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* Department of International Health, Rollins School of Public Health, Emory University, Atlanta, GA; and
Centro de Investigación en Nutrición y Salud, Instituto Nacional de Salud Pública (INSP), Cuernavaca, Morelos, Mexico
3To whom correspondence should be addressed. E-mail: uramakr{at}sph.emory.edu.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • iron • multivitamin-mineral • supplements • pregnancy • anemia
Anemia is a substantial public health problem in many developing countries and has been associated with a range of adverse consequences including poor mental development, reduced productivity, maternal mortality, and low birth weight (1–3). Iron deficiency is considered the main cause of anemia, especially among young children and pregnant women, who are at increased risk due to their increased requirements (4). Anemia during pregnancy, however, remains a problem in many settings despite the fact that routine provision of iron supplements has been recommended for pregnant women (5,6). The failure of iron supplementation programs to reduce anemia in pregnant women has been attributed to various factors that influence program delivery. These include lack of availability of supplements, poor coverage, inadequate provider knowledge, and poor compliance due to lack of motivation and/or side effects (6). However, more recently the efficacy of iron supplements has been questioned given the complex etiology of anemia.
Anemia may result from both nutritional and nonnutritional factors. Specifically, besides iron, deficiencies of micronutrients such as vitamins A, C, and B-12 and folate may contribute to the development of anemia (4). These nutrients may affect hemoglobin (Hb)4 synthesis either directly or indirectly by affecting absorption and/or mobilization. For example, vitamin A has been shown to play a role in the mobilization of iron for hematopoiesis and studies have shown that vitamin A supplementation along with routine iron supplements during pregnancy substantially reduced the prevalence of anemia when compared to only iron supplements (7,8). Similarly, vitamin C is known to enhance iron absorption. Folate and vitamin B-12 deficiency can independently cause megaloblastic anemia that differs from microcytic iron-deficiency anemia by affecting DNA synthesis.
In many developing countries, diets that are poor in iron are also poor in several other nutrients due to low intakes of animal foods and high intakes of foods rich in absorption-inhibiting factors such as phytates. This has therefore raised interest in providing nutrients besides iron to reduce the prevalence of anemia (9,10), but few studies have evaluated the impact of multivitamin-mineral supplements on anemia and iron status during pregnancy. Two randomized controlled trials (RCT) from Tanzania (11) and Nepal (12,13) have evaluated the benefits of multiple micronutrient supplements on pregnancy outcomes, but only one examined iron status and found that multiple micronutrients did not improve hematologic indicators when compared to patients who received iron-folate supplements (13). We recently completed an RCT that compared the effect of a daily prenatal multivitamin-mineral supplement to iron-only supplements on birth outcomes (14) and examine the effects on anemia and iron status in this paper.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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Data collection. At recruitment, the study physician and a team of trained nurses conducted a prenatal examination that included a detailed obstetric history, physical examination, and anthropometric assessment at the study headquarters. The first supplement was consumed on site, following which women were visited at their homes 6 days a week until delivery by trained workers who administered and recorded the consumption of supplements. Socioeconomic status was determined using a questionnaire regarding household building materials, possessions, and occupation, from which an index of economic status was derived using factor analysis (14). Venous blood samples were collected at the field headquarters by trained nurses from willing subjects at baseline, 32 wk of completed gestation, and 1 mo postpartum as part of routine prenatal and postpartum care. The blood samples were centrifuged at ambient temperature for 15 min at 2000 x g. Serum was transferred to trace element–free microtubes, frozen immediately at -20°C, and transferred within 1 week to -70°C until analysis.
Samples were analyzed at the INSP nutrition laboratories for serum ferritin and C-reactive protein (CRP) concentrations. The quantitative measurement of ferritin in serum was determined by sandwich immunoassay (ELISA, Opus Behring Laboratories) using commercial kits (Dade Behring). CRP in serum was measured using an immunonephelometry system (16,17), in which polystyrene particles coated with monoclonal antibodies to CRP are agglutinated when mixed with serum samples containing CRP.
Hemoglobin concentrations were measured in the field headquarters at the same time points by trained nurses using a portable photometer (Hemocue) from a capillary blood sample obtained by finger-prick. Appropriate referral and treatment for high-risk pregnancies were provided by the study physician, who worked closely with the local health authorities. Data entry and cleaning were carried out on an ongoing basis with supervision by INSP staff at the main office in Cuernavaca. Additional data cleaning was carried out at Emory University.
Data analysis. The main outcome variables were measures of iron status and anemia at 32 wk gestation and 1 mo postpartum. Because serum ferritin was not normally distributed, loge transformed values were used. A small value of 0.0001 was added to all values to ensure appropriate transformation of "zero" values. Anemia was defined as hemoglobin concentrations below 110, 105, and 120 g/L at recruitment, 32 wk gestation and 1 mo postpartum, respectively, whereas iron deficiency was defined as serum ferritin below 12 µg/L at all time points (18,19). Iron-deficiency anemia was indicated by the presence of both anemia and iron deficiency. Gestational age was based on recalled date of last menstrual period and overweight was defined as BMI above 25 kg/m2 (20). Compliance was calculated by expressing the total number of tablets consumed as a percentage of the total number that they could have consumed (6 d per wk from recruitment to delivery).
The study sample for this analysis was a subsample of all pregnancies assigned to treatment between July 1997 and December 31, 1999, that resulted in singleton live births and had data on measures of iron status at recruitment, 32 wk gestation, and 1 mo postpartum. Comparisons between the final sample and those not included were done for selected baseline characteristics and measures of compliance and the comparability of the two treatment groups in the final sample was tested for selected sociodemographic, health, and nutrition characteristics of the women at recruitment. These comparisons were done using Student’s t tests for means for normally distributed variables and chi-square tests of proportions for categorical variables.
Mean hemoglobin and serum ferritin concentrations were compared between supplement groups using general linear models to control for factors that differed between groups at recruitment. In the case of binary outcomes, namely anemia, iron-deficiency anemia (IDA), and iron deficiency, multivariate logistic regression models were used to compare the treatment groups. In both cases, the role of outliers and suitability of the models were examined. In addition, effect modification by characteristics selected a priori to data analysis (iron status and maternal BMI at recruitment) was tested. All statistical analyses were conducted using SAS 8.2. A P value < 0.05 for main effects and P < 0.15 for interaction terms were considered significant. Adjustments were also done for multiple comparisons as appropriate.
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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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The lack of benefit of MM supplements to improve iron status during pregnancy may be due to several reasons. Vitamin A may not have benefited our study population because the prevalence of deficiency was much lower when compared to the study in Indonesia that demonstrated reductions in anemia by vitamin A supplementation (7,21). Similarly, the contribution of folate and vitamin B-12 deficiencies to anemia may also have been less than expected as suggested by the similar prevalence of IDA and overall anemia at recruitment. Another important issue is the potential adverse interaction between iron and zinc (22,23). Zinc may have reduced the bioavailability of iron and therefore overridden any benefits that may have been attributable to other enhancers of ironabsorption such as vitamin C. Although little is known about the bioavailability of nutrients in multiple micronutrient supplements, results from an intervention trial in Peru showed that although iron interfered with zinc bioavailability (24), the inclusion of 15 mg zinc along with 60 mg iron and folate did not adversely affect changes in hemoglobin and iron status during pregnancy when compared to just iron-folate (25,26). Our supplements contained similar amounts of these nutrients and it therefore seems unlikely that competition between iron and zinc in the supplement explains the lack of impact.
Although the prevalence of anemia at recruitment was much lower than that reported in other developing countries, almost half the women had iron deficiency and these rates increased dramatically during pregnancy despite iron supplementation. The high prevalence of iron deficiency at 32 wk gestation and even at 1 mo postpartum was indeed surprising and cannot be attributed to low rates of compliance. It is not clear whether our serum ferritin values were affected by other factors, but controlling for levels of serum CRP, a marker for infections, did not alter our conclusions (results not shown). These findings suggest that iron supplementation during pregnancy is not adequate to compensate the high demands, especially in the context of poor prepregnant iron status, and emphasize the need for strategies to improve prepregnant nutritional status. Of particular interest are recent findings from an RCT in Tanzania (27) indicating that compared to a placebo, daily consumption of a multiple micronutrient-fortified beverage during pregnancy was effective in reducing anemia and preventing iron deficiency, especially among those who had IDA at baseline. Although it is not clear whether this intervention was more effective than iron supplements, the prevalence of iron deficiency at follow-up (8 wk) was much lower in the intervention group compared to both of our study groups and this approach may be more sustainable and could be used to improve micronutrient status of all women of reproductive age.
In conclusion, our study indicates that multivitamin-mineral supplements during pregnancy do not improve hematologic and iron status compared to iron only. These findings are consistent with recent data from Nepal where no additional benefits were seen in hematologic status during pregnancy by multiple micronutrient supplements compared to iron-folate supplements (13). Furthermore, both the above study and our work in Mexico (12,14) failed to detect any benefits of MM supplements for birth outcomes although an earlier trial conducted in HIV+ women in Tanzania demonstrated reductions in the prevalence of low birth weight and prematurity (11). Without doubt, we must proceed with caution, especially since we do not have any compelling evidence to date to provide multivitamin-mineral supplements in lieu of iron supplements.
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FOOTNOTES |
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2 Supported by the Thrasher Research Fund, NIH Grant HD-34531–05, UNICEF, New York, NY, Conacyt, and INSP, Mexico. None of the authors has any financial or personal interest with the above organizations.
4 Abbreviations used: CRP, C-reactive protein; FE, iron only; Hb, hemoglobin; IDA, iron-deficiency anemia; INSP, Instituto Nacional de Salud Publica; MM, multiple micronutrients; RCT, randomized controlled trial.
Manuscript received 28 October 2003. Initial review completed 1 December 2003. Revision accepted 5 January 2004.
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LITERATURE CITED |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Lozoff, B. & Wachs, T. D. (2001) Functional correlates of nutritional anemias in infancy and early childhood—child development and behavior. Ramakrishnan, U. eds. Nutritional Anemias 2001:69-88 CRC Press Boca Raton, FL. .
2. Haas, J. D. & Brownlie, T. (2001) Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J. Nutr. 131(2S-2):676S-688S.
3. Ramakrishnan, U. (2001) Functional consequences of nutritional anemia during pregnancy and early childhood. Ramakrishnan, U. eds. Nutritional Anemias 2001:43-68 CRC Press Boca Raton, FL. .
4. Allen, L. & Casterline-Sabel, J. (2001) Prevalence and causes of nutritional anemias. Ramakrishnan, U. eds. Nutritional Anemias 2001:7-22 CRC Press Boca Raton, FL. .
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6. Ekstrom, E. C. (2001) Supplementation for nutritional anemias. Ramakrishnan, U. eds. Nutritional Anemias 2001:129-152 CRC Press Boca Raton, FL. .
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11. Fawzie, W. W., Msamanga, G. I., Spiegelman, D., Urassa, E.J.N., McGrath, N., Mwakagile, D., Antelman, G., Mbise, R., Herrera, G., Kapiga, S., Willett, W. & Hunter, D. J., the Tanzania Vitamin & HIV Infection Trial Team (1998) Randomized trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. Lancet 351:1477-1482.[Medline]
12. 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: double blind randomised community trial. Br. Med. J. 326:571-579.
13. Christian, P., Shrestha, J., LeClerq, S. C., Khatry, S. K., Jiang, T., Wagner, T., Katz, J. & West, K. P. (2003) Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal. J. Nutr. 133:3492-3498.
14. Ramakrishnan, U., González-Cossío, T., Neufeld, L. M., Rivera, J. & Martorell, R. (2003) Multiple micronutrient supplements during pregnancy do not increase birth size compared to iron-only supplements: a randomized controlled trial in a semi-rural community in Mexico. Am. J. Clin. Nutr. 77:720-725.
15. National Research Council (U.S.) (1989) Subcommittee on the Tenth Edition of the RDAs. Recommended Dietary Allowances 1989 National Academy Press Washington, DC.
16. Behring Nephelometer 100 Analyzer Behring Laboratories, Messer Grisheim Gmbh Frankfurt/M., W. Germany.
17. Whicher, J. T., Ritchie, R. F., Johnson, A. M., Baudner, S., Bienvenu, J., Blirup-Jensen, S., Carlstrom, A., Dati, F., Ward, A. M. & Svendsen, P. J. (1994) New international reference preparation for proteins in human serum (RPPHS). Clin. Chem. 40:934-938.
18. WHO/UNICEF/UNU (World Health Organization, United Nations Children’s Fund, United Nations University) (1998) Indicators for Assessing Iron Deficiency and Strategies for Its Prevention 1998 World Health Organization Geneva.
19. Lynch, S. & Green, R. (2001) Assessment of nutritional anemias. Ramakrishnan, U. eds. Nutritional Anemias 2001:23-42 CRC Press Boca Raton, FL. .
20. WHO Expert Committee (1995) Physical Status: The Use and Interpretation of Anthropometry 1995:47 WHO Technical Report Series 854, World Health Organization Geneva.
21. Hernandez-Cordero, S., Rivera, J., Villalpando, S., Gonzalez-Cossio, T., Neufeld, L. M., Ramakrishnan, U. & Martorell, R. (2001) Multiple micronutrient supplementation during pregnancy: effect on breast milk retinol concentration at one month postpartum. FASEB J. 15(4) Abstract 505.7.
22. Solomons, N. W. & Ruz, M. (1997) Zinc and iron interaction: concepts and perspectives in the developing world. Nutr. Res. 17:177-185.
23. Solomons, N. W. (1986) Competitive interaction of iron and zinc in the diet: consequences for human nutrition. J. Nutr. 116:927-929.
24. O’Brien, K. O., Zavaleta, N., Caulfield, L. E., Wen, J. & Abrams, S. A (2000) Prenatal iron supplements impair zinc absorption in pregnant Peruvian women. J. Nutr. 130:2251-2255.
25. O’Brien, K. O., Zavaleta, N., Caulfield, L., Yang, L. E. & Abrams, S. (1999) Influence of prenatal iron and zinc supplements on supplemental iron absorption, red blood cell iron incorporation, and iron status in pregnant Peruvian women. Am. J. Clin. Nutr. 69:509-515.
26. Zavaleta, N., Caulfield, L. E. & Garcia, T. (2000) Changes in iron status during pregnancy in Peruvian women receiving prenatal iron and folic acid supplements with or without zinc. Am. J. Clin. Nutr. 71:956-961.
27. Makola, D., Ash, D. M., Tatala, S. R., Latham, M. C., Ndossi, G. & Mehansho, H. (2003) A micronutrient-fortified beverage prevents iron deficiency, reduces anemia and improves the hemoglobin concentration of pregnant Tanzanian women. J. Nutr. 133:1339-1346.
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