![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205
2To whom correspondence should be addressed. E-mail: pchristi{at}jhsph.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT Zinc, reproductive health and...Vitamin A and maternal...Multiple micronutrients and...Future areas for researchLITERATURE CITED |
|---|
KEY WORDS: • micronutrients • vitamin A • zinc • reproductive health • pregnancy outcomes
A vast disparity exists between the health and nutritional status of women living in the developing world and women living in industrialized countries. For example, low body mass index, a known risk factor for poor pregnancy outcome, is <18.5 in 34% of women in south Asia and 18% of women in sub-Saharan Africa in contrast to 4% in those in the developed world (1). Anemia affects 50–70% of women during pregnancy (1) and maternal night blindness, an indicator of vitamin A deficiency, is estimated to afflict about 10% of women during pregnancy in many regions of south Asia (2). The maternal mortality ratio is 50 and 80 times higher in south Asia and sub-Saharan Africa, respectively, than in the United States or Europe. In many rural areas most women receive no antenatal care and in excess of 90% deliver at home attended by local poorly trained and poorly equipped midwives or older relatives. Both in relative and absolute terms the burden of poor maternal nutritional and health status is extremely high in these two developing regions of the world.
Poor maternal health outcomes are often framed in terms of common and potentially severe maternal illnesses such as the hypertensive disorders of pregnancy, anemia and infection; and emergency obstetric complications such as hemorrhage, placental abruption and other complications of labor and delivery. Adverse outcomes also occur among the offspring, such as fetal death (miscarriage, stillbirth), preterm birth, intrauterine growth retardation, birth defects and other conditions that increase the risk of early infant death. Many of these conditions and outcomes are more frequent in undernourished than in well-nourished populations.
Vitamins and minerals, collectively referred to as micronutrients, can have important influences on the health of pregnant women and the growing fetus and newborn. The effects of giving women single or multiple micronutrients in supplement form on maternal health and outcomes of pregnancy are surprisingly poorly understood, especially in undernourished populations of the world. This paper illustrates the potential effects of micronutrient supplements in reproductive and newborn health by using contemporary studies highlighting evidence on two individual nutrients: zinc and vitamin A. It also examines findings from recent trials of multiple micronutrient supplementation on birth weight and infant survival.
|
Zinc, reproductive health and pregnancy outcome |
|---|
|
TOPABSTRACTZinc, reproductive health and...Vitamin A and maternal...Multiple micronutrients and...Future areas for researchLITERATURE CITED |
|---|
Animal experiments and observational studies in humans provide plausibility for numerous essential roles of zinc in the gestational health of the newborn and mother. Outcomes that appear to be zinc dependent include placental abruption, premature rupture of membranes and preterm labor as well as inefficient uterine contraction and prolonged 1st and 2nd stage labor, clearly pointing to the need for zinc adequacy during pregnancy [Table 1; (5–8)]. However, supplementation trials in humans have failed to show these effects may be because of flaws in study designs and because these studies were done primarily in zinc-replete populations [Table 2; (9–12)].
|
|
In a study in Bangladesh (15), the infants of supplemented and nonsupplemented women were followed up to age 6 mo. The investigators found that although maternal zinc supplementation did not affect birth weight, it resulted in a reduction in the number of episodes of acute diarrhea, dysentery and impetigo but not acute lower respiratory infection in infants (16). This reduction in health risks was observed in low birth weight but not normal weight infants. These data suggest that although infants of zinc-supplemented mothers may be born small, they may have a less compromised immune system and that low birth weight may only indicate risk rather than directly cause morbidity and mortality. In the study in Peru, maternal zinc supplementation showed improvements in indicators of fetal neurobehavioral development (17). These results are interesting and need further investigation in other settings.
|
Vitamin A and maternal morbidity and mortality |
|---|
|
TOPABSTRACTZinc, reproductive health and...Vitamin A and maternal...Multiple micronutrients and...Future areas for researchLITERATURE CITED |
|---|
|
A large trial in the south-central plains of Nepal assessed the effects of weekly supplementation of women of reproductive age with vitamin A (7000 µg retinol equivalents, RE) or ß-carotene (42 mg), given at a level that approximated the RDA, on pregnancy-related mortality, fetal loss and infant mortality (23). There were 110 deaths in the study: 55 in the placebo group, 33 in the vitamin A group and 26 in the ß-carotene group. With the placebo group as the reference group, the relative risk (RR) estimates (95% confidence limits, CL) were 0.60 (0.37, 0.97) for the vitamin A group and 0.51 (0.30, 0.86) for the ß-carotene group, indicating reductions in pregnancy-related mortality of 40 and 49%, respectively.
These findings have generated a lot of interest and debate in the scientific community regarding the role of vitamin A and ß-carotene supplementation in reducing the burden of maternal mortality in the developing world. Possible mechanisms that are postulated for this effect relate to the role of vitamin A in the prevention of obstetric hemorrhage, anemia, hypertension and pregnancy-related infections (24). The population in which this trial was conducted is a typical rural south Asian population and represents, in terms of diet, culture and population dynamics, the way of life of 
100 million women living in the great Gangetic plains of south Asia. The reproducibility of these findings is, however, currently being tested in other large trials, the results of which will become available in the next 2–3 y.
In the same study, maternal vitamin A supplementation reduced self-reported symptoms of nausea, faintness and night blindness during the last trimester of pregnancy as well as shortened the length of labor by 1.5 h and 50 min among nulliparous and mulitparous women, respectively (25). Both interventions also reduced the postpartum prevalence of diarrheal illness. Among women receiving vitamin A, the total number of days with any illness accrued over the last 12 wk of gestation was lower by 5 d compared with placebo recipients (25). ß-carotene supplementation had no such effect.
Although the effect on maternal mortality was substantial, there was no evidence of benefit on fetal or early infant mortality (26). The relative risks for both of these outcomes were close to one. These results suggest that the causes of early infant death may not be responsive to maternal supplementation with vitamin A or ß-carotene, at least in this setting. These findings are similar to the lack of effect on low birth weight or perinatal mortality due to maternal vitamin A supplementation in women in Tanzania infected with HIV-1 (27).
As mentioned previously, prevalence of night blindness during pregnancy in this rural population of Nepal is high and ranges from 12 to16% (20). This condition, which manifests in the latter part of pregnancy and is likely to disappear spontaneously after birth, has only recently been recognized as an important public health problem and indicator of vitamin A deficiency in women (20). In a case-control study in Nepal, night-blind pregnant case subjects were compared with control subjects, who were pregnant women without night blindness. Night-blind women were two to three times more likely to report illness symptoms of urinary and reproductive tract infection, diarrhea and dysentery, nausea, vomiting and poor appetite and symptoms of preeclampsia and eclampsia during and before their becoming night blind compared with non-night-blind control subjects (28).
Night blindness during pregnancy was also associated with a 2–4-fold increased risk of mortality among women in the early maternal period lasting through 6-wk postpartum, the late pregnancy period from 6 wk postpartum through 52-wk postpartum and even beyond 52 wk (29). This elevated risk of mortality persisted long after night blindness had been resolved in these women, suggesting chronic vitamin A deficiency. Further, although the excess mortality risk of pregnancy waned in the general population, it appeared to be sustained for an extended period in women who had been night blind in pregnancy. Vitamin A or ß-carotene supplementation ameliorated this excess risk of mortality to a large extent. Verbal autopsy data used to determine proximate cause of death in women revealed that night-blind women were five times more likely to have died of infection-related causes than were non-night-blind women (29). Obstetric and other causes of death did not differ by night blindness status.
|
Multiple micronutrients and pregnancy outcome |
|---|
|
TOPABSTRACTZinc, reproductive health and...Vitamin A and maternal...Multiple micronutrients and...Future areas for researchLITERATURE CITED |
|---|
One randomized, clinical trial (2 x 2 factorial design) in women infected with HIV-1 in Tanzania tested the efficacy of maternal vitamin A (1500 µg RE and 30 mg ß-carotene) and multivitamin supplementation during pregnancy in improving birth outcomes (27). Multivitamins were given at 2 to 10 times the RDA for pregnancy (20 mg thiamin, 20 mg riboflavin, 25 mg vitamin B-6, 100 mg niacin, 50 µg vitamin B-12, 500 mg vitamin C, 30 mg vitamin E and 0.8 mg folic acid). Vitamin A alone had no effect on birth outcomes. Multivitamin supplementation resulted in reductions of about 40% in low birth weight, preterm delivery, small size for gestational age and fetal deaths. The implications of these findings for populations not infected with HIV-1 are not clear; future studies should address this issue.
In south Asia multiple micronutrient deficiencies are believed to coexist (31). Among the candidate deficiencies are those of vitamin A, iron, folate and zinc. Other deficiencies that are likely to coexist but for which population data are poor to nonexistent are B-complex vitamins and vitamins D, E and K. An observational study in rural India found that micronutrient-rich food consumption—specifically that of milk, green leafy vegetables and fruits during pregnancy—and erythrocyte folate at 28 wk of gestation are independently positively associated with size of the infant at birth (32).
We recently undertook a randomized community-based trial of 5000 pregnant women to test the efficacy of giving women different combinations of micronutrient supplements daily from the first trimester through 3 mo postpartum on birth size, fetal loss and infant mortality (33). In all, 426 rural communities were randomly assigned to five different supplement groups (Table 4). In this population we had previously observed a 40% reduction in maternal mortality due to vitamin A (23) but no effect on fetal and infant mortality (26). Women were identified early in pregnancy through urine-based pregnancy testing and received one of the five supplements daily from the time pregnancy was detected through 12 wk postpartum.
|
These data suggest that maternal multiple micronutrient supplementation (1000 µg RE vitamin A, 10 µg vitamin D, 10 mg vitamin E, 1.6 mg thiamin, 1.8 mg riboflavin, 20 mg niacin, 2.2 mg vitamin B-6, 2.6 µg vitamin B-12, 65 mg vitamin C, 30 µg vitamin K, 400 µg folic acid, 60 mg iron, 30 mg zinc, 2.0 mg copper and 100 mg magnesium) has no beneficial effect on infant mortality despite a significant reduction in the incidence of low birth weight. Other limited combinations of micronutrients that included folic acid alone or with iron or iron plus zinc appear to reduce mortality in infants. The findings regarding multiple micronutrient supplementation are surprising and the actual mechanisms of the effects may be complex and remain to be elucidated. These results also suggest that improved maternal micronutrient nutriture may result in a survival benefit via mechanisms that may not be mediated by changes in birth weight.
Another trial that was recently completed in a semirural area of Mexico by Ramakrishnan et al. (35) also examined the effect of multiple micronutrient supplementation (containing 2150 IU vitamin A, 309 IU D3, 5.73 IU vitamin E, 1.94 mg vitamin B-6, 2.04 µg vitamin B-12, C 66.5 mg, 0.93 mg thiamin, 1.87 mg riboflavin, 15.5 mg niacin, 215 µg folic acid, 12.9 mg zinc, 62.4 mg iron and 252 mg magnesium) compared with iron (60 mg) alone on birth size. Maternal multiple micronutrient supplementation did not have any effect on birth size in comparison with iron. Mean birth weight (2.98 kg) and the incidence of low birth weight (8–9%) were comparable in both treatment groups. The results of the two studies (33,35) are strikingly similar with respect to birth weight as the outcome. Both studies found that multiple micronutrients do not have any additional benefit over iron and folate in improving birth weight.
|
Future areas for research |
|---|
|
TOPABSTRACTZinc, reproductive health and...Vitamin A and maternal...Multiple micronutrients and...Future areas for researchLITERATURE CITED |
|---|
Maternal multiple micronutrient supplementation needs a more careful evaluation before being used in large public health programs. Multiple micronutrient formulations used in the various studies were not similar. The right combination of nutrients might vary by population depending on the nutrients that are limiting in the population being studied. Also, nutrient–nutrient interactions can be both positive and negative, and research in understanding these more clearly is needed. Infant health and survival should be examined in efficacy trials testing the effects of micronutrient supplements. Appropriate biomarkers may also enhance the interpretation of future studies.
|
FOOTNOTES |
|---|
|
LITERATURE CITED |
|---|
|
TOPABSTRACTZinc, reproductive health and...Vitamin A and maternal...Multiple micronutrients and...Future areas for researchLITERATURE CITED |
|---|
1. United Nations Administrative Committee on Coordination (2000) Sub-committee on Nutrition (ACC/SCN). The 4th Report on the World Nutrition Situation 2000 ACC/SCN in collaboration with IFPRI Geneva, Switzerland.
2. West, K. P., Jr (2002) Extent of vitamin a deficiency among preschool children and women of reproductive age. J. Nutr. 132:2857S-2866S.
3. Parr, R. M. (1996) Assessment of dietary intakes. Trace elements in human nutrition and health 1996:265-288 World Health Organization Geneva, Switzerland.
4. Institute of Medicine (2002) Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 2002 National Academy Press Washington, DC.
5. Sikorski, S., Juszkiewicz, T. & Paszkowski, T. (1990) Zinc status in women with premature rupture of membranes at term. Obstet. Gynecol. 76:675-677.[Medline]
6. Scholl, T. O., Hediger, M. L., Schall, J. I., Fishcer, R. L. & Khoo, C. S. (1993) Low zinc intake during pregnancy: its association with preterm and very preterm delivery. Am. J. Epidemiol. 137:1115-1124.
7. Lazebnik, N., Kuhnert, B. R., Kuhnert, P. M. & Thompson, K. L. (1988) Zinc status, pregnancy complications, and labor abnormalities. Am. J. Obstet. Gynecol. 158:161-166.[Medline]
8. Dura-Trave, T., Puig-Abuli, M., Monreal, I. & Villa-Elizaga, I. (1984) Relation between maternal plasmatic zinc levels and uterine contractility. Gynecol. Obstet. Invest. 17:247-251.[Medline]
9. Mahomed, K., James, D. K., Golding, J. & McCabe, R. (1989) Zinc supplementation during pregnancy: a double blind randomised controlled trial. Br. Med. J. 299:826-830.
10. Kynast, G. & Saling, E. (1986) Effect of oral zinc application during pregnancy. Gynecol. Obstet. Invest. 21:117-123.[Medline]
11. Jameson, S. (1993) Zinc status in pregnancy: the effect of zinc therapy on perinatal mortality, prematurity, and placental ablation. Ann. NY Acad. Sci. 678:178-192.[Medline]
12. Simmer, K., Lort-Phillips, L., James, C. & Thompson, R.P.H. (1991) A double-blind trial of zinc supplementation in pregnancy. Eur. J. Clin. Nutr. 45:139-144.
13. Caulfield, L. E., Zavaleta, N., Shankar, A. H. & Merialdi, M. (1998) Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival. Am. J. Clin. Nutr. 68(suppl):499S-508S.[Abstract]
14. Osenderp, S.J.M., West, C. E. & Black, R. E. on behalf of the Maternal Zinc Supplementation Study Group. (2003) The need for maternal zinc supplementation in developing countries: An unresolved issue. J. Nutr. 133:817S-827S.
15. Osenderp, S.J.M., van Raaij, J.M.A., Arifeen, S. E., Wahed, M. A., Baqui, A. & H & Fuch, G. J. (2000) A randomized placebo-controlled trial of the effect of zinc supplementation during pregnancy and on pregnancy outcome in Bangladeshi urban poor. Am. J. Clin. Nutr. 71:114-119.
16. Osenderp, S.J.M., van Raaij, J.M.A., Darmstadt, G. L., Baqui, A. H., Hautvast, J.G.A.J. & Fuchs, G. J. (2001) Zinc supplementation during pregnancy and effects on growth and morbidity in low birth weight infants: a randomized placebo controlled trial. Lancet 357:1080-1085.[Medline]
17. Merialdi, M., Caulfield, L. E., Zavaleta, N., Figueroa, A. & DiPietro, J. A. (1999) Adding zinc to prenatal iron and folate tablets improves neurobehavioral development. Am. J. Obstet. Gynecol. 180:483-490.[Medline]
18. Rothman, K. J., Moore, L. L., Singer, M. R., Nguyen, U. S., Mannino, S. & Milunsky, A. (1995) Teratogenicity of high vitamin A intake. N. Engl. J. Med. 333:1369-1373.
19. Mills, J. L., Simpson, J. L., Cunningham, G. C., Conley, M. R. & Rhoads, G. G. (1997) Vitamin A and birth defects. Am J Obstet Gynecol 177:31-36.[Medline]
20. Christian, P. (2002) Recommendations for indicators: night blindness during pregnancy - a simple tool to assess vitamin A deficiency in a population. J. Nutr. 132:2884S-2888S.
21. Green, H. N., Pindar, D., Davis, G. & Mellanby, E. (1931) Diet as a prophylactic agent against puerperal sepsis. Br. Med. J. 2:595-598.
22. Suharno, D., West, C. E., Muhilal, , Karyadi, D. & Hautvast, J.G.A.J. (1993) Supplementation with vitamin A and iron for nutritional anemia in pregnant women in West Java, Indonesia. Lancet 342:1325-1328.[Medline]
23. 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. (1999) Low dose vitamin A or ß-carotene supplementation reduces pregnancy-related mortality: A double-masked, cluster randomized Prevention Trial in Nepal. B. M. J. 318:570-575.
24. Faisel, H. & Pittrof, R. (2000) Vitamin A and causes of maternal mortality: association and biological plausibility. Public Health Nutr 3:321-327.[Medline]
25. Christian, P., West, K. P., Jr, Khatry, S. K., Katz, J., LeClerq, S. C., Kimbrough-Pradhan, E., Dali, S. M. & Shrestha, S. R. (2000) Vitamin A or ß-carotene supplementation reduces symptoms of illness in pregnant and lactating Nepali women. J. Nutr. 130:2675-2682.
26. Katz, J., West, K. P., Jr, Khatry, S. K., Pradhan, E. K., LeClerq, S. C., Christian, P., Wu, L.S.F., Adhikari, R. K., Shrestha, S. R. & Sommer, A. (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.
27. Fawzi, W. W., Msamanga, G. I., Spiegelman, D., Ernest, J.N.U., McGrath, N., Mwakagile, D., Antelman, G., Mbise, R., Herrera, G., Kapiga, S., Willet, W. & Hunter, D. J. (1998) Randomised 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]
28. Christian, P., West, K. P., Jr, Khatry, S. K., Katz, J., Shrestha, S. R., Pradhan, E. K., LeClerq, S. C. & Pokhrel, R. P. (1998) Night blindness of pregnancy in rural Nepal - nutritional and health risks. Int. J. Epidemiol. 27:231-237.
29. Christian, P., West, K. P., Jr, Khatry, S. K., Kimbrough-Pradhan, E., LeClerq, S. C., Katz, J., Shrestha, S. R., Dali, S. M. & Sommer, A. (2000) Night blindness during pregnancy and subsequent mortality among women in Nepal: Effects of vitamin A and ß-carotene supplementation. Am. J. Epidemiol. 152:542-547.
30. Ramakrishnan, U., Manjrekar, R., Rivera, J., Gonzales-Cossio, T. & Martorell, R. (1999) Micronutrients and pregnancy outcome: A review of literature. Nutr. Res. 19:103-159.
31. Huffman, S. L., Baker, J., Shumann, J. & Zehner, E. R. (1999) The case for promoting multiple vitamin/mineral supplements for women of reproductive age in developing countries 1999 Linkages Project, Academy for Educational Development Washington D. C.
32. Rao, S., Yajnik, C. S., Kanade, A., Fall, C.H.D., Margetts, B. M., Jackson, A. A., Shier, R., Joshi, S., Rege, S., Lubree, H. & Desai, B. (2001) Intake of micronutrient-rich foods in rural Indian mothers is associated with the size of their babies at birth: Pune Maternal Nutrition Study. J. Nutr. 131:1217-1224.
33. 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.
34. Christian, P., West, K. P., Jr, Khatry, S. K., LeClerq, S. C., Pradhan, E. K., Katz, J., Shrestha, S. R. & Sommer, A. (2001) Effect of prenatal multiple micronutrient supplementation on low birth weight and 6-month mortality among infants in rural Nepal: A double-masked, randomized community trial. Ann Nutr Metab 45(suppl 1):463Abstract.
35. Ramakrishnan, U., Gonzalez-Cossio, T., Neufeld, L. M. & Rivera, J., Martorell (2003) Multiple micronutrient supplementation during pregnancy does not lead to greater infant birth size than does iron-only supplementation: a randomized controlled trial in a semirural community in Mexico. Am J Clin Nutr 77:720-725.
This article has been cited by other articles:
|
|
 |
|
  H.M. Salihu, O. Lynch, A.P. Alio, J.L. Kornosky, H.B. Clayton, and A.K. Mbah Extreme obesity and risk of placental abruption Hum. Reprod., February 1, 2009; 24(2): 438 - 444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-H. Hung, C.-C. Hsieh, J.-J. Hsu, L.-M. Lo, T.-H. Chiu, and T.-T. Hsieh Risk Factors for Placental Abruption in an Asian Population Reproductive Sciences, January 1, 2007; 14(1): 59 - 65. [Abstract] [PDF]
|
|
|
|
 |
|
 K. L Penniston and S. A Tanumihardjo The acute and chronic toxic effects of vitamin A Am. J. Clinical Nutrition, February 1, 2006; 83(2): 191 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Darnton-Hill, P. Webb, P. W. Harvey, J. M Hunt, N. Dalmiya, M. Chopra, M. J Ball, M. W Bloem, and B. de Benoist Micronutrient deficiencies and gender: social and economic costs Am. J. Clinical Nutrition, May 1, 2005; 81(5): 1198S - 1205S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Jiang, P. Christian, S. K. Khatry, L. Wu, and K. P. West Jr Micronutrient Deficiencies in Early Pregnancy Are Common, Concurrent, and Vary by Season among Rural Nepali Pregnant Women J. Nutr., May 1, 2005; 135(5): 1106 - 1112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Friis, E. Gomo, N. Nyazema, P. Ndhlovu, H. Krarup, P. Kaestel, and K. F Michaelsen Effect of multimicronutrient supplementation on gestational length and birth size: a randomized, placebo-controlled, double-blind effectiveness trial in Zimbabwe Am. J. Clinical Nutrition, July 1, 2004; 80(1): 178 - 184. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
