Reply to B Sreedhar

Department of Public Health and Clinical Medicine
Epidemiology and Public Health Science
Umeå University
S-901 87 Umeå
Sweden
E-mail: torbjorn.lind@epiph.umu.se

Lars-Åke Persson

International Maternal and Child Health
Department of Women’s and Children’s Health
Uppsala University
SE-751 85 Uppsala
Sweden
E-mail: lars-ake.persson@kbh.uu.se

Bo Lönnerdal

Department of Nutrition
University of California, Davis
One Shields Avenue
Davis, CA 95616
E-mail: bllonnerdal@ucdavis.edu

Dear Sir:

Sreedhar addresses several interesting issues in his comparison between the study by Dijkhuizen et al (1) and our study (2). Both studies have a factorial design in which rural, marginally malnourished Indonesian infants were provided with iron, zinc, or a combination of iron and zinc or placebo. The 2 studies share the general conclusion that simultaneous supplementation with iron and zinc is less efficacious in improving iron and zinc status than is supplementation with either iron or zinc alone. However, Dijkhuizen et al concluded that supplementation with a combination of iron and zinc could be safe and effective, whereas we stated that such a supplement is not optimal.

There are some differences between the 2 studies that may contribute to the differences in results and interpretation. First, whereas supplementation in our study commenced when the infants were 6 mo old, supplementation in the study by Dijkhuizen et al started when the infants were 4 mo old. A recent study by Domellöf et al (3) of iron supplementation in infancy showed that the initiation of iron supplementation at age 4 mo instead of at age 6 mo had significantly different effects on the hemoglobin response. That study also showed that the initiation of supplementation at 4 mo increased hemoglobin irrespective of iron status, which indicated an immature response to iron supplementation at that age, whereas supplementation from age 6 mo did not have that effect. Effects on zinc status were not reported in that study. The different ages at the start of supplementation in the study by Dijkhuizen et al and in our study may thus make a comparison difficult.

Second, our infant population had generally lower serum zinc concentrations than did the population in the other study. The serum zinc concentrations that we found in the group receiving only iron were lower than those in the placebo group, but this difference was not significant. However, the prevalence of low serum zinc (< 10.7 µmol/L) was significantly greater in the iron supplementation group than in the placebo group, which indicated a negative effect of iron supplementation on zinc status. It may be that this interaction is evident only in a more zinc-deficient population such as ours.

Third, our report included dose-effect analyses, which showed that an increased dose of combined supplement did not compensate for the lower efficacy of the combined supplement. This finding influenced our overall conclusion.

Sreedhar also inquired whether single supplements can promote catch-up growth in stunted and wasted populations or whether we have to look for other limiting factors. We are fully aware of the fact that these micronutrients are not the only limiting factors for growth: in our study, stunting increased despite the zinc supplementation. A meta-analysis on the subject showed that zinc supplementation improved growth in malnourished children (4). Findings of the growth effects of iron supplementation are also conflicting (5–8). The same is true for simultaneous iron and zinc supplementation (1, 9, 10); in one of those studies, Perrone et al (10) found an effect on growth if the iron and zinc supplements were consumed 12 h apart. Our data, not yet published, show positive effects of single zinc and iron supplementation on growth and psychomotor development but no such effect of combined supplementation. We therefore believe that, when a supplementation strategy is more feasible than is a food-based approach, innovative dose regimens for the provision of these micronutrients are needed.

REFERENCES

1. Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal. Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. J Nutr 2001;131:2860–5.
2. Lind T, Lönnerdal B, Stenlund H, et al. A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc. Am J Clin Nutr 2003;77:883–90.
3. Domellöf M, Cohen RJ, Dewey KG, Hernell O, Rivera LL, Lönnerdal B. Iron supplementation of breast-fed Honduran and Swedish infants from 4 to 9 months of age. J Pediatr 2001;138:679–87.
4. Brown KH, Peerson JM, Rivera J, Allen LH. Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2002;75:1062–71.
5. Aukett MA, Parks YA, Scott PH, Wharton BA. Treatment with iron increases weight gain and psychomotor development. Arch Dis Child 1986;61:849–57.
6. Angeles IT, Schultink WJ, Matulessi P, Gross R, Sastroamidjojo S. Decreased rate of stunting among anemic Indonesian preschool children through iron supplementation. Am J Clin Nutr 1993;58:339–42.
7. Idjradinata P, Watkins WE, Pollitt E. Adverse effect of iron supplementation on weight gain of iron-replete young children. Lancet 1994;343:1252–4.
8. Dewey KG, Domellöf M, Cohen RJ, Landa Rivera L, Hernell O, Lönnerdal B. Iron supplementation affects growth and morbidity of breast-fed infants: results of a randomized trial in Sweden and Honduras. J Nutr 2002;132:3249–55.
9. Rosado JL, Lopez P, Munoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Am J Clin Nutr 1997;65:13–9.
10. Perrone L, Salerno M, Gialanella G, et al. Long-term zinc and iron supplementation in children of short stature: effect of growth and on trace element content in tissues. J Trace Elem Med Biol 1999;13:51–6.