Iron-deficiency anaemia is a leading cause of morbidity and mortality worldwide and affects up to two-thirds of children in most developing countries (1). Infants and young children aged 6-18 months are particularly vulnerable to iron-deficiency anaemia because their requirement for iron is high (2). The effects of anaemia on child development are especially serious: poor cognitive development, decreased future learning and school achievement, decreased resistance to illness and disease, and eventually reduced wages and quality of life (3-6). Numerous studies have shown that moderate anaemia (haemoglobin <100 g/l) is associated with depressed mental (social and cognitive) and motor development in children, which may not be reversible (7-5). Prevention of anaemia in early childhood must therefore be the goal of intervention programmes.
In 1996, a group of consultants from the United Nations Children's Fund (UNICEF) reviewed possible interventions to treat and prevent anaemia. Although the available interventions (syrup and drops for infants and children, and capsules for women) were efficacious, they were not always effective (10). For many reasons, adherence to such treatments is poor --despite multiple efforts to influence and improve it--and this renders them ineffective for use as long-term prophylactics. The challenge therefore was to develop a new strategy to provide micronutrients (including iron) to at-risk populations. As a result, "sprinkles"--through which encapsulated micronutrients in powder form could be added directly to food at the household level--were developed. The micronutrients are encapsulated in a thin coating of a soy-based hydrogenated lipid, which prevents the micronutrients from oxidizing the food. Thus the colour or taste of food to which sprinkles are added does not change. The encapsulated micronutrients are packaged in single-dose sachets to ensure that the correct amount of iron is given. The contents of the sachets are then sprinkled onto whatever food is served in the household, including typical complementary and family foods. This type of intervention is called "home fortification", to distinguish it from "commercial fortification", in which the addition of fortificants to a complementary cereal occurs in a large central facility.
We recently showed that sprinkles are as efficacious as iron(II) sulfate drops in treating anaemia when added to complementary foods at the household level; treatment of anaemia was successful in 58% of Ghanaian infants who received sprinkles for two months (11). Moreover, the common side-effects associated with drops--such as teeth staining, unpleasant metallic taste, gastrointestinal upset and measurement difficulties--were avoided.
Concurrent multiple micronutrient deficiencies may limit the response of haemoglobin to iron. For example, strong evidence shows that concomitant iron and vitamin A deficiencies may exacerbate anaemia by limiting erythropoiesis. It has been suggested, therefore, that multiple micronutrient supplementation may be beneficial and might improve outcomes (12). Vitamin A and iron deficiency often coexist and result in nutritional anaemia (13). Nutrient interactions, however, mean that liquid iron-vitamin combination supplements suitable for use in infants and young children are not available widely (14). As the iron in "sprinkles" is microencapsulated, other micronutrients--such as vitamin A, folic acid, vitamin [B.sub.12] and ascorbic acid--can be included without significant loss of nutrient stability (11).
Long-term follow-up of infants and young children successfully treated for moderate anaemia, who are at high risk of recurrence, has not been documented. Whether these children would benefit from continued prophylactic supplementation and which form of iron would be most suitable for long-term use are uncertain. In the current study, our primary objectives were to compare the efficacy of microencapsulated iron(II) fumarate sprinkles (with and without vitamin A) and iron(II) sulfate drops with placebo sprinkles in preventing recurrence of anaemia and to determine the long-term haematological outcome in a cohort of high-risk children 12 months after supplementation ended.
Study area, participants and recruitment
The current study took place in the field study area of the Kintampo Health Research Centre in the Brong-Ahafo Region of Ghana. Directly before the study, all children had received treatment for moderate anaemia (haemoglobin, 70-100 g/l) with iron for two months (August-September 1999) (11). Only children who had been treated successfully to achieve haemoglobin levels [greater than or equal to] 100 g/l were eligible for the current study. Further eligibility criteria included that children were aged 8-20 months at recruitment, were ingesting a weaning food in addition to breast milk, and were expected to remain in the study district for 18 months.
Prophylactic supplementation was provided to children for six months between October 1999 and March 2000. Children who maintained a haemoglobin level [greater than or equal to] 100 g/1 at the end of the treatment period were reassessed at 12 months post-supplementation. Children who became anaemic by the end of the supplementation or post-supplementation periods were discharged and provided with appropriate treatment.
Children were randomized individually to one of four treatment groups (Fig. 1). Randomization used sealed opaque envelopes that contained group designations generated randomly by computer (Microsoft Access 97, Microsoft Corporation, Seattle, WA, USA). Blinding of the field staff or mothers to the group assignments was not feasible, because one group received drops, while the other three received sachets of sprinkles. All were blinded to the content of the sachets, however, and the people responsible for laboratory and data analyses were blinded to the group designations. The entire contents of a sachet were added to each infant's meal serving (after cooking) once daily. Iron drops were provided once daily on an empty stomach.
[FIGURE 1 OMITTED]
The dosage of elemental iron (12.5 mg/day) in the "gold standard" group (iron(II) sulfate drops) was based on recommendations from a UNICEF consultation group (10). The dosage of iron in the sachets (40 mg/day) was approximately three times that of the drops. This dosage was chosen on the basis of estimates that absorption of microencapsulated iron(II) fumarate sprinkled onto food would be about one-third of that of drops because of the presence of dietary phytate--a potent inhibitor of iron absorption (15). In addition to iron (40 mg), sachets in the iron + vitamin A group were formulated to contain a daily dose of vitamin A (600 pg retinol equivalents) as retinol acetate.
Field workers visited children every two weeks over a six-month period to distribute drops or sprinkles. Baseline assessments involved a questionnaire on sociodemographic, nutritional and health factors. At bi-monthly and final visits, side-effects, ease of use, and adherence to treatment were determined by questionnaire. Empty sachets were counted, and the …