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* Center for Human Nutrition, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, and
Nepal Nutrition Intervention Project-Sarlahi (NNIPS), Nepal Netra Jyoti Sangh, Tripureswor, Kathmandu, Nepal
1To whom correspondence should be addressed. E-mail: pchristi{at}jhsph.edu.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • anemia • micronutrients • iron status • pregnancy • postpartum • Nepal
Iron deficiency anemia is prevalent during pregnancy in both developing and developed countries. Hemoglobin (Hb)1 concentrations are known to decline from wk 10–12 through wk 32–34 of gestation due to increases in plasma volume, which can result in anemia. Increased iron requirements, low prepregnancy iron stores and continued inadequate dietary intakes of iron exacerbate this physiologic anemia during pregnancy in many regions of the world. Systematic evaluation of the efficacy of antenatal iron supplementation has shown that it raises Hb concentration, although its effects are dose-dependent and modified by prepregnancy status (1). Iron deficiency is known to cause 
50% of anemia in most Third World settings; other etiologic factors such as hookworm and malaria, chronic diseases, deficiencies of certain vitamins and other minor causes account for the remainder. The roles of folic acid, vitamins A, C, B-12 and riboflavin are considered important in enhancing iron metabolism and erythropoeisis (2). Vitamin A deficiency is causally linked to anemia through reduced mobilization of iron stores, disturbed iron and heme metabolism and impaired differentiation and proliferation of hematopoietic cells (2). Both folic acid and vitamin B-12 deficiency can result in megaloblastic anemia, whereas vitamin C is a potent enhancer of iron absorption in the gut. With the exception of vitamin A (3), the impact of vitamin supplementation in controlling anemia has not received sufficient attention. Furthermore, few studies have examined the additional benefit of multiple micronutrients over iron alone in reducing anemia and iron deficiency during pregnancy.
Recently, we completed a randomized community trial of alternative combinations of micronutrients given antenatally to examine the effects on birth weight (4) and infant mortality (5). The four different groups of micronutrients included folic acid (400 µg), folic acid plus iron (60 mg), folic acid plus iron and zinc (30 mg) and folic acid plus iron, zinc and 11 other nutrients (vitamin D, 10 µg; vitamin E, 10 mg; thiamine, 1.6 mg; riboflavin, 1.8 mg; niacin, 20 mg; pyridoxine, 2.2 mg; vitamin B-12, 2.6 µg; vitamin C, 100 mg; vitamin K, 65 µg; copper, 2.0 mg; and magnesium, 100 mg) all given with vitamin A [1000 µg retinol equivalents (RE) as retinol acetate] or vitamin A alone as the control group. In this population we have previously shown that vitamin A (or ß-carotene) supplementation reduces maternal mortality (6), night blindness (7) and anemia (8), but not infant mortality (9). Therefore, vitamin A alone was used as the control group in this study.
As part of the micronutrient trial, we also assessed Hb and iron status indicators at baseline and third trimester and Hb at 6-wk postpartum in a 20% subsample. In this study we examined the effects of these micronutrient formulations given daily on changes in Hb and iron indicators during pregnancy, and the prevalence of anemia in the third trimester and at 6-wk postpartum.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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The details of the study design and methodology have been previously described (4,5). Briefly, a double-masked randomized controlled trial was conducted in the Southeastern plains District of Sarlahi, Nepal from December 1998 through April 2001. The study area comprised 30 village development communities (VDC) that were further divided into 426 smaller communities called sectors. The unit of randomization was a sector comprising 100–150 households. In each sector a locally hired female worker called a sector distributor was responsible for enrolling pregnant subjects and distributing study supplements. A surveillance was set up throughout the study area to identify pregnancies early in gestation. Sector distributors enumerated women of reproductive age eligible to be pregnant within their area and visited them once every 5 wk to ask if they had menstruated in the past 30 d. If they had not, a urine-based human chorionic gonadotropin pregnancy test was immediately administered. Upon ascertainment of pregnancy, consenting women were enrolled in the study to receive their allocated supplement daily from early pregnancy through 3-mo postpartum in the case of a live birth and through 5-wk post outcome in the case of a miscarriage or stillbirth. Women were visited twice each week by sector distributors to replenish supplements and to monitor compliance by counting and recording the number of supplements that were replenished each time to make a total count of 15. Sector distributors provided counseling about possible side effects of taking the supplement.
The five treatment groups received the following micronutrients: C, control (vitamin A, 1000 µg RE as retinol acetate); FA, folic acid (400 µg); FAFe, FA plus iron (ferrous fumarate, 60 mg); FAFeZn, FAFe plus zinc (zinc sulfate, 30 mg); MN, FAFeZn plus other micronutrients2 (1).
Upon enrollment in the study, a baseline interview elicited household socioeconomic status and maternal 7-d history of diet, morbidity symptoms and work activities as well as consumption of alcohol and tobacco products. Maternal anthropometric measurements included weight, height and mid upper arm circumference.
In a purposively selected substudy area (9 VDC with 133 sectors), baseline (wk 10 of gestation) and third trimester (wk 32 of gestation) home-based venous blood was drawn by a special team of phlebotomists. A sample size of 200 per treatment group was calculated to detect a 
5 g/L difference in Hb concentrations relative to the control group or to observe reductions in anemia of 20% with 
= 0.05 and ß = 0.20. Thus, the required sample was 20% (n = 1000) of the sample size (n = 5000) for the larger study and was likely to be derived from 9 out of the 30 VDC in the study area.
Hb was assessed using a B-Hemoglobin Analyzer (HemoCue, Lake Forest, CA). HemoCue microcuvets were kept refrigerated and used within 5 d of opening the container. The HemoCue machines were checked daily against a standard. The blood draw was repeated at wk 32 of gestation. At both times, in the event that a woman refused a venous blood draw, she was asked to provide a finger prick blood draw for the Hb test. Approximately 9% (n = 73) of the women chose to provide finger stick blood either at baseline or follow-up. In a study by Sari et al., testing different methods for assessing Hb concentration, mean Hb measurements using venous or capillary blood was identical when using the Hemocue machine (10). However, capillary blood had lower sensitivity (70.6%) but comparable specificity (95.2%) relative to venous blood (82.4 and 94.2%, respectively) against the standard direct cyanmethemoglobin method for identifying anemic subjects (Hb < 110 g/L) in the same study (10). In the present study, excluding the 73 cases from the analysis did not alter the findings on the impact of supplementation on Hb concentration or anemia during pregnancy.
At 6-wk postpartum, only capillary blood was collected to perform Hb tests because compliance for venous blood draw for the third time from the study participants was expected to be low. Women with severe anemia (Hb < 70 g/L) in any of the three samples were treated with 120 mg of iron and 400 µg of folic acid for 3 mo per recommended guidelines (11). Venous blood was centrifuged at 1530 x g for 10 min. The serum was separated and stored in liquid nitrogen and transported to Johns Hopkins University where it was stored at -70°C until being analyzed for, among other nutrients, ferritin, iron and transferrin receptor. All women in the study were offered 400-mg single-dose albendazole in the second (20 wk) and third trimester (32 wk) of pregnancy because of the high prevalence of hookworm in this population (12). The second dose of albendazole was given in the same week as the second blood draw. At both times, 98% of women accepted and likely took the medicine. Women were not offered malaria prophylaxis because prevalence of Plasmodium vivax, which is the only type of malaria parasite identified in this area, is low and its attributable fraction as a cause of all anemia and moderate-to-severe anemia is only 5 and 16%, respectively (12).
Laboratory analysis.
Serum ferritin concentrations were analyzed by the ELISA procedure using a commercial fluoroimmunometric assay (DELFIA; Perkin Elmer Wallac, Norton, OH). Soluble serum transferrin receptor (sTfR) concentrations were measured using a commercial immunoassay kit (Ramco Laboratories, Houston, TX). Serum iron concentrations were analyzed by atomic absorption spectrometry on an Analyst 600 Analyzer (Perkin Elmer Life Sciences, Wellesley, MA).
Statistical analysis.
The analyses were performed on an intent-to-treat basis. Baseline iron and anemia status of pregnant women were compared across treatment groups. Mean relative difference and 95% confidence limits (CL), defined as the difference in the changes in Hb, serum ferritin, sTfR and serum iron concentrations from baseline to follow-up for each supplementation group compared with the control group, were estimated using a generalized estimating equations (GEE) linear regression model with an identity link and exchangeable correlation to account for the fact that we randomized sectors and not individuals to treatment groups (13). Anemic (Hb < 110 g/L) or nonanemic status was a dichotomous variable using third trimester Hb concentrations. Mild-to-moderate anemia was defined as Hb between 70 and 109 g/L and severe anemia was defined as Hb < 70 g/L. Iron-deficiency anemia was defined as Hb < 110 g/L and serum ferritin < 12 µg/L. PR and 95% CL for severe, mild-to-moderate and any anemia and that for iron deficiency anemia in the third trimester were estimated using a GEE binomial regression model with a log link and exchangeable correlation with vitamin A as the reference category (13). The analyses were repeated for any anemia and mean Hb change after stratifying for compliance to supplementation (using quartiles of supplement consumption from the time of enrollment through the third trimester visit) and baseline Hb concentrations for the FAFe versus the control group. The same GEE models were used for examining supplementation effects on Hb and anemia in the postpartum period.
The study was approved by the ethical review committees of the Ministry of Health in Nepal and the School of Public Health in Baltimore.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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Our study demonstrated an average reduction of 50% in the prevalence of anemia and 70% in the prevalence of iron-deficiency anemia with iron supplementation in the third trimester. This was achieved with a mean consumption of 120 daily supplements from the time of enrollment through the second assessment in the third trimester. The observed effects were in the presence of daily vitamin A supplementation and deworming medicine given twice during pregnancy. Both vitamin A deficiency and hookworm infections are major causes of anemia in this population, although P. vivax malaria may also be a contributor (12). Ferritin concentrations were higher relative to controls in all three groups given iron, although serum iron concentrations were higher only in the FAFe group. Serum TfR, which increases in iron deficient states, increased during pregnancy in the control group but not in the three groups given iron. Iron supplementation appeared to virtually prevent all severe anemia in the third trimester, yet caution is needed in the interpretation of these findings because the number of individuals who were severely anemic was small. Women who were severely anemic at baseline and received treatment were not excluded in this intent-to-treat analysis.
In the present study, FA alone appeared to have no impact on hematologic parameters, and may even have resulted in reducing serum iron and increasing sTfr (P = 0.09). It has been suggested that because iron stores are not used effectively due to impaired erythropoiesis, serum iron concentrations may be elevated in folate-deficient subjects and may fall after folate supplementation (14). The competition between bivalent iron and zinc for mucosal uptake in the gut may result in one interfering with the absorption of the other (15,16). Previously we have shown that improvement in Hb concentration due to iron-folic acid treatment, although not significant, was lower (4.8 g/L) among pregnant Nepalese women receiving supplemental zinc compared with those not receiving zinc (7.8 g/L) (17). A recent trial among Indonesian infants has also shown that combined iron and zinc supplementation is less efficacious than iron supplementation alone in improving iron status (18). In the present study, Hb concentrations improved by 13.8 g/L in the FAFe group compared with 10.0 g/L in the FAFe plus zinc group. Although this difference was not significant, it is suggestive of a negative effect of zinc supplementation on iron status. The failure of the full micronutrient complement (containing iron, folate and zinc) to increase Hb is also suggestive of zinc blocking iron uptake. The efficacy of a multiple micronutrient supplement that excludes zinc was not tested in this trial. Vitamins E, C, B-12, riboflavin and others may play a critical role in erythropoeisis and iron metabolism (2). It is plausible that multivitamins without added zinc may have improved hematologic measures compared with FAFe.
Among women with Hb < 90 g/L at baseline, despite achieving the highest magnitude of increase in Hb relative to controls (16.9 g/L), daily supplementation with 60 mg of iron did not result in 73% of the women testing above the 110 g/L cutoff by the third trimester. Even among those above 110 g/L at baseline, 43% had reached levels below Hb < 110 g/L despite iron supplementation. Furthermore, based on the analysis of the number of supplements consumed, it appeared that unless all women took at least 80 supplements during pregnancy, it was unlikely that anemia prevalence would substantially decrease. This challenges supplement programmers to reinvigorate antenatal iron-folic acid supplementation in the developing world. The high coverage and compliance achieved with iron supplementation during pregnancy in the present study demonstrates that noncompliance due to side effects is unlikely to contribute to the low coverage for iron supplementation programs in developing countries. Also, for the first time it has been demonstrated by results from this study that outcomes such as low birth weight (4) and possibly infant mortality (5) can be reduced with iron plus folic acid supplementation during pregnancy. Additional micronutrients do not appear to provide further benefit, although further research is required to determine the optimal mix of antenatal micronutrients that will improve pregnancy and newborn outcomes. In this context, a better understanding of nutrient-nutrient interactions is clearly needed.
In summary, daily iron (60 mg/d for 120 ± 55 d) with folic acid during pregnancy in this rural, Nepali population improved Hb concentrations by 13.8 g/L and reduced anemia by 54%, but additional micronutrients failed to add hematologic benefit.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Vitamin D (10 µg) as D3, vitamin E (10 mg) as d-alpha tocopherol, thiamine (1.6 mg), riboflavin (1.8 mg), niacin (20 mg), vitamin B-6 (2.2 mg), vitamin B-12 (2.6 µg), vitamin C (100 mg), vitamin K (65 µg) as K1, copper (2.0 mg) and magnesium (100 mg).
Manuscript received 13 May 2003. Initial review completed 30 June 2003. Revision accepted 10 September 2003.
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LITERATURE CITED |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Sloan, N. L., Jordan, E. & Winikoff, B. (2002) Effects of iron supplementation on maternal hematologic status in pregnancy. Am. J. Public Health 92:288-293.
2. Fishman, S., Christian, P. & West, K. P., Jr (2000) The role of vitamin supplementation in the prevention and treatment of anemia. Public Health Nutr. 3:125-150.[Medline]
3. Suharno, D., West, C. E., Muhilal, , Karyadi, D. & Hautvast, J.G.A.J. (1993) Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Lancet 342:1325-1328.[Medline]
4. Christian, P., Khatry, S. K., Katz, J., Pradhan, E. K., LeClerq, S. C., Shrestha, S. R., Adhikari, R. K., Sommer, A. & West, K. P., Jr (2003) Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal. A double-blind randomized community trial. BMJ 326:571-576.
5. Christian, P., West, K. P., Jr, Khatry, S. K., LeClerq, S. C., Pradhan, E. K., Katz, J., Shrestha, S. R. & Sommer, A. () Effects of maternal micronutrient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal. Am. J. Clin. Nutr. (in press).
6. West, K. P., Jr, Katz, J., Khatry, S. K., LeClerq, S. C., Pradhan, E. K., Shrestha, S. R., Connor, P. B., Dali, S. M., Christian, P., Pokhrel, R. P. & Sommer, A. A., On behalf of the NNIPS2 Study Group (1999) Low dose vitamin A or ß-carotene supplementation reduces pregnancy-related mortality: a double-masked, cluster randomized Prevention Trial in Nepal. BMJ 318:570-575.
7. Christian, P., West, K. P., Jr, Khatry, S. K., Katz, J., LeClerq, S. C., Pradhan, E. K. & Shrestha, S. R. (1998) Vitamin A or ß-carotene reduces but does not eliminate maternal night blindness in Nepal. J. Nutr. 128:1458-1463.
8. Stoltzfus, R. J., Dreyfuss, M. L., Shrestha, J. B., Khatry, S. K., Schulze, K. & West, K. P., Jr (1997) Effect of maternal vitamin A or ß-carotene supplementation on iron deficiency anaemia in Nepalese pregnant women, postpartum mothers and infants. Report of the XVIII International Vitamin A Consultative Group Meeting. Cairo, Egypt 1997 ISLI Research Foundation Washington D.C. (abstract).
9. Katz, J., West, K. P., Jr, Khatry, S. K., Pradhan, E. K., LeClerq, S. C., Christian, P., Wu, L. S., Adhikari, R. K., Shrestha, S. R. & Sommer, A., and the NNIPS-2 Study Group (2000) Low-dose vitamin A or beta-carotene supplementation does not reduce early infant mortality: a double-masked, randomized, controlled community trial in Nepal. Am. J. Clin. Nutr. 71:1570-1576.
10. Sari, M., de Pee, S., Martini, E., Herman, S., Sugiatmi, , Bloem, M. W. & Yip, R. (2001) Estimating the prevalence of anaemia: a comparison of 3 methods. Bull. WHO 79:506-511.[Medline]
11. Stoltzfus, R. J. & Dreyfuss, M. L. (1998) Guidelines for the use of iron supplements to prevent and treat iron deficiency anaemia 1998 INACG/WHO/UNICEF: ILSI Press Washington D.C.
12. Dreyfuss, M. L., Stoltzfus, R. J., Shrestha, J. B., Pradhan, E. K., LeClerq, S. C., Khatry, S. K., Shrestha, S. R., Katz, J. K., Albonico, M. & West, K. P., Jr (2000) Hookworms, malaria and vitamin A deficiency contribute to anemia and iron deficiency among pregnant women in the plains of Nepal. J. Nutr. 130:2527-2536.
13. Liang, K. Y. & Zeger, S. L. (1986) Longitudinal data analysis using generalized linear models. Biometrika 73:13-22.
14. Pryor, J. A. & Morrison, J. C. (1990) Nutritional anemias. Bern, M. M. Frigoletto, F. D., Jr eds. Hematologic Disorders i9n Maternal-Fetal Medicine 1990 Wiley-Liss New York. .
15. Solomons, N. W. & Ruz, M. (1997) Zinc and iron interaction: concepts and perspectives in the developing world. Nutr. Res. 17:177-185.
16. Solomons, N. W. (1986) Competitive interaction of iron and zinc in the diet: consequences for human nutrition. J. Nutr. 116:927-935.
17. Christian, P., Khatry, S. K., LeClerq, S. C., Shrestha, S. R., Kimbrough-Pradhan, E. & West, K. P., Jr (2001) Iron and zinc interactions among pregnant Nepali women. Nutr. Res. 21:141-148.
18. Lind, T., Lonnerdal, B., Stenlund, H., Ismail, D., Seswandhana, R., Ekstrom, E. C. & Presson, L. A. (2003) A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc. Am. J. Clin. Nutr. 77:883-890.
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