Vitamin A, iron and zinc deficiency in Indonesia : micronutrient interactions and effects of supplementation

The research described in this thesis was concerned with vitamin A, iron and zinc deficiency in pregnant and lactating women and in infants. The effects of supplementation withβ-carotene, iron and zinc on micronutrient status, growth, pregnancy outcome and immune function, and interactions between micronutrients were investigated.

Deficiencies of vitamin A, iron and zinc are prevalent worldwide. Vitamin A deficiency leads to increased risk of morbidity and mortality, and vitamin A supplementation can reduce child mortality by 20-30%, regardless of the prevalence of xerophthalmia in the population. In developing countries, pro-vitamin A carotenoids, especiallyβ-carotene, from plant foods is the most important source of vitamin A, but bioavailability and conversion are highly variable, and less than often assumed. Iron deficiency is the most common micronutrient deficiency globally, affecting over 50% of the women in developing countries. Iron deficiency leads to anaemia, but in children also to delayed psychomotor development and impaired learning, and possibly affects immunocompetence. Diets rich in phytate and low in animal products result in a low availability of iron, and predisposes to iron deficiency.

Zinc availability is impaired by the same factors as iron, and hence zinc deficiency is presumed to be very widespread also. Zinc status however, is difficult to assess due to homeostasis, and the absence of real body stores. Zinc deficiency causes especially growth impairment and decreased immunocompetence, although probably many metabolic functions are affected.

In Indonesia, both vitamin A deficiency and iron deficiency are major health problems, affecting especially pregnant and lactating women, and infants. Zinc deficiency is also thought to be important, and has been implicated in the growth impairment commonly seen in infants in Indonesia. Also, maternal and infant mortality remain high, despite significant improvements in vaccination coverage and access to primary health care. There are several programmes in Indonesia to combat vitamin A and iron deficiency. For example, there is a national iron and folic acid supplementation programme for pregnant women, and there is a programme for intermittent high dose vitamin A supplementation with capsules for children. The vitamin A supplementation programme has successfully decreased the prevalence of xerophthalmia, but marginal vitamin A deficiency remains a problem. Also, because of possible toxicity, young infants and pregnant women are not included in the vitamin A supplementation programme.

The research described in this thesis comprises three studies. The objective of the first study was to assess the prevalence of deficiency of vitamin A, iron and zinc in lactating mothers and their infants as well as the interrelationships of these deficiencies with each other, and with growth impairment and immune function. In the second study, the effects of supplementation of infants withβ-carotene, iron and zinc on micronutrient status and deficiency, and on growth and immune function were investigated. In the third study, the effects of supplementation of pregnant women withβ-carotene and zinc in addition to iron and folic acid on pregnancy outcome, micronutrient status of mothers and newborns, and growth of the newborn during the first 6 months were investigated.

The main findings of the research described in this thesis are summarized in relation to several topics important for mother and child health. An important finding in all three studies is not only that deficiency of vitamin A, iron and zinc are prevalent in infants and mothers, but also that these deficiencies are likely to occur concomitantly. Furthermore, micronutrient status of the mother is strongly related to that of her infant, and breast milk is a key connecting factor between mother and infant for vitamin A status.

Supplementation of infants with iron and zinc was effective in reducing the prevalence of anaemia and deficiencies of iron and zinc. Although supplementation of iron combined with zinc reduced the efficacy of iron supplementation, the combined supplement still effectively reduced the prevalence of anaemia and iron deficiency, and in addition reduced zinc deficiency. This shows that although zinc partially inhibits iron uptake, zinc is still a valuable addition to iron supplementation. Supplementation of women during pregnancy withβ-carotene combined with zinc improved vitamin A status of both mother and newborn 6 months post-partum, whereas supplementation withβ-carotene alone had no effect. This indicates that zinc plays an important role in the conversion ofβ-carotene to retinol. Therefore zinc is necessary to improve vitamin A status withβ-carotene supplementation in pregnant women. The synergistic effect of zinc onβ-carotene supplementation is not apparent in infants, but infants may have a reduced capacity to metabolise or storeβ-carotene. In contrast, iron supplementation was found to have an antagonistic effect on vitamin A status of infants, resulting in lower plasma retinol concentrations, and higher prevalence of vitamin A deficiency in the iron supplemented infants. Concomitantly hepatic stores of vitamin A were increased, suggesting that iron supplementation causes a redistribution of vitamin A from the plasma to the liver. Hence, iron supplementation in infants should not be given without measures to improve vitamin A status also.

Supplementation of pregnant women withβ-carotene and zinc improved birth weight, but only in boys. However, supplementation with only zinc in addition to iron and folic acid, increased the prevalence of complications during delivery. In view of the concurrent occurrence of deficiency of various micronutrients, supplementation of only zinc or onlyβ-carotene, in addition to iron and folic acid, may not address all micronutrient requirements during pregnancy.

Although zinc deficiency has been implicated in the growth impairment commonly seen in infants in developing countries, supplementation of infants with zinc did not improve growth performance. Also, supplementation of women during pregnancy with zinc did not improve growth of the infant during the first 6 months of life. Apparently, additional factors are involved in the growth impairment of these infants.

Various micronutrients have profound, albeit different effects on immune function. Infants with vitamin A deficiency had lower ex vivo type-1 cytokine response, but higher in vivo macrophage activity. Zinc deficiency was accompanied by reduced white blood cell numbers, as well as lower ex vivo type-2 cytokine production. Supplementation with iron resulted in higher type-1, and lower type-2 cytokine production, whilst supplementation withβ-carotene and zinc seem to have opposite effects on immune function. Deficiency of various micronutrients can impair the ability to produce pro-inflammatory cytokines in response to infection. Supplementation of different micronutrients can have opposing immunomodulatory effects, but implications for immunocompetence are less clear.

Concluding, the studies described in this thesis clearly and repeatedly show that concomitant deficiencies of various micronutrients are the norm rather than the exception. Supplementation with single micronutrients is not optimal. The expected effectiveness of supplementation with one micronutrient will not be achieved if the utilisation of the micronutrient is impaired by deficiency of another micronutrient. Health benefits of supplementation will also fall short of expectations as long as deficiencies of other micronutrients are not addressed. Therefore supplementation with more than one micronutrient is recommended, not only for infants but also for pregnant women.