Iron Deficiency, Part 3

Two previous articles published on this website have dealt with iron nutrition. This third article in the series deals with a recent document from the Scientific Committee for Food (SCF) of the European Union (EU), which has proposed changes in the iron content of infant and follow-on formulas.

Proposals and current directive
The table below compares the SCF proposals with the current EU Directive and the recommendations of the Life Sciences Research Office (LSRO) of the USA.

Two major changes have been proposed:

1. A formula without added iron is no longer included as permissible.
2. The maximum iron content of a follow-on formula is reduced from 2 to 1.7 mg per 100kcal.

General considerations
The process of weighing scientific evidence and making a recommendation, either by an individual expert or as a consensus statement from a group of experts, is a very valuable exercise. There are many statements of this variety, often from groups appointed by professional societies (the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) or the American Academy of Pediatrics (AAP), for example) or by national or international governments (individual countries, EU, WHO).

The SCF is in this later category, but unlike the others, its recommendations pass into law and are mandatory for all EU countries once they are accepted. Therefore, these recommendations must be much more evidence-based than those made by professional societies and individuals. This applies even more strongly if the recommendation (in effect, the directive) changes what has been previously accepted as standard practice.

So, the question becomes, "Is the evidence sufficiently strong to exclude the use of iron unfortified infant formulas and to introduce a mandatory change in the maximum concentration of iron in a follow-on formula?"

It is important to differentiate infant formulas (intended to provide all of the nutritional requirements of an infant during the first four to six months of life and which may also be used after this age if fortified with adequate amounts of iron) and follow-on formulas (to be consumed from the age of four to six months with a mixed diet consisting of the follow-on formula plus 'weaning' or 'complementary foods'.) The latter are rarely used in the United States but are used elsewhere. Many paediatricians suggest that from about the age of six months the mother may continue to offer an infant formula. Alternatively, if the mother wishes to see some progress in her child's diet, a follow-on formula may be used instead. In either case, cows milk (whole, semi-skimmed (2%fat), or fully-skimmed) should not be used until at least the first birthday (National recommendations vary).

Infant formulas without added iron

All of the infant formulas currently available in Europe have added iron. There is one without added iron in USA and there is also one formula for preterm children in the UK without added iron; these leave the prescription of extra iron, if necessary for the infant, to the individual paediatrician. The American Academy of Pediatrics Committee on Nutrition advises that formulas without added iron should not normally be used.

There are some theoretical arguments for permitting iron-unfortified formulas:

1. There is very little iron in breast milk; even though that which is present is well absorbed, the absolute amount absorbed is well below that from a fortified infant formula. To not allow an iron-unfortified formula is therefore against the principle of mimicking, where possible, the composition and physiological effect of breast milk.
   
   
2. Extra iron may saturate the lactoferrin in the breast milk ingested by infants who are receiving both breast milk and complements of infant formula. This may negate the immunological properties of lactoferrin; but while this has been shown in vitro, there is no in vivo evidence.
   
   
3. There is a small but definite effect on the faecal flora of the infant, moving it a little further away from that seen in breast fed children.

Apart from these theoretical arguments there is also the evidence of a randomised trial of a no added iron formula (<0.1 mg Fe 100 ml) compared with a standard formula (Standard; 0.5 mg Fe 100 ml) for the first three months of life There were no significant differences between mean values for haemoglobin, mean cell volume and ferritin at three and twelve months of age. The authors concluded, "The universal supplementation of formulae with iron during this initial period needs further consideration." (Tuthill et al Acta Paediatr 2002, 91:119-24.)

Although most paediatricians would recommend an iron-fortified infant formula, the evidence does not seem so overwhelming as to ban the use of unfortified formulas during the early months of life.

Follow-on formulas
Many studies have shown the positive effect of iron-fortified formulas instead of cow's milk on iron status in infants more than six months old and in toddlers in the second year of life. Three important points must be made:

1. It is not certain to what extent this reflects solely the effect of a greater intake of iron, or is due also to the following "other qualities" of an infant /follow on formula:

   a. The greater absorption of iron because of the higher vitamin C content,

   b. Less inhibition of absorption because of the lower concentrations of protein, calcium and phosphorus, (although one study found that the addition of calcium glycerophosphate did not adversely affect iron status (Dalton, M.A., Sargent, J.D., O'Connor, G.T., Olmstead, E.M., Klein, R.Z. (1997) Calcium and phosphorus supplementation of iron fortified infant formula: no effect on iron status of healthy full term infants. American Journal of Clinical Nutrition. 65, 921-9260.)
   
   c. Less immunologically induced milk enteropathy and iron loss.

   This same argument also applies to the points above concerning the use of iron-unfortified infant formulas. Probably both the iron fortification and the "other qualities" are factors. Three British studies of the use of follow-on formulas or cow's milk from the age of six months support that conclusion. Iron deficiency was least common in those receiving an iron-fortified formula, more common in those receiving an unfortified-formula and most common in those on pasteurised cow's milk (Daly A., MacDonald, A., Aukett, A., Williams, J., Wolf, A., Davidson, J., Booth, and I.W. (1996) Prevention of anaemia in inner city toddlers by an iron supplemented cows milk formula. Archives of Diseases in Childhood. 75, 9-16., Gill, D.G., Vincent, S., Segal, D.S. (1997) Follow-on formula in the prevention of iron deficiency: a multicentre study. Acta-Paediatrica. 86, 683-689. Stevens, D., Nelson, A., The effect of iron in formula milk after 6 months of age. (1995) Archives of Disease in Childhood. 73,216-220.)

2. The Daly study quoted above showed a higher intake of iron and a better iron status in those receiving a follow-on formula (1.8 mg/100kcal) rather than cows' milk. However, almost all the children receiving the formula had an iron intake above the reference nutrient intake (RNI) whereas the mean intake of a population should be at approximately the RNI. (Not all of the population should be above the RNI.) This suggests a number of children were receiving higher intakes than necessary. There is no objective evidence of harm from such intakes but it is right to be wary of them. On the other hand, these children were later shown to have better mental development. (Williams et al BMJ 1999;318:693-8.)
   
   
3. Unfortunately, the straight comparison of infant formula (at 0.7mg/100kcal) and a follow-on formula (at 1.8mg/100kcal) as a means of maintaining good iron status in late infancy and the early toddler years has not been performed. While evidence is accumulating that a level of fortification in an infant formula, lower than used previously, can be effective in maintaining adequate absorption and/or iron status (8mg/litre.) (Fomon, S.J., Ziegler, E.E., Serfass, R.E., Nelson, S.E., Frantz, J.A. (1997) Erythrocyte incorporation of iron is similar in infants fed formulas fortified with 12mg/L or 8mg/ L of iron. 127, 83-88.) 3mg (Haschke, F., Vanura, H., Male, C., Owen, G., Pietschnig, B., Schuster, E., Krobath, E., Huemer, C. (1993). Iron nutrition and growth of breast and formula fed infants during the first 9 months of life. Journal of Pediatric Gastroenterology and Nutrition. 16,151-6.) 2mg (Walter, T., Pino, P., Pizarro, F., Lozoff, B. (1998). Prevention of iron deficiency anemia: comparison of high and low iron formulas in term healthy infants after six months of life. Journal of Pediatrics.132, 635-40.) The periods of surveillance were for three to six months only and did not follow infants into the second year of life when anaemia is most common.

From six months of age, a formula will not be the only source of iron. Nevertheless, many weaning diets (particularly those prepared at home, not including meat, in poorer inner city areas, or immigrant families) provide only small amounts of iron, so the infant has to rely on the fortified formula for an adequate intake. The objective evidence is that children in these circumstances who receive a formula containing 1.8mg/100kcal achieve more satisfactory iron status and have less iron deficiency (ID) anaemia (Daly). Moreover, those children receiving the formula had better mental development than those who did not (Williams see references above).

The SCF recommendation would mean that this formula, shown to have advantageous effects on haematology and development, would no longer be allowed. In line with the clinical evidence, the maximum figure should at least be 1.8; and to allow reasonable tolerance in manufacture. there are arguments for it to be a little higher.

This maximum may be lowered when there is evidence that a newer, lower maximum limit is effective in maintaining an adequate iron status up to the age of eighteen months, and, perhaps, of supporting adequate motor and mental development.

Conclusion
There are reasonable arguments to:

1. Continue the existing EU directive allowing an infant (starting) formula not fortified with extra iron, for use up to at least three months of age.
   
   
2. Allow iron up to 1.8mg/100kcal in a follow-on formula plus some extra for manufacturing tolerance.
   
   
3. Lower the minimum iron allowed in iron-fortified infant formulas to less than the previous minimum limit of 0.5/100kcal, [as suggested by SCF], particularly as the iron enhancing properties of an infant formula (compared to unmodified cows milk) are due to many other properties apart from the formula's iron content.

See Also: Iron Deficiency, Part 1 and Iron Deficiency, Part 2

This material has been prepared by members of the IFM's Advisory Committee on Child Health and Nutrition. It does not necessarily represent the views of the Infant Food Manufacturers Association.

September 2004