron supplementation of 4 mg/kg/day of iron (as ferrous sulfate), with 25 IU/day of vitamin E supplementation (Group III, n = 10), or without vitamin E supplementation (Group II, n = 10). Iron supplementation was commenced on the 15th day of life
No iron supplementation group: placebo (Group I, n = 10) or 25 IU/day of vitamin E supplementation (Group IV, n = 10)

Outcomes

Primary: haemoglobin concentration and hematocrit
Secondary: weight, length and head circumference; reticulocytes, platelets and red cell resistance to hydrogen peroxide
Timing: 24 to 72 hours of age and 2 months of age

Notes

Although the infants included in the analysis were followed to completion of the study, it is stated that regular attendance at follow-up appointments was a prerequisite for inclusion in the study; it is not stated how many infants were initially randomised but later excluded due to loss to follow-up or other prespecified events such as the need for blood transfusion, or other 'interfering events' that resulted in cessation of treatment

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Quasi-randomised

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (author communication - quasi-randomised)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes (placebo used)
Blinding of outcome measurement: yes (author communication)

Incomplete outcome data (attrition bias) Unclear risk

Complete follow-up: not known (100% implied)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other known bias

Franz 2000

Methods

Blinding of randomisation: no (author communication)
Blinding of intervention: yes; but allocation became obvious due to stool colour
Complete follow-up: no (65%)
Blinding of outcome measurement: yes

Participants

Gestation: no limit
Birth weight: less than 1301 g
Feeding: either breast fed or received an iron-fortified formula (12 mg/L, or approximately 1.9 mg/kg/day of iron)
Exclusion criteria: major anomalies, haemolytic disease and twin-to-twin transfusion
Blood transfusion policy: permitted, before and after entry; restrictive transfusion policy

Interventions

Iron supplementation group: 2 mg/kg/day of iron as ferrous sulfate, commenced as soon as enteral feedings were tolerated (n = 105)
No iron supplementation group: 2 mg/kg/day of iron as ferrous sulfate, commenced at 61 days of life (n = 99)
Management of anaemia: when the hematocrit level fell below 0.30, the dose of iron was increased to 4 mg/kg/day. The policy for the administration of blood transfusions was clearly outlined

Outcomes

Primary outcome: serum ferritin and incidence of iron deficiency
Secondary outcomes: transferrin, transferrin saturation, serum iron, reticulocytes, hematocrit; number of transfusions required and blood volume transfused
Timing: birth; at 1.6 times birth weight; at 61 days of life; and opportunistically when the hematocrit level was < 0.25

Notes

Randomised on day 7 of life. The infants either received breast milk or iron-fortified formula (12 mg/L, approximately 1.9 mg/kg/day) The iron intake due to formula was reported to be similar between the two groups

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generated. Reported in Steinmacher 2007 (continuation of this study)

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (author communication)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes; but allocation became obvious due to stool colour
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) High risk

Follow-up to completion: 65%

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Friel 2001

Methods

Blinding of randomisation: yes (author communication)
Blinding of intervention: yes
Complete follow-up: no (72.4%)
Blinding of outcome measurement: yes

Participants

Gestation: term or preterm
Birth weight: low birth weight (< 2500 g)
Feeding: formula
Exclusions: bronchopulmonary dysplasia, hydrocephalus, liver dysfunction or had congenital malformations
Blood transfusion policy: not stated

Interventions

High iron group (HiFe): approximately 3.4 mg/kg/day of iron (in formula containing 21 mg/L of iron) (n = 29)
Low iron group (MidFe): approximately 2.1 mg/kg/day of iron (in formula containing 13.4 mg/L of iron) (n = 29)
Infants were assigned to groups at close to 2000 g weight and when on full oral feeds

Outcomes

Primary outcomes: Griffith Developmental Assessment score (at 3, 6, 9 and 12 months corrected), weight, and height. Haemoglobin level, hematocrit, ferritin, transferrin, transferrin saturation, and plasma iron
Secondary outcomes: malondialdehyde level, plasma zinc and copper levels, red blood cell fragility, catalase level, superoxide dismutase level and glutathione peroxidase level
Timing: baseline, discharge, and 3, 6, 9 and 12 months corrected age

Notes

Randomisation was achieved using a random number table and concealed allocation was performed using opaque sealed envelopes

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random number table (author communication)

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes (author communication)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) High risk

Follow-up to completion: 72.4%

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Gorten 1964

Methods

Blinding of randomisation: yes (sealed envelopes)
Blinding of intervention: yes
Complete follow-up: no (55.9% at 12 months)
Blinding of outcome measurement: yes

Participants

Gestation: premature
Birth weight: mean birth weight was 1.84 kg (29.9 weeks gestation) in the study group; and 1.89 kg (33.5 weeks gestation) in the control group
Feeding: formula
Blood transfusion policy: not stated

Interventions

Iron supplementation group: approximately 2 mg/kg/day of iron (as formula containing 12 mg per quart (13 mg/L) of iron (n = 69)
No iron supplementation group: formula containing no added iron (n = 76)
Enrolled in the first week of life

Outcomes

Primary outcome: incidence of iron deficiency (haemoglobin level below 9.0 g/dL, hematocrit below 0.32)
Secondary outcomes: haemoglobin concentration, red blood cell count, white blood cell count, hematocrit, red cell indices. Weight and length
Timing: first week of life, as required during admission, and at each clinic visit after discharge (up to 80 weeks postnatal)

Notes

Management of anaemia: when Hb < 9 g/dL and HcT < 0.32, changed to iron-containing formula. Infants in the control group removed from further analysis

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not stated

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes (sealed envelopes)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) High risk

Complete follow-up: no (55.9% at 12 months)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Griffin 1999

Methods

Blinding of randomisation: yes (author communication)
Blinding of intervention: yes
Complete follow-up: yes (96.2%)
Blinding of outcome measurement: yes

Participants

Gestation: 32 weeks or less
Birth weight: 1750 g or less
Feeding: formula feeding after commencement of intervention
Exclusions: systemically unwell, requiring supplemental oxygen, or on any medications other than vitamin drops
Blood transfusion policy: permitted before enrolment (at discharge), but infants excluded from study if required after enrolment

Interventions

Iron supplementation group: approximately 1.5 mg/kg/day of iron (in formula containing 9 mg/L of iron) (n = 29)
No iron supplementation group: approximately 0.8 mg/kg/day of iron (in formula containing 5 mg/L of iron) (n = 34)
Iron supplementation commenced at discharge from hospital
Short duration group: 9 mg/L (approximately 1.5 mg/kg/day) of iron (as high iron formula) from discharge, then changed to the lower iron formula at term (n = 15)
Prior to discharge the infants received the high-iron formula or a combination of breast milk and formula feeds

Outcomes

Primary outcomes: haemoglobin concentration and plasma ferritin
Timing: every 2 weeks from discharge to term, then monthly to 6 months corrected age (approximately 8 months postnatal age)

Notes

Infants were randomised using sealed envelopes 48 hours before discharge. Three infants were excluded from analysis because they received blood transfusions after discharge. The outcome statistics are presented in graphical form, with statistical significance data derived by ANOVA

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generated (author communication)

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes (author communication)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes (96.2%)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Groh-Wargo 1990

Methods

Blinding of randomisation: not known
Blinding of intervention: yes (double-blind)
Complete follow-up: not known
Blinding of outcome assessment: not known

Participants

Gestation: no limit stated
Birth weight: less than 1500 g birth weight
Feeding: low-iron formula
Exclusions: none stated
Blood transfusion policy: permitted

Interventions

High iron group (HiFe) (Group 2): iron supplementation (as Fer-in-Sol) of 4 mg/kg/day (n = 18)
Low iron group (MidFe) (Group 1): iron supplementation (as Fer-in-Sol) of 2 mg/kg/day (n = 18)
Iron supplementation was commenced at 2 weeks postnatal age

Outcomes

Primary outcomes: weight, haemoglobin, MCV, FEP, % saturation and ferritin
Timing: 0.5 months, 2 months, and 4 months

Notes

There is no description of the number of eligible patients who were not included in the trial

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not stated

Allocation concealment (selection bias) Unclear risk

Blinding of randomisation: not known

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: yes (double-blind)
Blinding of outcome assessment: not known

Incomplete outcome data (attrition bias) Unclear risk

Complete follow-up: not known

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Unclear risk

Insufficient information to inform assessment of risk of other bias

Gross 1985

Methods

Blinding of randomisation: not known
Blinding of intervention: not known
Complete follow-up: yes (100%)
Blinding of outcome assessment: not known

Participants

Gestation: 27 to 33 weeks
Birth weight: < 1500 g (AGA)
Feeding: breast milk or formula
Exclusions: any major disease or haemolytic disease, hematocrit level < 0.40, unable to begin enteral feeds in first week of life
Transfusions: nil received

Interventions

Iron supplementation group: 2 mg/kg/day of iron as ferrous sulfate, from 2 weeks of age (fed preterm human milk, mature human milk or formula)
No iron supplementation group: no ferrous sulfate (fed preterm human milk, mature human milk or formula)

Outcomes

Primary outcome: serum vitamin E concentration
Secondary outcomes: vitamin E/lipid ratio, hydrogen peroxide haemolysis, hematocrit, reticulocyte count
Timing: day 1 and after 6 weeks of feeding (0 to 7 weeks postnatal) (vitamin E measures) and 2 weeks and 4 weeks of feeding (2 to 5 weeks postnatal) (other measures)

Notes

The infants were assigned to 1 of 6 groups by means of a random number table. Follow-up was complete

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random number table

Allocation concealment (selection bias) Unclear risk

Blinding of randomisation: not known

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Blinding of outcome assessment: not known

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes (100%)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Hall 1993

Methods

Blinding of randomisation: not known
Blinding of intervention: yes (double-blind)
Complete follow-up: no (37.3%)
Blinding of outcome measurement: yes

Participants

Gestation: less than 35 weeks
Birth weight: less than 1800 g (AGA)
Feeding: formula or breast fed
Exclusions: chronic lung disease, NEC, neurological disease interfering with nutrition, other conditions affecting nutrient intake
Blood transfusions: permitted

Interventions

Iron supplementation group: approximately 2.4 mg/kg/day of iron (in formula containing 15 mg/L of iron) (n = 36)
No iron supplementation group: approximately 0.5 mg/kg/day of iron (in formula containing 3 mg/L of iron) (n = 43)
The above formulas were used from study entry to discharge
At the time of hospital discharge, all formula-fed infants were changed to a cow-milk based formula containing 12 mg/L of iron

Futher group not included in systematic review: 'Comparison group' receiving breast milk fortified with iron to provide 1.7 mg/L of iron (n = 71)

Outcomes

Primary outcomes: plasma iron, ferritin, transferrin, transferrin saturation
Secondary outcomes: haemoglobin, hematocrit, red blood cell count, MCV, MCH, MCHC and reticulocyte count. Weight, length, head circumference, arm circumference and triceps skinfold thickness
Timing: haematological outcomes: study entry (up to 21 days postnatal), hospital discharge (approximately 5 to 6 weeks postnatal), and 8 weeks after discharge (approximately 13 to 14 weeks postnatal). Anthropomorphic outcomes: study entry, hospital discharge and 2, 4, 8 and 12 weeks postdischarge

Notes

The method of randomisation was not described. Infants were enrolled within 21 days of birth. 56 infants completed the study (37.3%) - 20/36 in the high iron (HiFe) formula group, 23/43 in the low iron (MidFe) formula group, and 13/71 in the breast milk group

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not reported

Allocation concealment (selection bias) Unclear risk

Blinding of randomisation: not known

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes (double-blind)
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) High risk

Follow up to completion: 37.3%

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Halliday 1983

Methods

Blinding of randomisation: yes (author communication)
Blinding of intervention: yes (placebo used)
Complete follow-up: not known (100% follow-up implied)
Blinding of outcome measurement: yes (author communication)

Participants

Gestational age 28 to 36 weeks
Birth weight: no limit stated
Feeding: mostly fed evaporated milk supplemented with a multivitamin preparation
Exclusions: significant respiratory problems, SGA
Blood transfusion: nil received

Interventions

Iron supplementation group (also early iron group) (Group A): approximately 6 mg/kg/day (12 mg) of elemental iron (as ferrous sulphate with ascorbic acid) until one year of age (n = 16)
No iron supplementation group (Group B): ascorbic acid solution without iron until 1 year of age (n = 17)
Late iron group (Group C): placebo until 8 weeks, then 6 mg/kg/day (12 mg) of elemental iron daily until 1 year of age (n = 16)
Iron supplementation was commenced on the 7th day of life and increased from 2 mg to 12 mg daily by the 6th week

Outcomes

Primary outcomes: iron intake, haemoglobin concentration, serum iron, serum transferrin and serum ferritin
Timing: day 3 postnatally, then 3 weekly until 12 weeks and then at 18, 24, 36 and 54 weeks postnatal

Notes

The method of randomisation and the means of allocation concealment are not described. However, the author indicated in correspondence that the randomisation was generated by a statistician and allocation was by sealed envelopes. No loss to follow-up was recorded, although the number of babies analysed at each time interval is not specified

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Author communication

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes (author communication)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes (placebo used)
Blinding of outcome measurement: yes (author communication)

Incomplete outcome data (attrition bias) Unclear risk

Complete follow-up: not known (100% follow-up implied)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Hanninen 1961

Methods

Blinding of randomisation: no (quasi-randomised) to one of three groups
Blinding of intervention: not known
Complete follow-up: not known
Blinding of outcome measurement: not known

Participants

Gestation: preterm
Birth weight: between 1060 g to 2400 g
Feeding: not stated
Management of anaemia: excluded from analysis

Interventions

Iron supplementation group (Group 1): approximately 27 mg/kg/day of iron (as ferricholincitrate equivalent to 24 mg of iron twice daily) from the fourth week of life
No iron supplementation group (Group 3): no supplemental iron
Further group (Group 2) not included in the systematic review: approximately 64 mg/kg/day of iron (as ferrogluconate equivalent to 29 mg of iron 4 times a day) from the fourth week of life
Total n = 95: breakdown of infant numbers into study groups is not given

Outcomes

Primary outcome: haemoglobin, MCH
Timing: day 1 postnatal, 3 weeks of age, 3 months and six months postnatal

Notes

Infants were assigned on the basis of their order of admission. It is not clear whether the feeding method was the same between the two groups. It is stated that some of the babies in the control group were excluded because of anaemia. However, the rate of study completion was not stated

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Quasi-randomised

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (quasi-randomised) to one of three groups

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Blinding of outcome measurement: not known

Incomplete outcome data (attrition bias) Unclear risk

Complete follow-up: not known

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other known risk of bias

Jansson 1979

Methods

Blinding of randomisation: not known
Blinding of intervention: not known
Complete follow-up: yes (90.3%)
Blinding of outcome measurement: not known

Participants

Gestation: 35 weeks or less
Birth weight: 2000 g or less
Feeding: human milk until at least 2 weeks of age or a weight of 2100 g. From this point, they either continued to receive their mother's milk, or a formula containing 10 mg/L of ferrous sulphate
Exclusions: initial haemoglobin level below 150 g/L or above 260 g/L; signs or haemolysis
Blood transfusions: excluded

Interventions

Early iron group (Group A) : 2 to 3 mg/kg/day of iron (as ferrous succinate) from 3 weeks of age (n = 15)
Late iron group (Group B): 2 to 3 mg/kg/day of iron (as ferrous succinate) from 2 months of age (n = 13)
Both groups received the same vitamin supplement

Outcomes

Primary outcome: serum ferritin
Secondary outcomes: haemoglobin concentration, reticulocyte count, platelet count
Timing: 24hours, 8 to 10 weeks and 6 months of age

Notes

3 infants were subsequently excluded for not following the feeding regimen, leaving 28 infants for analysis (90.3%). It is recorded that 2 infants were partially breast fed while receiving iron-fortified formula; which group these belonged to is not documented, nor the possible effect of this on the results taken into account. Both groups received iron-fortified formula in addition to the intervention (early or late enteral iron supplementation)

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not reported

Allocation concealment (selection bias) Unclear risk

Blinding of randomisation: not known

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Blinding of outcome measurement: not known

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes (90.3%)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Lundstrom 1977

Methods

Blinding of randomisation: no (quasi-randomised)
Blinding of intervention: not known
Complete follow-up: yes (117/125, 93.6%), but 53 excluded from analysis
Blinding of outcome measurement: not known

Participants

Birth weight: 1050 g to 2000 g
Feeding: all received breast milk in hospital. The continuation of breastfeeding was encouraged after discharge, but some were weaned to formula. Exclusions: if clinical course had been complicated before 2 weeks of age. Any infant requiring an exchange transfusion was excluded
Transfusions: those requiring transfusion after enrolment were subsequently excluded

Interventions

Iron supplementation group: ferrous sulfate 2 mg/kg/day (as ferrous sulfate) from 2 weeks of age (n = 60). Some of these were weaned to a formula containing 11 mg/L of iron (providing approximately 1.8 mg/kg/day of iron), and thus had their oral iron supplement ceased
No iron supplementation group: no iron supplementation (n = 57)

Outcomes

Primary outcomes: haemoglobin concentration, serum iron, total iron binding capacity, serum ferritin, reticulocyte count, platelet count
Timing: 2 weeks, 1 month postnatal, then monthly until 6 months postnatal

Notes

Allocation to groups was based on birth date. 7 infants were excluded for receiving blood transfusions, and one for being diagnosed with hereditary spherocytosis. 44 of the unsupplemented group were excluded from analysis as they developed anaemia requiring iron therapy. A further 9 were inadvertently started too early on iron therapy, and also excluded

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Quasi-randomised

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (quasi-randomised)

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Blinding of outcome measurement: not known

Incomplete outcome data (attrition bias) Low risk

Follow-up to completion: 93.6%

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Melhorn 1971

Methods

Blinding of randomisation: not known
Blinding of intervention: not known
Complete follow-up: yes (79%)
Blinding of outcome measurement: not known

Participants

Gestation: before 40 weeks
Birth weight: below 2400 g
Feeding: formula
Exclusions: pre-existing haematological abnormalities, infections or surgery, SGA or LGA

Interventions

Iron supplementation group: approximately 8.7 mg/kg/day of iron as 10 mg, 15 mg or 20 mg of oral iron daily, depending on birth weight (< 1500 g, 1501 g to 2000 g and 2001 g to 2400 g respectively), with (Group 4, n = 50) or without (Group 3, n = 44) the addition of vitamin E, 25 IU/day orally
No iron supplementation group: no supplement (Group 1, n = 45) or vitamin E, 25 IU/day orally (Group 2, n = 47)

Vitamin E was given from the 8th to the 42nd day of life, and iron from the 15th to the 42nd day. All infants were fed a low iron formula (1.5 mg/L, or approximately 0.2 mg/kg/day of iron) while in hospital, but on discharge the babies in the iron supplementation group received a high iron formula (8.4 mg/L, or approximately 1.3 mg/kg/day of iron)

Outcomes

Primary outcomes: haemoglobin, hematocrit, reticulocyte count, platelet count, red cell fragility, serum tocopherol, serum iron
Timing: day 1 postnatal, then weekly until 4 weeks, then 2 to 4 weekly until 16 weeks postnatal

Notes

Infants in the groups receiving iron supplementation received an iron-fortified formula between hospital discharge and 4 months of age (8 mg/quart or 8.4 mg/L of iron), and the others a low iron formula (1.4 mg/quart or 1.5 mg/L). As planned, infants who developed a haemoglobin concentration below 75 g/L were removed from the study. Of the 234 infants enrolled, 186 were studied. 38 infants were removed from the study, 10 because of haemoglobin levels below 75 g/L

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not stated

Allocation concealment (selection bias) Unclear risk

Blinding of randomisation: not known

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Blinding of outcome measurement: not known

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes (79%)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Melnick 1988

Methods

Blinding of randomisation: no (author communication)
Blinding of intervention: no (author communication)
Complete follow-up: not known (implied to be complete)
Blinding of outcome measurement: no (author communication)

Participants

38 LBW (AGA) infants

Interventions

Iron supplementation group: approximately 2.4 mg/kg/day of iron (in formula containing 15 mg/L of iron)
No iron supplementation group: approximately 0.8 mg/kg/day of iron (in formula containing 3.5 mg/L of iron)
Total n = 19

Outcomes

Primary outcomes: haemoglobin, serum ferritin, transferrin concentration
Timing: study entry, day 15 and day 29 (postnatal age uncertain but estimated to be approximately 2 weeks, 4 weeks and 6 weeks postnatal)

Notes

The number of infants in each study group is not recorded, nor is the adequacy of follow-up. No loss to follow-up was recorded

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not stated

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (author communication)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no (author communication)
Blinding of outcome measurement: no (author communication)

Incomplete outcome data (attrition bias) Unclear risk

Complete follow-up: not known (implied to be complete)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Quilligan 1954

Methods

Blinding of randomisation: no (quasi-randomised)
Blinding of intervention: not known
Complete follow-up: no (approximately 50%)
Blinding of outcome measurement: not known

Participants

38 premature infants. The mean weight and gestation of the cohort was not reported
Feeding method: not known
Blood transfusion policy: not stated

Interventions

Iron supplementation group (Group 3): approximately 10 mg/kg/day of iron (as ferrous sulfate, 22.5 mg/day), and 40 mg of cobalt chloride daily
No iron supplementation group (Group 1): no supplement (n = 12)
Further group, not included in systematic review (Group 2): 75 mg of ferrous sulfate mixture daily (n = 10) (no data on this group because of loss to follow-up)

Outcomes

Primary outcomes: haemoglobin, hematocrit, red blood cell count, reticulocyte count
Secondary outcome: weight
Timing: weekly while the infants were inpatients, approximately every 10 days after discharge, up to 60 days postnatal

Notes

Divided on a quasi-randomised fashion (based on 'serial admissions'). It is not clear whether the groups were treated equally in all other respects; for example, the method of feeding is not documented. The authors reported a poor follow-up rate, but did not publish exact numbers. Attendence at the follow-up visits was variable, with as few as 5 of 12 infants in the control group presenting in day 41 to 50 and 8 of 16 in the treatment group being tested on day 51 to 60

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Quasi-randomised

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (quasi-randomised)

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: not known
Blinding of outcome measurement: not known

Incomplete outcome data (attrition bias) High risk

Complete follow-up: no (approximately 50%)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Unclear risk

Insufficient information

Reedy 1952

Methods

Blinding of randomisation: no (quasi-randomised)
Blinding of intervention: no (no placebo)
Complete follow-up: no (20.7%)
Blinding of outcome assessment: not known

Participants

Gestation: premature
Birth weight: 2268 g or below
Feeding: breast milk initially, with most changed later to a formula
Exclusions: poor clinic attendance
Blood transfusion: excluded from study

Interventions

Iron supplementation group (Group 1): approximately 1.3 mg/kg/day of iron until discharge, then approximately 5.4 mg/kg/day of iron, as iron mixture. The iron mixture consisted of a mixture of liver concentrate, copper sulfate, iron and ammonium citrate (elemental iron 66 mg per ounce, or approximately 2.3 mg/mL), at a dose of 15 drops (approximately 1.4 mg iron) per day as inpatients, and 1 teaspoon (approximately 11.5 mg) per day from discharge (at standard discharge weight of 2126 g) (n = 30)
Control group: no supplement or placebo (n = 32)
Short duration group: iron mixture for the first three months only (n = 17)

Outcomes

Primary outcomes: red cell count, haemoglobin, reticulocyte count, leukocyte count, eosinophil count
Secondary outcome: weight
Timing: 24 to 48 hours postnatal, every 7 days while inpatients, then monthly as outpatients until 12 months postnatal

Notes

Infants were assigned on the basis of their order of admission to the nursery (i.e. quasi-randomised), with alternate infants receiving iron supplementation from the 7th day of life. 382 babies were commenced on the study; 24 discontinued because of need for blood transfusion; 10 were excluded because of poor clinic attendance; and 269 were lost to follow-up or died. Thus, 79 infants were included in the analysis

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Quasi-randomised

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (quasi-randomised)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no (no placebo)
Blinding of outcome assessment: not known

Incomplete outcome data (attrition bias) High risk

Complete follow-up: no (20.7%)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Rudolph 1981

Methods

Blinding of randomisation: yes (author communication)
Blinding of intervention: no
Complete follow-up: no (60% at 6 weeks)
Blinding of outcome measurement: yes

Participants

Gestation: 32 weeks or less
Birth weight: 1001 to 1600 g
Feeding: formula
Exclusions: haemolytic disease, clinical illness, or a hematocrit level > 0.38 on day 5 to 6
Transfusions: policy not stated

Interventions

Iron supplementation group: approximately 1.9 mg/kg/day of iron (in formula containing 12 mg/L of iron) (formula A1) (n = 10)
No iron supplementation group: cow's milk-based formula containing only a trace of iron (formula A) (n = 10)
Further group not analysed in systematic review: soy-based formula containing 12 mg/L of iron (n = 10)

Outcomes

Primary outcomes: haemoglobin, hematocrit, reticulocytes, hydrogen peroxide haemolysis, serum cholesterol, serum vitamin E
Secondary outcomes: red cell and plasma selenium
Timing: weekly until 6 weeks postnatal

Notes

Assignment was at 5 to 6days of age. There was no cross-over in groups for analysis. 30 infants were entered into the study. Of these 26 were followed up until 6 weeks of age, or hospital discharge at approximately 5 weeks of age. 18/30 (60%) were analysed at 6 weeks

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method not stated

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes (author communication)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no
Blinding of outcome measurement: yes

Patient care staff were not blinded; laboratory personnel were blinded

Incomplete outcome data (attrition bias) High risk

Follow-up to completion: 60%

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Sankar 2009

Methods

Blinding of randomisation: yes
Blinding of intervention: no
Complete follow-up: yes (91%)
Blinding of outcome measurement: yes

Participants

Gestation: mean 32 weeks, all preterm
Birthweight: < 1500 g (mean approximately 1200 g)
Feeding: > 90% exclusively or predominantly breast fed at enrolment
Exclusions: major anomalies; rhesus haemolytic disease
Transfusions: permitted (restrictive policy)

Interventions

Iron supplementation group (enteral colloidal iron preparation): 3 mg/kg/day (birth weight 1000 g to 1500 g) or 4 mg/kg/day (birth weight < 1000 g); preparation also contained folic acid (200 mcg/mL) and vitamin B12 (5 mcg/mL). Formula fed babies received iron-fortified formula (13.6 mg/L), with equivalent iron amount subtracted from daily supplement
Control group: no iron supplement. No placebo control. Formula fed babies received iron-fortified formula (13.6 mg/L)

Outcomes

Primary outcome: serum ferritin at 60 days
Secondary outcomes (at 60 days): haemoglobin concentration; hematocrit; weight; requirement for blood transfusion; re-hospitalisation; composite of morbidities (NEC, PVL, ROP, CNLD); sepsis/pneumonia

Notes

All infants received recommended intake of vitamins including folic acid and B12 through breast milk fortification or infant formula

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generation

Allocation concealment (selection bias) Low risk

Blinding of randomisation: yes

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) Low risk

Follow-up to completion: 91%

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Steinmacher 2007

Methods

Blinding of randomisation: no (author communication)
Blinding of intervention: yes; but allocation became obvious due to stool colour
Complete follow-up: yes (85%)
Blinding of outcome measurement: yes

Participants

Gestation: no limit
Birth weight: less than 1301 g
Feeding: either breast fed, or received an iron-fortified formula (12 mg/L, or approximately 1.9 mg/kg/day of iron)
Exclusion criteria: major anomalies, haemolytic disease and twin-to-twin transfusion
Blood transfusion policy: permitted, before and after entry; restrictive transfusion policy

Interventions

Iron supplementation group: 2 mg/kg/day of iron as ferrous sulfate, commenced as soon as enteral feedings were tolerated (n = 105)
No iron supplementation group: 2 mg/kg/day of iron as ferrous sulfate, commenced at 61 days of life (n = 99)
Management of anaemia: when the hematocrit level fell below 0.30, the dose of iron was increased to 4 mg/kg/day. The policy for the administration of blood transfusions was clearly outlined

Outcomes

Primary outcome: serum ferritin and incidence of iron deficiency
Secondary outcomes: transferrin, transferrin saturation, serum iron, reticulocytes, hematocrit; number of transfusions required and blood volume transfused
Additional outcomes at 5 years of age: clinical neurological examination; mobility assessment (Gross Motor Functioning Classification Scale (GMFCS)); motor co-ordination (Lincoln-Oseretzky Scale (short form) 18); cognitive function (Kaufmann Assessment Battery for Children, including MPC); visual assessment; behaviour (Child Behaviour Check List)

Notes

This study was a continuation of Franz 2000, using the original randomised cohort

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generation

Allocation concealment (selection bias) High risk

Blinding of randomisation: no (author communication)

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention: yes; but allocation became obvious due to stool colour
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes (85%)

Selective reporting (reporting bias) Unclear risk

No known selectivity

Other bias Low risk

No other risk of bias identified

Footnotes

ANOVA: analysis of variance
AGA: appropriate for gestational age
BUN: blood urea nitrogen
EPO: erythropoietin
FEP: free erythrocyte porphyrin
Hb: haemoglobin
HcT: hematocrit
HMF: human milk fortifiers
IU: international units
IVH: intraventricular haemorrhage
MCH: mean cell haemoglobin
MCHC: mean cell haemoglobin concentration (or mean erythrocyte haemoglobin concentration)
MCV: mean corpuscular volume
NEC: necrotising enterocolitis
RCC: red cell count
SGA: small for gestational age

Characteristics of excluded studies

Arnon 2007

Reason for exclusion

All study subjects were included in Arnon 2009. All outcomes are included in Arnon 2009 (published and unpublished data)

Brozovic 1974

Reason for exclusion

Not a controlled trial of iron

Carnielli 1998

Reason for exclusion

Oral versus IV iron

Creutz 1958

Reason for exclusion

Not an RCT

Del Mundo 1964

Reason for exclusion

Not preterm or low birth weight infants

Dewey 2004

Reason for exclusion

Intervention is not iron supplementation, and 4 to 6 month old infants

Friel 1995

Reason for exclusion

IV iron administration

Friel 2003

Reason for exclusion

Study population is term infants of normal birth weight

Fydryk 1962

Reason for exclusion

Not a controlled trial

Garry 1981

Reason for exclusion

Study population is term infants of normal birth weight

Graeber 1977

Reason for exclusion

IV iron only

Greer 1988

Reason for exclusion

Not a trial of iron therapy

Gross 1974

Reason for exclusion

Method of allocation not stated

Heese 1990

Reason for exclusion

Compares IM and oral iron

James 1960

Reason for exclusion

IV iron administered

Jobert 1975

Reason for exclusion

Not an RCT

Kivivuori 1999

Reason for exclusion

Oral versus IM iron

Lindberg 1973

Reason for exclusion

Not an RCT

Meyer 1996

Reason for exclusion

Oral versus IV iron

Miller 2006

Reason for exclusion

Not an RCT

Naude 2000

Reason for exclusion

Two groups received same iron dose, but different oral formulations

Nazir 2002

Reason for exclusion

Subjects were on erythropoietin treatment

Nelson 1988

Reason for exclusion

Study population is term infants

Niccum 1953

Reason for exclusion

Not an RCT

Olivares 1992

Reason for exclusion

Not an RCT

Oski 1972

Reason for exclusion

Letter to the editor - not an RCT

Owen 1981

Reason for exclusion

Study population is term infants

Picciano 1980

Reason for exclusion

Study population is term infants

Rothe-Meyer 1953

Reason for exclusion

Not an RCT

Saarinen 1978

Reason for exclusion

Study population is term infants

Siep 1956

Reason for exclusion

Not an RCT

Singhal 2000

Reason for exclusion

Study population term babies with normal birth weight

Sitarz 1960

Reason for exclusion

IV iron administered

Tevetoglu 1958

Reason for exclusion

Not an RCT

Tuttle 1952

Reason for exclusion

Not an RCT

Victorin 1984

Reason for exclusion

Not an RCT

Footnotes

IM: intramuscular
IV: intravenous
RCT: randomised controlled trial

Characteristics of studies awaiting classification

Hurgoiu 1986

Methods

Awaiting translation

Participants
Interventions
Outcomes
Notes

Neimann 1957

Methods

Awaiting translation

Participants
Interventions
Outcomes
Notes

Characteristics of ongoing studies

  • None noted.

Summary of findings tables

  • None noted.

Additional tables

1 Summary of results by study

Study

Primary outcome

Secondary outcomes

Aggarwal 2005

  • Haemoglobin concentration: favoured iron supplementation group at 4 months postnatal, but not 3 months postnatal. Greater increase in haemoglobin from baseline at 3 months postnatal (not significant at 4 months postnatal)
  • Peripheral smear, serum ferritin, weight, length, head circumference: no differences

Arnon 2009

  • Alpha-tocopherol levels: no difference at 2, 4 and 8 weeks
  • Iron, ferritin and reticulocyte count: higher in early iron group at 8 weeks; no difference at 2 and 4 weeks
  • Haemoglobin level: higher in early iron group at 4 and 8 weeks
  • Serum transferrin receptor level: lower in early iron group at 4 and 8 weeks
  • Proportion of subjects having transfusions during study period: fewer in early iron group at 4 and 8 weeks

Barclay 1991

  • Erythrocyte superoxide dismutase levels: lower activity in high iron group when compared with iron supplementation and no iron supplementation groups, but not in iron supplementation versus no iron supplementation groups
  • Haemoglobin concentration and reticulocyte count: no difference
  • Plasma copper and zinc levels: no difference
  • Plasma ferritin levels: increased in high iron group compared with no iron supplementation group, but not significantly increased in iron supplementation group
  • Weight, length and head circumference: no difference

Berglund 2010

  • Haemoglobin level (at 6 months): high iron group > low iron group > no iron group
  • MCV: high iron group > no iron group; low iron group > no iron group
  • Ferritin: high iron group > low iron group > no iron group
  • Iron level: high iron group > no iron group; low iron group > no iron group
  • Transferrin saturation: high iron group > no iron group; low iron group > no iron group
  • Transferrin level and transferrin receptor level: low iron group < no iron; high iron group < no iron group
  • Growth (weight, length, head circumference, knee-heel length): no differences

Berseth 2004

  • Weight gain: no difference
  • Length and head circumference: no difference
  • Haematocrit, albumin, transthyretin, alkaline phosphatase, BUN, triglycerides, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, zinc, copper, ferritin and vitamin D: no difference
  • Incidence of feed intolerance (gastric residuals, abdominal distention and emesis): no difference
  • Incidence of NEC: no difference
  • Need for blood transfusion: lower in iron supplementation group from days 15-28

Coles 1954

  • Haemoglobin concentration: higher at 4, 5 and 6 months in iron supplementation group. Fewer infants in the iron supplementation and red blood cell count

Diamond 1958

  • Haemoglobin concentration: no difference

Ferlin 1998

  • Haemoglobin concentration and hematocrit: no difference
  • Weight, length and head circumference: no difference
  • Reticulocytes, platelets and red cell resistance to hydrogen peroxide: no difference

Franz 2000

  • Serum ferritin: no difference
  • Incidence of iron deficiency: increased in no iron supplementation group
  • Transferrin, transferrin saturation, hematocrit: no difference
  • Reticulocytes: higher in iron supplementation group
  • Number of transfusions required and blood volume transfused (after day 14): lower in iron supplementation group

Friel 2001

  • Griffith Developmental Assessment score: no difference
  • Weight, height: no difference.
  • Haemoglobin level, hematocrit, ferritin, transferrin, transferrin saturation and plasma iron: no difference
  • Malondialdehyde level, catalase level: no difference
  • Plasma zinc and copper levels: lower in high iron group, but not statistically significant
  • Red blood cell fragility, superoxide dismutase level: no difference
  • Glutathione peroxidase level: slightly higher in high iron group

Gorten 1964

  • Incidence of iron deficiency: lower in the iron supplementation group
  • Haemoglobin concentration, red blood cell count, hematocrit, MCV, MCH, MCHC: higher in the iron supplementation group from 10 to 14 weeks

Griffin 1999

  • Haemoglobin concentration: no difference
  • Plasma ferritin: no difference

Groh-Wargo 1990

  • Weight: no difference
  • Haemoglobin, MCV, FEP, transferrin saturation and ferritin: no difference

Gross 1985

  • Serum vitamin E concentration: lower in the iron supplementation group. Also lower in infant formula group compared with breast milk, and mature milk compared with preterm milk
  • Vitamin E/lipid ratio, hydrogen peroxide haemolysis, Haematocrit, reticulocyte count: no difference between iron supplementation and no iron supplementation group

Hall 1993

  • Plasma ferritin: higher in high iron group
  • Transferrin saturation: no difference
  • Serum iron: no difference
  • Transferrin: no difference between high iron and low iron groups
  • Haemoglobin, hematocrit, red blood cell count, MCH and reticulocyte count: no difference
  • MCV and MCHC: higher in high iron group
  • Weight, length, head circumference, arm circumference and triceps skinfold thickness: no difference

Halliday 1983

  • Iron intake, haemoglobin concentration, serum iron, serum transferrin and serum ferritin: no difference between iron supplementation and no iron supplementation group, nor between early iron and late iron group

Hanninen 1961

  • Haemoglobin, MCH: both higher in the iron supplementation group from 3 to 6 months postnatal

Jansson 1979

  • Serum ferritin: no difference
  • Haemoglobin concentration, reticulocyte count, platelet count: no difference

Lundstrom 1977

  • Haemoglobin concentration, MCV, transferrin saturation: higher in iron supplementation group from 3 months postnatal
  • Serum ferritin: higher in iron supplementation group from 2 months postnatal
  • Reticulocyte count, platelet count: no difference

Melhorn 1971

  • Haemoglobin: decreased in iron supplementation group (without vitamin E), but this effect ameliorated by addition of vitamin E
  • Reticulocyte count: increased in iron supplementation group (without vitamin E), but effect ameliorated from 8 weeks by addition of vitamin E
  • Platelet count: higher in non-vitamin E supplemented group
  • Red cell fragility: higher in non-vitamin E supplemented group, but not in iron supplemented group
  • Serum tocopherol: no difference between iron groups, but higher in vitamin E supplemented groups

Melnick 1988

  • Haemoglobin concentration: no difference
  • Serum ferritin: higher in iron supplementation group at 29 days
  • Transferrin concentration: no difference

Quilligan 1954

  • Haemoglobin concentration, hematocrit: higher in iron supplementation group
  • Red blood cell count, reticulocyte count: no difference
  • Weight: higher in no iron supplementation group at 11 to 20 days, but not thereafter

Reedy 1952

  • Red cell count: no difference, except at 5 months when RBC count was higher in iron supplementation group
  • Haemoglobin concentration: higher in iron supplementation group
  • Leukocyte count, eosinophil count: no difference (note: low rate of follow-up)
  • Weight: lower in the no iron supplementation group (low rate of follow-up)

Rudolph 1981

  • Haemoglobin, hematocrit, reticulocytes, hydrogen peroxide haemolysis, serum cholesterol and serum vitamin E: no difference
  • Red cell and plasma selenium: from weeks 4 to 6 postnatally, red cell selenium was higher in the iron supplementation group. Otherwise, no difference

Sankar 2009

  • Serum ferritin at 60 days of age: no difference
  • Haemoglobin and hematocrit: no difference
  • Neonatal morbidities: no difference
  • Weight: no difference
  • Blood transfusion, re-hospitalisation and sepsis/pneumonia: no difference

Steinmacher 2007

  • As per Franz 2000, plus additional measures at 5 years of age
  • neurologic examination: higher proportion normal in early iron group
  • Weight, length, head circumference, mobility, cognitive development, composite outcomes:no difference

[top]

References to studies

Included studies

Aggarwal 2005

Aggarwal D, Sachdev HP, Nagpal J, Singh T, Mallika V. Haematological effect of iron supplementation in breast fed term low birth weight infants. Archives of Disease in Childhood 2005;90:26-9.

Arnon 2009

Arnon S, Regev RH, Bauer S, Shainkin-Kestenbaum R, Shiff Y, Bental Y et al. Vitamin E levels during early iron supplementation in preterm infants. American Journal of Perinatology 2009;26:387-92.

Barclay 1991

Barclay SM, Aggett PJ, Lloyd DJ, Duffty P. Reduced erythrocyte superoxide dismutase activity in low birth weight infants given iron supplements. Pediatric Research 1991;29:297-301.

Berglund 2010

Berglund S, Westrup B, Domellöf M. Iron supplements reduce the risk of iron deficiency anemia in marginally low birth weight infants. Pediatrics 2010;126:e874-83.

Berseth 2004

Berseth CL, Van Aerde JE, Gross S, Stolz SI, Harris CL, Hansen JW. Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier. Pediatrics 2004;114:e699-706.

Coles 1954

Coles BL, James U. The effect of cobalt and iron salts on the anaemia of prematurity. Archives of Disease in Childhood 1954;29:85-96.

Diamond 1958

Diamond EF, Gonzales FG, Pisani A. The effect of cobalt-iron therapy on the blood picture in premature infants. Illinois Medical Journal 1958;113:154-6.

Ferlin 1998

Ferlin MLS, Chuan LS, Jorge SM, Vannucchi H. Early anemia of prematurity. Nutrition Research 1998;18:1161-73.

Franz 2000

Franz AR, Mihatsch WA, Sander S, Kron M, Pohlandt F. Prospective randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams. Pediatrics 2000;106:700-6.

Friel 2001

* Andrews WL, Friel JK, Simmons B, Aziz K, Kwa PG, Downton G. Effect of two levels of iron supplementation of infant formulas on developmental outcome and iron nutrition in very low birth weight infants. Pediatric Research 1998;43:255A.

Friel JK, Andrews WL, Aziz K, Kwa PG, Lepage G, L'Abbe MR. A randomized trial of two levels of iron supplementation and developmental outcome in low birth weight infants. Journal of Pediatrics 2001;139:254-60.

Gorten 1964

Gorten MK, Cross ER. Iron metabolism in premature infants: II. Prevention of iron deficiency. Journal of Pediatrics 1964;64:509-20.

Griffin 1999

Griffin IJ, Cooke RJ, Reid MM, McCormick KP, Smith JS. Iron nutritional status in preterm infants fed formulas fortified with iron. Archives of Disease in Childhood Fetal and Neonatal Edition 1999;81:45-9.

Groh-Wargo 1990

Groh-Wargo SL, Danish EH, Super DM. Iron therapy in the premature infant. Pediatric Research 1990;27:284A.

Gross 1985

Gross SJ, Gabriel E. Vitamin E status in preterm infants fed human milk or infant formula. Journal of Pediatrics 1985;106:635-9.

Hall 1993

Hall RT, Wheeler RE, Benson J, Harris G, Rippetoe L. Feeding iron-fortified premature formula during initial hospitalization to infants less than 1800 grams birth weight. Pediatrics 1993;92:409-14.

Halliday 1983

Halliday HL, Lappin TR, McClure BG. Do all pre-term infants need iron supplements? Irish Medical Journal 1983;76:430-2.

Hanninen 1961

Hanninen P, Peltonen T, Salmi T. On the use of iron in the treatment of premature infants. Kinderarztliche Praxis 1961;29:521-4.

Jansson 1979

Jansson L, Holmberg L, Ekman R. Medicinal iron to low birth weight infants. Acta Paediatrica Scandinavica 1979;68:705-8.

Lundstrom 1977

Lundstrom U, Siimes MA, Dallman PR. At what age does iron supplementation become necessary in low-birth-weight infants? Journal of Pediatrics 1977;91:878-83.

Melhorn 1971

Melhorn DK, Gross S. Vitamin E-dependent anemia in the premature infant effects of large doses of medicinal iron. Journal of Pediatrics 1971;79:569-80.

Melnick 1988

Melnick G, Crouch JB, Caksackkas HL, Churella HR. Iron status of low-birth-weight infants fed formulas containing high or low iron content. Pediatric Research 1988;23:488A.

Quilligan 1954

Quilligan JJ Jr. Effect of a cobalt-iron mixture on the anemia of prematurity. Texas State Journal of Medicine 1954;50:294-6.

Reedy 1952

Reedy ME, Schwartz SO, Plattner EB. Anemia of the premature infant: a two-year study of the response to iron medication. Journal of Pediatrics 1952;41:25-39.

Rudolph 1981

Rudolph N, Preis O, Bitzos E, Reale MM, Wong SL. Hematologic and selenium status of low-birth-weight infants fed formulas with and without iron. Journal of Pediatrics 1981;99:57-62.

Sankar 2009

Sankar MJ, Saxena R, Mani K, Agarwal R, Deorari AK, Paul VK. Early iron supplementation in very low birth weight infants - a randomized controlled trial. Acta Paediatrica 2009;98:953-8.

Steinmacher 2007

Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, Franz AR. Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams: neurocognitive development at 5.3 years' corrected age. Pediatrics 2007;120:538-46.

Excluded studies

Arnon 2007

Arnon S, Shiff Y, Litmanovitz I, Regev RH, Bauer S, Shainkin-Kestenbaum R et al. The efficacy and safety of early supplementation of iron polymaltose complex in preterm infants. American Journal of Perinatology 2007;24:95-100.

Brozovic 1974

Brozovic B, Burland WL, Simpson K, Lord J. Iron status of preterm low birthweight infants and their response to oral iron. Archives of Disease in Childhood 1974;49:386-9.

Carnielli 1998

Carnielli VP, Da Riol R, Montini G. Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants. Archives of Disease in Childhood Fetal and Neonatal Edition 1998;79:F44-8.

Creutz 1958

Creutz E, Steinhoff A. Prevention of anemia in the newborn with cobalt-ferrlecit. Kinderarztliche Praxis 1958;26:17-20.

Del Mundo 1964

Del Mundo F, Adiao AC, Sta. Ana P. A study of iron depletion prophylaxis by the use of iron-containing milk formulas. Journal of the Philippine Medical Association 1964;40:779-86.

Dewey 2004

Dewey KG, Cohen RJ, Brown KH. Exclusive breast-feeding for 6 months, with iron supplementation, maintains adequate micronutrient status among term, low-birthweight, breast-fed infants in Honduras. Journal of Nutrition 2004;134:1091-8.

Friel 1995

Friel JK, Andrews WL, Hall MS, Rodway MS, McCloy UC, Matthew JD et al. Intravenous iron administration to very-low-birth-weight newborns receiving total and partial parenteral nutrition. Journal of Parenteral and Enteral Nutrition 1995;19:114-8.

Friel 2003

Friel JK, Aziz K, Andrews WL, Harding SV, Courage ML, Adams RJ. A double-masked, randomized control trial of iron supplementation in early infancy in healthy term breast-fed infants. Journal of Pediatrics 2003;143:582-6.

Fydryk 1962

Fydryk J, Lacki L, Cieslak E. Treatment of hypochromic anemia in underweight infants with oral iron preparations. Pediatria Polska 1962;37:919-26.

Garry 1981

Garry PJ, Owen GM, Hooper EM, Gilbert BA. Iron absorption from human milk and formula with and without iron supplementation. Pediatric Research 1981;15:822-8.

Graeber 1977

Graeber JE, Williams ML, Oski FA. The use of intramuscular vitamin E in the premature infant. Optimum dose and iron interaction. Journal of Pediatrics 1977;90:282-4.

Greer 1988

Greer FR, McCormick A. Growth and calcium metabolism in premature infants fed varying amounts of protein and minerals during the first year of life. Pediatric Research 1988;23:492A.

Gross 1974

Gross S, Melhorn DK. Vitamin E-dependent anemia in the premature infant. Journal of Pediatrics 1974;85:753-9.

Heese 1990

Heese HD, Smith S, Watermeyer S, Dempster WS, Jakubiec L. Prevention of iron deficiency in preterm neonates during infancy. South African Medical Journal 1990;77:339-45.

James 1960

James JA, Combes M. Iron deficiency in the premature infant: Significance, and prevention by the intramuscular administration of iron-dextran. Pediatrics 1960;26:368-74.

Jobert 1975

Jobert J, Bachelot C, Jerome JM, Sele M, Bost M. Trial treatment of early anemia in premature infants. Pediatrie 1975;30:809-20.

Kivivuori 1999

Kivivuori SM, Virtanen M, Raivio KO, Viinikka L, Siimes MA. Oral iron is sufficient for erythropoietin treatment of very low birth-weight infants. European Journal of Pediatrics 1999;158:147-51.

Lindberg 1973

* Lindberg T. Supply of vitamins and iron to premature babies. Lakartidningen 1973;70:3260-2.

Meyer 1996

Meyer MP, Haworth C, Meyer JH, Commerford A. A comparison of oral and intravenous iron supplementation in preterm infants receiving recombinant erythropoietin. Journal of Pediatrics 1996;129:258-63.

Miller 2006

Miller SM, McPherson RJ, Juul SE. Iron sulfate supplementation decreases zinc protoporphyrin to heme ratio in premature infants. Journal of Pediatrics 2006;148:44-8.

Naude 2000

Naude S, Clijsen S, Naulaers G, Daniels H, Vanhole C, Devlieger H. Iron supplementation in preterm infants: a study comparing the effect and tolerance of a Fe2+ and a nonionic FeIII compound. Journal of Clinical Pharmacology 2000;40:1447-51.

Nazir 2002

Nazir S, Peverini RL, Derning DD, Hopper AO, Vyhmeister NR. Comparison of 2 iron doses in infants receiving recombinant human erythropoietin therapy. Archives of Pediatrics and Adolescent Medicine 2002;156:540-4.

Nelson 1988

Nelson SE, Ziegler EE, Copeland AM, Edwards BB, Fomon SJ. Lack of adverse reactions to iron-fortified formula. Pediatrics 1988;81:360-4.

Niccum 1953

Niccum WL, Jackson RL, Stearns G. Use of ferric and ferrous iron in the prevention of hypochromic anemia in infants. American Journal of Diseases in Children 1953;86:553-67.

Olivares 1992

Olivares M, Llaguno S, Marin V, Hertrampf E, Mena P, Milad M. Iron status in low-birth-weight infants, small and appropriate for gestational age. Acta Paediatrica 1992;81:824-8.

Oski 1972

Oski FA. Iron-fortified formulas in infancy: best form of iron supplementation? Journal of Pediatrics 1972;80:524-5.

Owen 1981

Owen GM, Garry PJ, Hooper EM, Gilbert BA, Pathak D. Iron nutriture of infants exclusively breast-fed the first five months. Journal of Pediatrics 1981;99:237-40.

Picciano 1980

Picciano MF, Deering RH. The influence of feeding regimens on iron status during infancy. American Journal of Clinical Nutrition 1980;33:746-53.

Rothe-Meyer 1953

Rothe-Meyer A, Kreutzfeldt H. Iron therapy for the premature infant. Ugeskrift for Laeger 1953;115:331-3.

Saarinen 1978

Saarinen UM. Need for iron supplementation in infants on prolonged breast feeding. Journal of Pediatrics 1978;93:177-80.

Siep 1956

Halvorsen S, Seip M. Erythrocyte production and iron stores in premature infants during the first months of life; the anemia of prematurity-etiology, pathogenesis, iron requirement. Acta Paediatrica 1956;45:600-17.

Singhal 2000

Singhal A, Morley R, Abbott R, Fairweather-Tait S, Stephenson T, Lucas A. Clinical safety of iron-fortified formulas. Pediatrics 2000;105:E38.

Sitarz 1960

Sitarz AL, Wolff JA, Von Hofe FH. Comparison of oral and intramuscular administration of iron for prevention of the late anemia of premature infants. Pediatrics 1960;26:375-86.

Tevetoglu 1958

Tevetoglu F, Ozkaragoz K. Cobalt-iron therapy in the treatment and prevention of the anemia of prematurity. Medical Times 1958;86:81-7.

Tuttle 1952

Tuttle AH, Etteldorf JN. Molybdenized ferrous sulfate (mol-iron) in the treatment of the anemia of premature infants. Journal of Pediatrics 1952;41:170-5.

Victorin 1984

Victorin LH, Olegard R. Iron in the preterm infant: a pilot study comparing Fe2+ and Fe3+ tolerance and effect. Journal of Pediatrics 1984;105:151-2.

Studies awaiting classification

Hurgoiu 1986

Hurgoiu V, Rub-Saidac A, Filipas V, Marcu A, Adam M. Test of maternal milk supplemented with iron in the feeding of premature infants. Revista de Pediatrie, Obstetrica Si Ginecologie Pediatria 1986;35:91-5.

Neimann 1957

Neimann N, De Vezeaux De Lavergne E, Pierson M, Stehlin S, Daubinet G. Iron metabolism in infants and the problem of physiological hypochromic anemia in infancy, results of iron therapy. Semaine des Hopitaux 1957;33:4007-18P.

Ongoing studies

  • None noted.

Other references

Additional references

AAP 1985

American Academy of Pediatrics Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatrics 1985;75:976-86.

Baker 2010

Baker RD, Greer FR; Committee on Nutrition American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age). Pediatrics 2010;126:1040-50.

Brown 1996

Brown MS. Effect of transfusion and phlebotomy on serum ferritin levels in low birth weight infants. Journal of Perinatology 1996;16:39-42.

Cooke 1997

Cooke RW, Drury JA, Yoxall CW, James C. Blood transfusion and chronic lung disease in preterm infants. European Journal of Pediatrics 1997;156:47-50.

Dani 2001

Dani C, Reali MF, Bertini G, Martelli E, Pezzati M, Rubaltelli FF. The role of blood transfusions and iron intake on retinopathy of prematurity. Early Human Development 2001;62:57-63.

Doyle 1992

Doyle JJ, Zipursky A. Neonatal blood disorders. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:425.

Hesse 1997

Hesse L, Eberl W, Schlaud M, Poets CF. Blood transfusion. Iron load and retinopathy of prematurity. European Journal of Pediatrics 1997;156:465-70.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Hyams 1995

Hyams JS, Treem WR, Etienne NL, Weinerman H, MacGilpin D, Hine P et al. Effect of infant formula on stool characteristics of young infants. Pediatrics 1995;95:50-4.

Inder 1997

Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA. High iron status in very low birth weight infants is associated with an increased risk of retinopathy of prematurity. Journal of Pediatrics 1997;131:541-4.

Lozoff 1987

Lozoff B, Brittenham GM, Wolf AW, McClish DK, Kuhnert PM, Jimenez E et al. Iron deficiency anaemia and iron therapy effects on infant developmental test performance. Pediatrics 1987;79:981-95.

McGuire 2003

McGuire W, Anthony MY. Donor human milk versus formula for preventing necrotising enterocolitis in preterm infants: systematic review. Archives of Disease in Childhood Fetal & Neonatal Edition 2003;88:F11-4.

Ng 2001

Ng PC, Lam CW, Lee CH, To KF, Fok TF, Chan IH et al. Hepatic iron storage in very low birthweight infants after multiple blood transfusions. Archives of Disease in Childhood Fetal & Neonatal Edition 2001;84:F101-5.

Rao 2002

Rao R, Georgieff RR. Perinatal aspects of iron metabolism. Acta Paediatrica Suppl 2002;91:124-9.

RevMan 2011

Review Manager (RevMan) [Computer program]. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011, Version 5.1.

Shaw 1982

Shaw JC. Iron absorption by the premature infant. The effect of transfusion and iron supplements on the serum ferritin levels. Acta Paediatrica Scandinavica Suppl 1982;299:83-9.

Walter 1989

Walter T, De Andraca I, Chadud P, Perales CG. Iron deficiency anemia: adverse effects on infant psychomotor development. Pediatrics 1989;84:7-17.

Other published versions of this review

  • None noted.

Classification pending references

  • None noted.

[top]

Data and analyses

1 Enteral iron supplementation versus no iron supplementation

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Weight at 12 months or less [g] 4 Mean Difference (IV, Fixed, 95% CI [g]) No totals
1.1.1 Full or partial breast feeding, or not stated 4 Mean Difference (IV, Fixed, 95% CI [g]) No totals
1.2 Length at 12 months or less [cm] 3 Mean Difference (IV, Fixed, 95% CI [cm]) No totals
1.2.1 Full or partial breast feeding, or not stated 3 Mean Difference (IV, Fixed, 95% CI [cm]) No totals
1.3 Head circumference at 12 months or less [cm] 3 Mean Difference (IV, Fixed, 95% CI [cm]) No totals
1.3.1 Full or partial breast feeding, or not stated 3 Mean Difference (IV, Fixed, 95% CI [cm]) No totals
1.4 Haemoglobin concentration at 6 to 8 weeks [g/L] 9 526 Mean Difference (IV, Fixed, 95% CI [g/L]) 1.43 [-0.20, 3.07]
1.5 Haemoglobin concentration at 3 to 4 months [g/L] 5 269 Mean Difference (IV, Fixed, 95% CI [g/L]) 2.46 [-0.04, 4.95]
1.6 Haemoglobin concentration at 6 to 9 months [g/L] 3 458 Mean Difference (IV, Fixed, 95% CI [g/L]) 5.91 [4.25, 7.58]
1.6.1 Fully formula fed 2 132 Mean Difference (IV, Fixed, 95% CI [g/L]) 6.56 [3.07, 10.05]
1.6.2 Full or partial breast feeding, or not stated 1 165 Mean Difference (IV, Fixed, 95% CI [g/L]) 8.00 [5.20, 10.80]
1.6.3 Full or partial breastfeeding (1 mg/kg/day iron) 1 161 Mean Difference (IV, Fixed, 95% CI [g/L]) 3.80 [1.23, 6.37]
1.7 Haemoglobin concentration at 12 months [g/L] 1 81 Mean Difference (IV, Fixed, 95% CI [g/L]) 16.00 [10.66, 21.34]
1.8 Serum ferritin at 6 to 8 weeks [mcg/L] 3 124 Mean Difference (IV, Fixed, 95% CI [mcg/L]) 6.70 [0.13, 13.27]
1.9 Serum ferritin at 3 to 4 months [mcg/L] 3 104 Mean Difference (IV, Fixed, 95% CI [mcg/L]) 11.13 [0.74, 21.52]
1.10 Serum ferritin at 6 to 9 months [mcg/L] 1 Mean Difference (IV, Fixed, 95% CI [mcg/L]) No totals
1.10.1 2 mg/kg/day 1 Mean Difference (IV, Fixed, 95% CI [mcg/L]) No totals
1.10.2 1 mg/kg/day 1 Mean Difference (IV, Fixed, 95% CI [mcg/L]) No totals
1.11 MCV at 6 to 9 months [fL] 1 326 Mean Difference (IV, Fixed, 95% CI [fL]) 2.10 [1.24, 2.96]
1.11.1 2 mg/kg/day iron 1 165 Mean Difference (IV, Fixed, 95% CI [fL]) 2.50 [1.28, 3.72]
1.11.2 1 mg/kg/day iron 1 161 Mean Difference (IV, Fixed, 95% CI [fL]) 1.70 [0.49, 2.91]
1.12 Transferrin saturation at 6 to 8 weeks [%] 1 Mean Difference (IV, Fixed, 95% CI [%]) No totals
1.13 Transferrin saturation at 3 to 4 months [%] 1 Mean Difference (IV, Fixed, 95% CI [%]) No totals
1.14 Transferrin saturation at 6 to 9 months [%] 1 326 Mean Difference (IV, Fixed, 95% CI [%]) 7.14 [5.19, 9.08]
1.14.1 2 mg/kg/day iron 1 165 Mean Difference (IV, Fixed, 95% CI [%]) 9.10 [5.97, 12.23]
1.14.2 1 mg/kg/day iron 1 161 Mean Difference (IV, Fixed, 95% CI [%]) 5.90 [3.42, 8.38]
1.15 Subgroup analyses - Hb at 6 to 8 weeks [g/L] 9 Mean Difference (IV, Fixed, 95% CI [g/L]) Subtotals only
1.15.1 Fully formula fed 5 389 Mean Difference (IV, Fixed, 95% CI [g/L]) 0.71 [-1.14, 2.55]
1.15.2 Full or partial breast feeding, or not stated 4 137 Mean Difference (IV, Fixed, 95% CI [g/L]) 4.14 [0.59, 7.70]
1.15.3 Early commencement 8 463 Mean Difference (IV, Fixed, 95% CI [g/L]) 1.55 [-0.12, 3.23]
1.15.4 Late commencement 1 63 Mean Difference (IV, Fixed, 95% CI [g/L]) -1.10 [-8.82, 6.62]
1.15.5 Low dose 3 209 Mean Difference (IV, Fixed, 95% CI [g/L]) 3.92 [1.53, 6.32]
1.15.6 High dose 6 317 Mean Difference (IV, Fixed, 95% CI [g/L]) -0.76 [-3.01, 1.49]
1.15.7 Under 1500 g mean birth weight 5 203 Mean Difference (IV, Fixed, 95% CI [g/L]) -0.42 [-4.27, 3.43]
1.15.8 1500 g or over mean birth weight 3 305 Mean Difference (IV, Fixed, 95% CI [g/L]) 0.77 [-1.16, 2.69]
1.16 Enteral feed intolerance 1 Risk Ratio (M-H, Fixed, 95% CI) No totals
1.17 Subgroup analyses - Hb at 3 to 4 months [g/L] 5 Mean Difference (IV, Fixed, 95% CI [g/L]) Subtotals only
1.17.1 Fully formula fed 3 208 Mean Difference (IV, Fixed, 95% CI [g/L]) 2.39 [-0.42, 5.21]
1.17.2 Full or partial breast feeding 2 61 Mean Difference (IV, Fixed, 95% CI [g/L]) 2.69 [-2.70, 8.08]
1.17.3 Early commencement 3 180 Mean Difference (IV, Fixed, 95% CI [g/L]) 0.75 [-2.36, 3.85]
1.17.4 Late commencement 2 89 Mean Difference (IV, Fixed, 95% CI [g/L]) 5.59 [1.39, 9.79]
1.17.5 Low dose 2 165 Mean Difference (IV, Fixed, 95% CI [g/L]) 4.00 [0.85, 7.15]
1.17.6 High dose 3 104 Mean Difference (IV, Fixed, 95% CI [g/L]) -0.15 [-4.24, 3.94]
1.17.7 Under 1500 g mean birth weight 2 106 Mean Difference (IV, Fixed, 95% CI [g/L]) 0.98 [-2.89, 4.84]
1.17.8 1500 g or over birth weight 3 163 Mean Difference (IV, Fixed, 95% CI [g/L]) 3.52 [0.25, 6.79]

2 Early versus late iron supplementation

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Neurodevelopmental outcome (MPC) at 5 years 1 164 Mean Difference (IV, Fixed, 95% CI) 3.00 [-2.06, 8.06]
2.2 Haemoglobin concentration at 6 to 8 weeks [g/L] 2 144 Mean Difference (IV, Fixed, 95% CI [g/L]) 15.49 [12.74, 18.24]
2.3 Haemoglobin concentration at 6 to 9 months [g/L] 1 Mean Difference (IV, Fixed, 95% CI [g/L]) No totals
2.4 Ferritin level at 6 to 8 weeks [mcg/L] 1 116 Mean Difference (IV, Fixed, 95% CI [mcg/L]) 25.00 [16.94, 33.06]

3 High dose versus low dose iron supplementation

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Neurodevelopmental outcome (Grifiths Developmental Assessment score) at 12 months or less 1 Mean Difference (IV, Fixed, 95% CI) No totals
3.2 Haemoglobin concentration at 6 to 8 weeks [g/L] 2 77 Mean Difference (IV, Fixed, 95% CI [g/L]) -1.41 [-8.24, 5.42]
3.2.1 Full formula feeding 1 41 Mean Difference (IV, Fixed, 95% CI [g/L]) -5.00 [-17.86, 7.86]
3.2.2 Full or partial breast feeding, or not stated 1 36 Mean Difference (IV, Fixed, 95% CI [g/L]) 0.00 [-8.06, 8.06]
3.3 Haemoglobin concentration at 3 to 4 months [g/L] 3 117 Mean Difference (IV, Fixed, 95% CI [g/L]) 4.49 [0.84, 8.13]
3.3.1 Full formula feeding 2 81 Mean Difference (IV, Fixed, 95% CI [g/L]) 4.34 [0.21, 8.47]
3.3.2 Full or partial breast feeding, or not stated 1 36 Mean Difference (IV, Fixed, 95% CI [g/L]) 5.00 [-2.79, 12.79]
3.4 Haemoglobin concentration at 6 to 9 months [g/L] 1 Mean Difference (IV, Fixed, 95% CI [g/L]) No totals
3.5 Haemoglobin concentration at 12 months [g/L] 1 Mean Difference (IV, Fixed, 95% CI [g/L]) No totals
3.6 Mean corpuscular volume at 3 to 4 months [fL] 1 Mean Difference (IV, Fixed, 95% CI [fL]) No totals
3.7 Serum ferritin at 6 to 8 weeks [mcg/L] 1 Mean Difference (IV, Fixed, 95% CI [mcg/L]) No totals
3.8 Serum ferritin at 3 to 4 months [mcg/L] 2 82 Mean Difference (IV, Fixed, 95% CI [mcg/L]) 4.15 [-3.71, 12.02]
3.9 Serum ferritin at 6 to 9 months [mcg/L] 1 Mean Difference (IV, Fixed, 95% CI [mcg/L]) No totals
3.10 Serum ferritin at 12 months [mcg/L] 1 Mean Difference (IV, Fixed, 95% CI [mcg/L]) No totals
3.11 Transferrin saturation at 6 to 8 weeks [%] 1 Mean Difference (IV, Fixed, 95% CI [%]) No totals
3.12 Transferrin saturation at 3 to 4 months [%] 2 85 Mean Difference (IV, Fixed, 95% CI [%]) 1.74 [-1.23, 4.71]
3.13 Transferrin saturation at 6 to 9 months [%] 1 Mean Difference (IV, Fixed, 95% CI [%]) No totals
3.14 Transferrin saturation at 12 months [%] 1 Mean Difference (IV, Fixed, 95% CI [%]) No totals

4 Short duration versus long duration iron supplementation

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
4.1 Haemoglobin at 6 to 8 weeks [g/L] 1 44 Mean Difference (IV, Fixed, 95% CI [g/L]) 3.70 [-3.79, 11.19]
4.2 Haemoglobin at 3 to 4 months [g/L] 1 44 Mean Difference (IV, Fixed, 95% CI [g/L]) 1.50 [-3.92, 6.92]
4.3 Haemoglobin at 6 to 9 months [g/L] 1 44 Mean Difference (IV, Fixed, 95% CI [g/L]) 5.70 [0.50, 10.90]

[top]

Figures

  • None noted.

[top]

Sources of support

Internal sources

  • Grantley Stable Neonatal Unit, Royal Women's Hospital, Brisbane, Australia
  • Dept of Paediatrics and Child Health, University of Queensland, Brisbane, Australia
  • Dept of Paediatrics, Logan Hospital, Australia

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

[top]

Feedback

  • None noted.

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2012 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.