University of Michigan
Department of Pediatrics
Evidence-Based Pediatrics Web Site

Question

• How much iron do premature infants weighing <1800g at birth and <35 weeks GA require in their initial feedings to have adequate iron stores at discharge?

Clinical Bottom Lines

1. Premature infants weighing <1800g at birth appear to benefit from formula with 15mg/L or approximately 1.3mg/kg/d. 
2. Premature infants feed formula with an iron content of 15mg/L during their initial feeds while hospitalized appear to have better iron stores at discharge.
3. To prevent an infant from having a hemoglobin less than 9 g/dL at discharge, two infants would have to be treated with the higher iron formula (NNT=2).

Summary of Key Evidence

1. Premature infants <1800g at birth and <35 week GA receiving low iron content formula (3mg/L) had evidence of decreased iron stores at the time of hospital discharge compared to infants receiving high iron content formula (15mg/L).  The low iron content group had a significantly lower mean plasma ferritin and an increased incidence of low Hgb (<9g/dL) and low transferrin saturation.¹
2. There was no evidence of hemolytic anemia in the high iron content group, theoretically due to the Vit E::PUFA (poly-unsaturated fatty acid) ratio of >1 in the formula preventing Vit E deficiency.
3. Red cell indices (MCV and MCHC) and were found to be too age dependent to be reliable indicators of iron status in the identified population.

Additional Comments

• Preterm infants are particularly susceptible to iron deficiency anemia due to the lack of iron stores built up in the 3rd trimester and also due to the large number of blood draws required during their hospitalizations.
• AAP recommends 2-3 mg/kg/day iron supplementation in preterm infants by 2 months of age.  This study suggests that there may be some benefit to starting this level of supplementation with the initial feeds.  If birth weight is 1000-1500g, the suggestion has been made that iron doses of 4mg/kg/day may be required.  With the adequate dose of Vit E in the formula, no real risk is identified to supplementing these infants with iron.
• Anemia of prematurity is felt to be due to a failure of premature infants to produce adequate amounts of erythropoietin.  This is attributed to a delay in the switch from liver to kidney as the primary site for erythropoietin production.  The liver cell's oxygen sensors are fairly insensitive to hypoxia due to the low oxygen tension in utero.  This leads to difficulty in the liver being able to respond to an anemic and hypoxic stimuli in the extrauterine environment.  Contributing to this is the increased volume of distribution and clearance of erythropoietin in the preterm infant.
• There is an increasing amount of research surrounding the use of erythropoietin therapy to treat anemia of prematurity.  If used, increased erythropoiesis may cause decreased iron stores and may require supplementation doses of up to 6mg/kg/day during therapy.

Citation

1. Hall RT, Wheeler RE, Benson J, Harris G, Rippetoe L.  Feeding Iron-Fortified Premature Formula During Initial Hospitalization to Infants <1800 Grams Birth Weight.  Pediatrics 1993:92(3):409-414.
2. Roth P. Anemia in Preterm Infants.  Pediatrics in Review 1996, 17(10).
3. Attias D.  Pathophysiology and Treatment of Anemia of Prematurity.  Journal of Pediatric Hematology/Oncology 1995, 17(1):13-18.
4. Groh-Wargo SL, Danish EH, Super DM.  Iron Therapy in the Premature Infant.  Pediatric Res 1990, 27:284A.

CAT Author: Patty Buck, MD

CAT Appraisers: John G. Frohna, MD

Date appraised: October 26, 1998