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Djoko Suharno and Muhilal
A cross-sectional study of the prevalence of iron and vitamin A deficiencies in 318 pregnant women revealed that 50.7% had iron deficiency and 21.3% had marginally deficient or deficient vitamin A status. Based on results, the influence of vitamin A and iron supplementation was studied in 305 anaemic pregnant women in west Java, in a randomized, doubleblind, placebo-controlled field trial. The women with a haemoglobin between 80 and 109 g/L were randomly allocated to four groups: vitamin A (2.4 mg retinol) and placebo iron tablets; iron (60 mg elemental iron as ferrous sulphate) and placebo vitamin A; vitamin A and iron; and both placebos, all daily for eight weeks. Maximum haemoglobin was achieved with both vitamin A and iron supplementation (12. 78 g/L, 95% Cl 10.86 to 14.70), with one-third of the response attributable to vitamin A (3.68 g/L, 2.03 to 5.33) and two-thirds to iron (771 g/L, 5.97 to 9.45). After supplementation, the proportion of women who became non-anaemic was 35 % in the vitamin Asupplemented group, 68% in the ironsupplemented group, 97% in the group supplemented with both, and 16% in the placebo group. We conclude that improvement in vitamin A status may contribute to the control of anaemia in pregnant women.
Vitamin A deficiency and nutritional anaemia are among the major nutritional deficiencies in developing countries, especially in pregnant and lactating women and children. Iron status is influenced by a variety of factors, including dietary components that either promote or inhibit iron absorption, and parasites that reduce iron status. Studies in both humans and laboratory animals have shown that vitamin A deficiency can contribute to nutritional anaemia, and vitamin A supplementation can have positive effects on iron status.
Correlation of vitamin A and iron status
In September and October 1989 in a rural area of west Java, we performed a cross-sectional study of the prevalence of iron and vitamin A deficiencies in 318 clinically healthy pregnant women age 20 to 35 years. The women were in the second or third trimester of pregnancy and came from the middle and lower socio-economic classes. A haemoglobin concentration below 110 g/L was found in 157 (49.4%) of the women. A low serum ferritin concentration (12 µg/L was measured in 160 women (50.3%), and elevated free erythrocyte protoporphyrin ( > 1.25 µmol/L, 700 µg/L) in 237 (74.5%). Based on several criteria, 143 (50.7%) women had iron-deficiency anaemia, 71 (25.2%) had deficient erythropoiesis, and 22 (7.8%) had iron depletion. Serum retinol values revealed that 3.0% of the pregnant women were vitamin A deficient and 18.3% had marginal vitamin A status. The findings are summarized in table 1.
TABLE 1. Iron and vitamin A status in 318 pregnant women
|iron-deficiency anaemia||143 (50 7)|
|iron depletion||22 (7.8)|
|marginally deficient||49 (18.3)|
After multiple regression analysis to adjust for effects of state of gestation, parity, and subdistricts, serum retinol remained significantly positively associated with haemoglobin, haematocrit, and serum iron (table 2). An increase of 1 µmol/L in the retinol concentration was significantly (p < .01) associated with an increase of 4.30 g/L haemoglobin, 1.37 L/L haematocrit, and 1.18 µmol/L serum iron, and tended to be associated (p=.065) with a decrease of free erythrocyte protoporphyrin of 0.132 µmo/L red blood cells.
TABLE 2. Multiple regression coefficient with iron index as dependent variable and serum retinol as independent variable
|Dependent variable||Independent variablea||P|
|Haemoglobin (g/L)||4.30 + 1.432||<.01|
|Haematocrit (L/L)||1.37 + 0.430||<.01|
|Serum iron (µmol/L)||1.18 + 0.385||<.01|
a Coefficient adjusted for subdistrict, parity, and stage of gestation.
TABLE 3. Effect of supplementation with vitamin A and iron on haemoglobin levels (g/L)a
|Intervention||Change in haemoglobin level (g/L)|
|Vitamin A||3.68 (2.03 to 5.33)|
|Iron||7.71 (5.97 to 9.45)|
|Vitamin A + iron||12.78 (10.86 to 14.70)|
a Increase in treatment group minus increase in control group, mean (95% CI). All three figures indicate a significant effect of supplementation (p < .01).
Effect of supplementation
Because the cross-sectional study showed a relationship between the metabolism of vitamin A and that of iron, an intervention study with vitamin A and iron supplementation was conducted from April to September 1992 in the same area. The study's hypothesis was that if the association of vitamin A with iron status were causal, supplementation of pregnant women with vitamin A would have an important effect on public health by simultaneously reducing nutritional anaemia among these women and providing the additional vitamin A required during pregnancy.
Three hundred five pregnant women, age 17 to 35 years, parity 0 to 4, gestation 16 to 24 weeks, and haemoglobin between 80 and 109 g/L, were allocated in a randomized, double-blind, placebo-controlled field trial. Subjects were randomly assigned to four groups: vitamin A (2.4 mg retinol as retinyl palmitate) and placebo iron tablets; iron (60 mg elemental iron as ferrous sulphate) and placebo vitamin A; vitamin A and iron; and both placebos. After determining baseline vitamin A and iron status, preparations were administered daily for eight weeks with very close monitoring and strict supervision. None of the subjects had received treatment with vitamin A or iron during the six months preceding the study, or received extra supplements during the study.
Of the 305 women, complete data were available for 251 (82%). There were no differences at baseline in age, height, weight, gravidity, parity, or stage of gestation between women who finished the study and those who did not.
Vitamin A and iron supplementation significantly increased haemoglobin by 12.78 g/L (95 % confidence interval 10.86 to 14.70) compared with the double-placebo group. One-third (3.68 g/L) of the increase could be attributed to vitamin A supplementation and two-thirds (7.71 g/L) to supplementation with iron (table 3). The pattern of changes in packed cell volume was similar to that in haemoglobin.
The proportion of anaemic women who became non-anaemic (haemoglobin > 110 g/L) was 35% in the vitamin A-supplemented group, 68% in the iron-supplemented group, 97% in the group supplemented with both vitamin A and iron, and 16% in the double-placebo group (table 4). Supplementation with iron resulted in an increase in serum ferritin and a decrease in total iron-binding capacity, although vitamin A supplementation had no effect on these variables. The concentration of iron in serum and transferrin saturation increased with iron supplementation, but to a lesser extent with vitamin A. Supplementation with vitamin A increased serum retinol levels but, as would be expected, iron supplementation had no effect.
TABLE 4. Proportion of 251 anaemic women who became non-anaemica
|Type of intervention||Total no||Women who became non-anaemic||95% Cl|
|Placebo||62||10||16||7 to 29|
|Vitamin A||63||22||35||22 to 48|
|Iron||63||43||68||54 to 79|
|Vitamin A + iron||63||61||97||88 to 99|
a Haemoglobin > 100 g/L.
Nutritional anaemia is a very serious problem worldwide, and pregnant women and children are at particular risk. Because the disease is so difficult to control, it is important to look at possible interventions in addition to iron supplementation.
Several studies investigated the possible association and interrelationship between indexes of iron status and those of vitamin A status. In our study, serum retinol concentration was significantly associated with haematocrit, haemoglobin, and serum iron. In a comparable cross-sectional study with children in north-east Thailand, serum retinol was positively associated with haematocrit and serum iron . An association was found between serum retinol and serum transferrin or serum ferritin, but none between serum retinol and haemoglobin. In a study in Ethiopian children, however, a significant correlation was found between serum retinol levels and haemoglobin .
A series of intervention studies investigated the role of vitamin A in controlling nutritional anaemia. Eight volunteers with very low vitamin A intakes developed moderate anaemia that did not respond to medicinal iron but did respond to vitamin A . A positive correlation was found between serum iron and blood haemoglobin in children with adequate intakes of iron, but not in children with inadequate intakes . In Guatemala, a vitamin A fortification programme resulted in improved iron status . A controlled intervention trial in children with commercially marketed monosodium glutamate fortified with vitamin A reported an increase in haemoglobin . Haemoglobin in pre-school children was increased three weeks after a single dose of vitamin A .
Although supplementation with vitamin A increases haemoglobin in children, little attention has been paid to pregnant women. In one study, however, haemoglobin at 26 to 28 weeks' gestation was increased more in women supplemented with iron plus vitamin A than in those supplemented with iron alone .
Our intervention study included enough subjects to answer the question of whether iron supplementation should be given, either alone or in combination with vitamin A supplementation, to control nutritional anaemia. An approach to controlling the disorder that also improves vitamin A status is doubly beneficial. The increase in haemoglobin was more than 50% greater when vitamin A was supplied with iron than when iron was provided alone, and sufficient to eliminate the anaemia in 97% of women who received both nutrients.
No conclusions can be drawn from our study regarding the mechanism by which vitamin A increases haemoglobin, since no significant changes occurred in total iron-binding capacity, which is an indicator of transferrin level. Elucidation of the mechanism involved will probably require animal studies. Studies to date have shown that absorption of iron is not decreased in vitamin A deficiency but is increased . Haemoglobin synthesis is reduced in vitamin A deficiency, but whether this is due to a decreased supply of iron to the bone marrow or to inhibition of erythropoiesis is unknown .
Our intervention study, using a pharmaceutical approach, showed that supplementation can eliminate nutritional anaemia. Since food supplementation is probably the only sustainable approach in the long term, more studies are required to investigate whether the use of locally available and acceptable foods can achieve the same result.
A large body of evidence indicates that vitamin A deficiency is an important factor in the aetiology of nutritional anaemia. Our findings suggest that measures to combat anaemia in pregnant women at the population level should involve improving nutrition status with respect not only to iron but also to vitamin A.
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