title: Special comments - Neonatal Intensive Care Drug Manual
text: Evidence
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  Efficacy
  Enteral iron prophylaxis in preterm and low birthweight infants
  A Cochrane 2012 review by Mills et al found (1) enteral iron supplementation of both preterm (<33 weeks GA) and low birth weight infants (<2500 g) of either term or preterm confers an improvement in haemoglobin and ferritin concentrations after eight weeks postnatal age and reduces the risk of anaemia, (2) no significant benefit in providing more than 2–3 mg/kg/day of elemental iron, (3) commencement of iron early (<28 days postnatal age) results in improved haematological parameters from as early as eight weeks of age onwards, and (4) less abnormal clinical neurological examination in early iron supplementation (commencement at <28 days of age) group (17% versus 35%; P = 0.02).6 (LOE I GOR A)
  McCarthy 2019 systematic review investigated the effects of enteral iron supplementation in preterm (<37 weeks’ gestation) and low-birthweight (LBW, <2500 g) infants.5 Iron supplementation was as either medicinal iron, infant formula or human milk fortifier. Iron at 2–4 mg/kg/d was found to have no effect on ferritin, haematocrit or haemoglobin concentrations in VLBW (<1500 g) infants. Higher dose (average 7–10 mg/kg/d) had no effect on ferritin, iron, transferrin saturation, transferrin receptors or total iron-binding capacity (TIBC). In marginally LBW infants (2000–2499 g), 2 mg/kg/d increased circulating iron, ferritin, transferrin saturation, transferrin receptors, mean corpuscular volume (MCV) and haemoglobin at 6 months and increased ferritin concentrations at 12 months. Long term (≥8 weeks) supplementation was associated with a decreased prevalence of iron deficiency and anaemia in preterm and LBW infants. Neither short-term nor long-term supplementation had effect on growth parameters including weight, head circumference and length. Short-term supplementation had no effect on neurological development. There was a trend towards benefit of early initiation: 35% of the late initiation group had an abnormal neurological examination result compared to 19% of the early initiation group. Long-term supplemented children had a significantly lower prevalence of behavioural problems than those in the placebo group (3% vs 13%, respectively) at 3.5 years and had significantly lower scores in externalising-type behaviours (aggression/attention seeking) at 7 years. No article reported on iron overload.5 (LOE I GOR A)
  Moreno-Fernandez 2019’s descriptive review of reports published between 2008 and 2018 included 16 studies enrolling 1743 neonates of 24–36 weeks gestation and drew similar conclusions as McCarthy et al.18
  Iron prophylaxis in marginally low birthweight infants: In a trial by Berglund et al, 285 infants with marginally low birth weights 2000–2500 g were randomised to 0, 1 or 2 mg/kg/day of medicinal iron from 6 weeks to 6 months of age. A dose of 2 mg/kg/day significantly reduced the risk of IDA at 6 months relative to placebo.7 Thirty-six percent and 10% of the infants who received the placebo developed iron deficiency and IDA, respectively, but only 4% and 0% of the infants in the group that received 2 mg/kg/day did. Iron supplements did not adversely affect infant growth, infections or other morbidity. In a follow-up study, they observed a significantly higher proportion of abnormal behavioural scores at 3.5 years of age in the placebo group.19 (LOE II GOR B)
  Iron supplementation at discharge and post-discharge in VLBW infants: Preterm infants with an average birth weight of 1.46 kg were given an iron intake of 6 versus 3 mg/kg/day at discharge and about 3 versus 2 mg/kg/day at 3 to 9 months. There was no difference between the 2 groups in anaemia prevalence or neurodevelopment at 12 months, but the high-iron group had higher glutathione peroxidase concentrations (a marker of oxidative stress), lower plasma zinc and copper concentrations, and more respiratory tract infections, suggesting possible adverse effects from the higher intake.20 (LOE II GOR B)
  Iron fortified formulas at discharge in LBW infants: Preterm infants with birth weights <1800 g do not achieve iron sufficiency on a formula containing ≤3 mg/L.21 Formulas containing 5–9 mg/L of iron appear to meet the iron requirements of erythropoiesis in healthy preterm infants during the first 6 months of life.22 However, 18% of the infants receiving the 9 mg/L formula and 30% of those receiving the 5 mg/L formula developed iron deficiency (serum ferritin concentration <10 microg/L) between 4 and 8 months of age in this study.22 (LOE II GOR B). NOTE: Common commercially available formulas in Australia contain 5–8 mg/L of iron.
  Early versus late iron supplementation in VLBW infants: Franz et al randomised 204 infants with an average birth weight of 0.87 kg into an early iron group receiving 2 to 4 mg/kg/day of iron supplements from about 2 weeks and a late iron group that did not receive iron supplements until 2 months of age. There were no differences in serum ferritin and haematocrit at 2 months of age but infants in the late iron group had received more blood transfusions.23 (LOE II GOR B)
  Iron supplementation as per serum ferritin: ESPGHAN 2013 cut-offs for definition of iron deficiency anaemia: 0–1 week: Hb <135 g/L and serum ferritin <40 microg/L; 1 week – 2 months: Hb <90 g/L and serum ferritin <40 microg/L. Serum ferritin <10 microg/L is considered low from 6 months of age.24 (LOE V)
  There are no specific guidelines with respect to iron supplementation in preterm infants with high serum ferritin concentrations. High serum ferritin has been suggested to be associated with high incidence of ROP.30 Serum ferritin concentrations >350 microg/L are generally accepted as high level.12,17,31 ESPGHAN 2005 recommendations suggested to limit serum ferritin concentrations to <500 micrograms/L.14 (LOE V)
  Some preterm infants with elevated serum ferritin may simultaneously have iron deficient erythropoiesis, suggesting inability to release ferritin bound hepatic iron to the bone marrow.32 Park et al31 compared serum ferritin in 46 very low birthweight infants with respect to (a) no transfusion, (b) transfusion volumes <100 mL/kg during the NICU stay and (c) transfusion volumes ≥100 mL/kg. When the infants reached enteral feeding of 100 mL/kg, iron supplementation (2 mg/kg) was started. No infant developed iron deficiency defined as serum ferritin <10 ng/mL. Mean serum ferritin was comparable at discharge among 3 groups. Maximum serum ferritin during the NICU stay was significantly higher in transfused ≥100 mL/kg (555.6±476.3, 352.1±276.7, 705.7±388.7 respectively). (LOE IV, GOR C)
  Parenteral iron prophylaxis during Rh EPO therapy
  There is a paucity of studies in relation to intravenous iron in neonates. Carnielli et al,13 in their RCT of recombinant human erythropoietin (r-HuEPO) therapy for low birth weight infants <1750 g administered IV iron polymaltose at 20 mg/kg weekly (equivalent to 2.8 mg/kg/day) as an IV infusion over 3 hours from 2nd day of life to 8th week of life (or hospital discharge). Meyer et al 1996 compared oral and IV iron supplementation in 42 preterm infants (<33 weeks' gestation, birth weight <1500 gm) being treated with recombinant human erythropoietin. Infants were randomly assigned to receive either oral iron (12 mg/kg/day) or IV iron sucrose (6 mg/kg per week). Both groups were given rHuEpo 600 U/kg per week in 3 divided doses subcutaneously. Iron sucrose was given over an hour in 10 ml of normal saline solution. IV iron was ceased temporarily for a week when serum ferritin increased to 275 micrograms/L. Supplements were given weekly thereafter. Both iron preparations were safe and well tolerated. The IV supplemented group did not have a decline in serum ferritin during EPO therapy. There was also a significant improvement in weight gain after IV administration of iron.36 Their study showed that IV iron sucrose of 6 mg/kg/week is enough to achieve erythropoiesis during Rh EPO therapy in stable infants. Ohls et al,12 in their RCT of EPO in infants <750 g administered 1 mg/kg/day IV iron-dextran in the first 14 days of life through PN solutions. The combination of EPO and IV iron resulted in fewer transfusions during their first 3 weeks of life in their study. No adverse effects were reported. Pollak et al, in their RCT trial of recombinant human erythropoietin (r-HuEPO) therapy for low birth weight infants <31 weeks and birthweight <1300 g, administered 2 mg of intravenous iron sucrose/kg/day diluted in sodium chloride 0.9% to a final concentration of 2 mg/mL and infused daily over 2 hours in one of 3 arms. No side effects were reported in this arm.37 Infants in this study were 3 weeks of age and clinically stable at the time of enrolment. A parenteral dose less than 2 mg/kg/day has been suggested by the authors to reduce the potential adverse effects of parenteral iron.
  ANMF consensus: IV iron dose of 1 mg/kg/day is sufficient during Rh EPO therapy. (LOE II GOR B)
  James BE et al,34 reported no adverse effects in 5 preterm infants given iron dextran at a dose of 10–450 microg/kg per day. No complications were observed in a study of 14 very low birth weight infants receiving IV iron dextran supplementation at a dose of 200–250 microg/kg per day.35
  Enteral iron supplementation after packed red cell transfusion
  Post-mortem liver iron study by Ng et al39 showed elevated liver iron stores with increasing volumes of transfusions. VLBW infants who received <180 mL of packed cells did not exhibit excessive hepatic iron storage, and those who received > 180 mL had hepatic iron concentrations > 40 micromol/g dry weight and/or histochemical liver iron grading ≥2. Authors concluded that routine iron supplementation in the latter group of infants would probably be unnecessary.39 Park et al investigated the iron status (serum ferritin) of very low birth weight infants receiving multiple erythrocyte transfusions and found that total volume of erythrocyte transfusion was not correlated to maximum serum ferritin concentrations until volume of transfusion was >100 mL/kg.31
  ANMF Consensus: Preterm infants receiving red cell transfusion volumes greater than 100 mL/kg may not need routine iron supplementation or require periodic (2-weekly) serum ferritin concentrations. (LOE IV GOR C)
  Oral iron therapy during recombinant human erythropoietin therapy: The European multicentre erythropoietin group administered oral iron 2 mg/day from day 14 onwards in their trial. If serum ferritin fell below 100 microgram/L, dose of iron was increased.40. Emmerson et al,41 in their RCT of RhEPO vs placebo used 6.25 mg oral iron daily from 4 weeks of age to discharge. Shannon KM et al 1995 commenced at 3 mg/kg/day of oral iron and increased to 6 mg/kg/day during their multicentre RCT of rhEPO. Messer et al started 3 mg/kg/dose of oral iron and increased to 8 mg/kg/day in their rhEPO stdy. Carnielli et al 1998 administered IV iron 20 mg/kg weekly equivalent to 3 mg/kg/day.42
  Safety
  Iron during NICU stay: In systematic reviews by Mills et al and McCarthy et al,5-6 only a small number of studies reported on clinical morbidities including necrotising enterocolitis, retinopathy of prematurity, chronic lung disease, periventricular leukomalacia, oxidative stress and sepsis. Patel et al,4 in a retrospective analysis of 598 VLBW infants ≤1500 g found that the cumulative dose of supplemental enteral iron exposure was independently associated with an increased risk of BPD (adjusted relative risk [RR] per 50 mg increase: 1.07, 95% CI 1.02–1.11; p = 0.002). Similarly, a greater total volume of RBC transfusion was independently associated with a higher risk of BPD (adjusted RR per 20 mL increase in RBCs transfused, 1.05; 95% CI, 1.02–1.07; p < 0.001). A prospective observational study in VLBW infants by Inder et al showed an independent significant association of retinopathy of prematurity with high serum iron concentrations at 7 days of age and may be an association with 28-day serum ferritin concentrations (OR: 1.86; 95% CI 0.99-4.83).2 Given the iron content of blood, and previous research which has suggested that preterm infants who receive multiple transfusions are at risk of iron overload,39 Brown et al 1996 suggests that the measurement of ferritin concentrations in preterm neonates who have received transfusions may be useful to guide the initiation of iron therapy, but again this remains untested.43
  Iron post-NICU: Excess iron has been associated with decreased growth, impaired cognitive development and an increased risk of infection, with evidence also emerging of altered gut microbiota in infants and young children.44,45 A meta-analysis has shown that iron supplementation leads to increased risk for malaria and other infections in malaria regions.46
  Bioavailability
  The absorption of iron from human milk is >50% and from cow milk-based formulas is approximately 4–12%. Absorption is better from whey predominant formula than casein-based formula. Only 1–7% of iron in soy milk-based formula is absorbed. The absorption and retention of oral medicinal iron depends upon the postnatal age and iron status of the infant. Absorption is better if medicinal iron is supplemented with breast milk or between meals. Approximately 25–30% of the administered iron is absorbed. Approximately 10–25% of the iron supplemented between feeding is incorporated into erythrocytes within 2 weeks. Ascorbic acid favours absorption. Iron absorption from fortified breast milk appears to be intact despite the high calcium content of the fortifier.17
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