Multiple Micronutrient Supplementation during Pregnancy in Developing-Country Settings: Policy and Program Implications of the Results of a Meta-Analysis

Abstract

Background

An independent Systematic Review Team performed a meta-analysis of 12 randomized, controlled trials comparing multiple micronutrients with daily iron–folic acid supplementation during pregnancy.

Objective

To provide an independent interpretation of the policy and program implications of the results of the meta-analysis.

Methods

A group of policy and program experts performed an independent review of the meta-analysis results, analyzing internal and external validity and drawing conclusions on the program implications.

Results

Although iron content was often lower in the multiple micronutrient supplement than in the iron–folic acid supplement, both supplements were equally effective in tackling anemia. Community-based supplementation ensured high adherence, but some mothers still remained anemic, indicating the need to concomitantly treat infections. The small, significant increase in mean birthweight among infants of mothers receiving multiple micronutrients compared with infants of mothers receiving iron-folic acid is of similar magnitude to that produced by food supplementation during pregnancy. Larger micronutrient doses seem to produce greater impact. Meaningful improvements have also been observed in height and cognitive development of the children by 2 years of age. There were no significant differences in the rates of stillbirth, early neonatal death, or neonatal death between the supplemented groups. The nonsignificant trend toward increased early neonatal mortality observed in the groups receiving multiple micronutrients may be related to differences across trials in the rate of adolescent pregnancies, continuing iron deficiency, and/or adequacy of postpartum health care and merits further investigation.

Conclusions

Replacing iron–folic acid supplements with multiple micronutrient supplements in the package of health and nutrition interventions delivered to mothers during pregnancy will improve the impact of supplementation on birthweight and on child growth and development.

Keywords

Antenatal care birthweight iron-folic acid supplementation multiple micronutrient supplementation neonatal death pregnancy stillbirth

References

McLean

Cogswell

Egli

Wojdyla

de Benoist

. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993–2005. Public Health Nutr 2009;12:444–54. Epub 2008 May 23.

Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, Mathers C, Rivera J, for the Maternal and Child Undernutrition Study Group. Maternal and child undernutrition: Global and regional exposures and health consequences. Lancet 2008;371:243–60.

Ramakrishnan

Huffman

. Multiple micronutrient malnutrition: What can be done? In: Semba

Bloem

, eds. Nutrition and health in developing countries, 2nd ed. Totowa, NJ, USA: Humana Press, 2008.

Huffman

Baker

Schumann

Zehner

. The case for promoting multiple vitamin and mineral supplements for women of reproductive age in developing countries. Food Nutr Bull 1999;20:379–94.

UNICEF/World Health Organization/United Nations University. Composition of a multi-micronutrient supplement to be used in pilot programmes among pregnant women in developing countries. Report of a workshop held at UNICEF headquarters, New York, July 9, 1999. New York: UNICEF, 1999.

World Health Organization/World Food Programme/UNICEF. Preventing and controlling micronutrient deficiencies in populations affected by an emergency. Available at: http://www.who.int/nutrition/publications/WHO_WFP_UNICEFstatement.pdf. Accessed 17 August 2009.

UNICEF/World Health Organization/United Nations University Study Team. Multiple micronutrient supplementation during pregnancy (MMSDP): Efficacy trials. London: University College London, 2002.

UNICEF/United Nations University/World Health Organization Study Team. Multiple micronutrient supplementation during pregnancy (MMSDP): A review of progress in efficacy trials. Bangkok: UNICEF, 2004.

Margetts BM, Fall CHD, Ronsmans C, Allen LH, Fisher DJ, Maternal Micronutrient Supplementation Study Group (MMSSG). Multiple micronutrient supplementation during pregnancy in low-income countries: Review of methods and characteristics of studies included in the meta-analyses. Food Nutr Bull 2009;30:S517–26.

10.

Allen LH, Peerson JM, Maternal Micronutrient Supplementation Study Group (MMSSG). Impact of multiple micronutrient versus iron–folic acid supplements on maternal anemia and micronutrient status in pregnancy. Food Nutr Bull 2009;30:S527–32.

11.

Fall CHD, Fisher DJ, Osmond C, Margetts BM, Maternal Micronutrient Supplementation Study Group (MMSSG). Multiple micronutrient supplementation during pregnancy in low-income countries: A meta-analysis of effects on birth size and length of gestation. Food Nutr Bull 2009;30:S533–46.

12.

Ronsmans C, Fisher DJ, Osmond C, Margetts BM, Fall CHD, Maternal Micronutrient Supplementation Study Group (MMSSG). Multiple micronutrient supplementation during pregnancy in low-income countries: A meta-analysis of effects on stillbirths and on early and late neonatal mortality. Food Nutr Bull 2009;30:S547–55.

13.

Tofail

Persson

El Arifeen

Hamadani

Mehrin

Ridout

Ekstrom

Hudna

Grantham-McGregor

. Effects of prenatal food and micronutrient supplementation on infant development: A randomized trial from the Maternal and Infant Nutrition Interventions, Matlab (MINIMat) study. Am J Clin Nutr 2008;87:704–11.

14.

Sunawang Utomo

Hidayat

Kusharisupeni Subarkah . Preventing low birthweight through maternal multiple micronutrient supplementation: A cluster-randomized, controlled trial in Indramayu, West Java. Food Nutr Bull 2009;30:S488–95.

15.

Shankar A, and the Multiple Micronutrients Intervention Trial (SUMMIT) Study Group. Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia: A double-blind cluster-randomised trial. Lancet 2008;371:215–27.

16.

Ramakrishnan

Gonzalez-Cossio

Neufeld

Rivera

Martorell

. 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 2003;77:720–5.

17.

Christian

Khatry

Katz

Pradhan

Le Clerq

Shrestha

Adhikari

Sommer

West

. Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: Double blind randomised community trial. Br Med J 2003;326:571–6.

18.

Osrin

Vaidya

Shrestha

Baniya

Manandhar

Adhikari

Filteau

Tomkins

Costello

AM de L

. Effects of antenatal multiple micronutrient supplementation on birthweight and gestational duration in Nepal: Double-blind, randomised controlled trial. Lancet 2005;365:955–62.

19.

Bhutta Z, Rizvi A, Raza F, Hotwani S, Zaidi S, Soofi S, Bhutta S, Maternal Micronutrient Supplementation Study Group. A comparative evaluation of multiple micronutrient and iron–folic acid supplementation during pregnancy in Pakistan: Impact on pregnancy outcomes. Food Nutr Bull 2009;30:S496–505.

20.

Zagré

Desplats

Adou

Mamadoultaibou

Aguayo

. Prenatal multiple micronutrient supplementation has greater impact on birthweight than supplementation with iron and folic acid: A cluster-randomized, double-blind, controlled programmatic study in rural Niger. Food Nutr Bull 2007;28:317–27.

21.

Roberfroid D, Huybregts L, Lanou H, Henry M, Meda N, Menten J, Kolsteren P, MISAME Study Group. Effects of maternal multiple micronutrient supplementation on fetal growth: A double-blind, randomised controlled trial in rural Burkina Faso. Am J Clin Nutr 2008;88:1330–40.

22.

Zeng

Dibley

Cheng

Dang

Chang

Kong

Yan

. Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation and perinatal mortality in rural western China: Double-blind cluster randomised controlled trial. BMJ. 2008;337:a2001. doi: 10.1136/bmj.a2001.1–11.

23.

Kaestel

Michaelsen

Aaby

Friis

. Effects of prenatal micronutrient supplements on birth weight and perinatal mortality: A randomised controlled trial in Guinea Bissau. Eur J Clin Nutr 2005;59:1081–9.

24.

Friis

Gomo

Nyazema

Ndhlovu

Krarup

Kaestel

Michaelsen

. Effect of multimicronutrient supplementation on gestational length and birth size: A randomised, placebo-controlled, double-blind effectiveness trial in Zimbabwe. Am J Clin Nutr 2004;80:178–84.

25.

Huy

Hop

Shrimpton

Hoa

Arts

. An effectiveness trial of multiple micronutrient supplementation during pregnancy in Vietnam: Impact on birthweight and on stunting in children at around 2 years of age. Food Nutr Bull 2009;30:S506–16.

26.

UNICEF/United Nations University/World Health Organization. Iron deficiency anaemia assessment, prevention and control: A guideline for programme managers. Geneva, WHO, 2001.

27.

Christian

Shrestha

Leclerq

Khatry

Jiong

Wagner

Katz

West

. Supplementation with micronutrients in addition to iron and folic acid does not further improve hematologic status of pregnant women in rural Nepal. J Nutr 2003;133:3492–8.

28.

Christian

Khatry

West

. Antenatal anthelmintic treatment, birthweight and infant survival in rural Nepal. Lancet 2004;364:981–3.

29.

Allen

Shrimpton

. The International Research on Infant Supplementation study: Implications for programmes and further research. J Nutr 2005;135:666S–9S.

30.

Kaestel

. Micronutrient supplementation and other predictors of birth size and perinatal mortality in Guinea-Bissau. Royal Veterinary and Agriculture University. Reported by Kaestel, P, K. Fleiscer Michaelsen, and H. Friis. Programmes implications of prenatal multiple micronutrient supplementation trials. Report UNICEF, April 2004. New York: UNICEF 2004.

31.

Christian

Jiang

Khatry

LeClerq

Shrestha

West

Jr . Antenatal supplementation with micronutrients and biochemical indicators of status and subclinical infection in rural Nepal. Am J Clin Nutr 2006;83:788–94.

32.

Allen

. Multiple micronutrients in pregnancy and lactation: An overview. Am J Clin Nutr 2005;81(suppl): 1206S–12S.

33.

Obeid

Munz

Jäger

Schmidt

Herrmann

. Biochemical indexes of the B vitamins in cord serum are predicted by maternal B vitamin status. Am J Clin Nutr 2005;82:133–9.

34.

Dijkhuizen

Wieringa

West

Muhilal . Zinc plus β-carotene supplementation of pregnant women is superior to β-carotene supplementation alone in improving vitamin A status in both mothers and infants. Am J Clin Nutr 2004;80:1299–307.

35.

Kramer

Victora

. Low birth weight and perinatal mortality. In: Semba

Bloem

, eds. Nutrition and health in developing countries. Totowa, NJ, USA: Humana Press, 2001:57–69.

36.

Vaidya

Saville

Shrestha

Costello

Manandhar

Osrin

. Effects of antenatal multiple micronutrient supplementation on children's weight and size at 2 years of age in Nepal: Follow-up of a double-blind randomised controlled trial. Lancet 2008;371:492–9.

37.

Puffer

Serrano

. 1976 results of the inter-American investigations of mortality relating to reproduction. Bull Pan Am Health Organ 1976;10:131–42.

38.

Ashworth

. Effects of intrauterine growth retardation on mortality and morbidity in infants and young children. Eur J Clin Nutr 1998;52(suppl 1):S34–41.

39.

Shrimpton

. Preventing low birthweight and reduction of child mortality. Trans R Soc Trop Med Hyg 2003;97:39–42.

40.

Shrimpton

Dalmiya

Darnton-Hill

Gross

. Micronutrient supplementation in pregnancy. Lancet 2005;366:2001–2.

41.

Huffman

Habicht

Scrimshaw

. Micronutrient supplementation in pregnancy. Lancet 2005;366:2001.

42.

Peña-Rosas

Viteri

. Effects of routine oral iron supplementation with or without folic acid for women during pregnancy. Cochrane Database Syst Rev 2006;3:CD004736.

43.

United Nations Administrative Committee on Coordination/Sub-Committee on Nutrition (ACC/SCN). Controlling iron deficiency. ACC/SCN State of the Art Series. Nutrition Policy Discussion Paper No. 9. Geneva: UN Standing Committee on Nutrition, 1991.

44.

Galloway

McGuire

. Determinants of compliance with iron supplementation: Supplies, side effects, or psychology? Soc Sci Med 1994;39:381–90.

45.

Aguayo

Koné

Bamba

Diallo

Sidibé

Traoré

Signé

Baker

. Acceptability of multiple micronutrient supplements by pregnant and lactating women in Mali. Public Health Nutr 2005;8:33–7.

46.

Rosenberg

. Metabolic programming of offspring by vitamin B12/folate imbalance during pregnancy. Diabetologia 2008;51:6–7.

47.

Yajnik

Deshpande

Jackson

Refsum

Rao

Fisher

Bhat

Naik

Coyaji

Joglekar

Joshi

Lubree

Deshpande

Rege

Fall

. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: The Pune Maternal Nutrition Study. Diabetologia 2008;51:29–38.

48.

Berger

Thanh

Cavalli-Sforza

Smitasiri

Khan

Milani

Hoa

Quang

Viteri

. Community mobilization and social marketing to promote weekly iron-folic acid supplementation in women of reproductive age in Vietnam: Impact on anemia and iron status. Nutr Rev 2005;63(12 pt 2):S95–108.

49.

Ekström

Hyder

Chowdhury

Lönnerdal

Habicht

Persson

. Efficacy and trial effectiveness of weekly and daily iron supplementation among pregnant women in rural Bangladesh: Disentangling the issues. Am J Clin Nutr 2002;76:1392–400.

50.

World Health Organization/UNICEF. Focusing on anaemia: Towards an integrated approach for effective anaemia control. Available at: http://www.who.int/topics/anaemia/en/who_unicef-anaemiastatement.pdf. Accessed 17 August 2009.

51.

van den Broek

Letsky

. Etiology of anaemia in pregnancy in south Malawi. Am J Clin Nutr 2000;72(suppl):247S–56S.

52.

Bondevik

Eskeland

Ulvik

Ulstein

Lie

Schneede

Kvåle

. Anaemia in pregnancy: Possible causes and risk factors in Nepali women. Eur J Clin Nutr 2000;54:3–8.

53.

Mburu

Thurnham

Mwaniki

Muniu

Alumasa

de Wagt

. The influence and benefits of controlling for inflammation on plasma ferritin and haemoglobin responses following a multi-micronutrient supplement in apparently healthy, HIV+ Kenyan adults. J Nutr 2008;138:613–9.

54.

Friis

Mwaniki

Omondi

Muniu

Thiong'o

Ouma

Magnussen

Geissier

Michaelsen

. Effects on haemoglobin of multi-micronurient supplementation and multi-helminth chemotherapy: A randomized, controlled trial in Kenyan school children. Eur J Clin Nutr 2003;57:573–9.

55.

Taylor

Jinabhai

Couper

Kleinschmidt

Jogessar

. The effect of different anthelmintic treatment regimens combined with iron supplementation on the nutritional status of schoolchildren in KwaZulu-Natal, South Africa: A randomized controlled trial. Trans R Soc Trop Med Hyg 2001;95:211–6.

56.

Thi Le

Brouwer

Burema

Nguyen

Kok

. Efficacy of iron fortification compared to iron supplementation among Vietnamese schoolchildren. Nutr J 2006;5:32. 1–8.

57.

García-Guerra

Neufeld

Hernández-Cordero

Rivera

Martorell

Ramakrishnan

. Prenatal multiple micronutrient supplementation impact on biochemical indicators during pregnancy and postpartum. Salud Publica Mex. 2009 51(4): 327–35.

58.

Villard

Bates

. Effect of vitamin A supplementation on plasma and breast milk vitamin A levels in poorly nourished Gambian women. Hum Nutr Clin Nutr 1987;41:47–58.

59.

Bates

Prentice

Paul

Sutcliffe

Watkinson

Whitehead

. Riboflavin status in Gambian pregnant and lactating women and its implications for recommended dietary allowances. Am J Clin Nutr 1981;34:928–35.

60.

Bates

Prentice

Lamb

Whitehead

. The effect of vitamin C supplementation on lactating women in Keneba, a West African rural community. Int J Vit Nutr Res 1983;5:68–76.

61.

Sneed

Zane

Thomas

. The effects of ascorbic acid, vitamin B-6, vitamin B-12 and folic acid supplementation on the breast milk and maternal status of low socioeconomic lactating women. Am J Clin Nutr 1981;34:1338–46.

62.

Shrimpton

Alencar

Vasconcelos

Rocha

. Effects of maternal zinc supplementation on the growth and diarrhoeal status of breastfed infants. Nutr Res 1985;(suppl 1):338–42.

63.

Baylin

Villamor

Rifai

Msamanga

Fawzi

. Effect of vitamin supplementation to HIV-infected pregnant women on the micronutrient status of their infants. Eur J Clin Nutr 2005;59:960–8.

64.

Kramer

Kakuma

. Energy and protein intake in pregnancy. Cochrane Database Syst Rev 2003;3:CD000032.

65.

Rasmussen

Stoltzfus

. New evidence that iron supplementation during pregnancy improves birth weight: New scientific questions. Am J Clin Nutr 2003;78:673–4.

66.

Haider

Bhutta

. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev 2006;4:CD004905.

67.

Hininger

Favier

Arnaud

Faure

Thoulon

Hariveau

Favier

Roussel

. Effects of a combined micronutrient supplementation on maternal biological status and newborn anthropometrics measurements: A randomized double-blind, placebo-controlled trial in apparently healthy pregnant women. Eur J Clin Nutr 2004;58:52–9.

68.

Gupta

Ray

Dua

Radhakrishnan

Kumar

Sachdev

. Multimicronutrient supplementation for undernourished pregnant women and the birth size of their offspring: A double-blind, randomized, placebo-controlled trial. Arch Pediatr Adolesc Med 2007;161:58–64.

69.

Winkvist

Habicht

Rasmussen

. Linking maternal and infant benefits of a nutritional supplement during pregnancy and lactation. Am J Clin Nutr 1998;68:656–61.

70.

Garn

La Velle

Rosenberg

Hawthorne

. Maturational timing as a factor in female fatness and obesity. Am J Clin Nutr 1986;43:879–83.

71.

Demerath

Sun

Chumlea

Remsberg

Czerwinski

Towne

Siervogel

. Fifty-year trends in serial body mass index during adolescence in girls: The Fels Longitudinal Study. Am J Clin Nutr 2004;80:441–6.

72.

Riley

Huffman

Chowdhury

. Age at menarche and postmenarcheal growth in rural Bangladeshi females. Ann Hum Biol 1989;16:347–59.

73.

Scholl

Hediger

Schall

Khoo

Fischer

. Maternal growth during adolescent pregnancy. JAMA 1994;274:26–7.

74.

Rah

Christian

Shamim

Arju

Labrique

Rashid

. Pregnancy and lactation hinder growth and nutritional status of adolescent girls in rural Bangladesh. J Nutr 2008;138:1505–11.

75.

Flores

Neufeld

González-Cossío

Rivera

Martorell

Ramakrishnan

. Multiple micronutrient supplementation and dietary energy intake in pregnant women. Salud Publica Mex 2007;49:190–8.

76.

Ninh

Thissen

Collette

Gerard

Khoi

Ketelslegers

. Zinc supplementation increases growth and circulating insulin-like growth factor I (IGF-I) in growth-retarded Vietnamese children. Am J Clin Nutr 1996;63:514–9.

77.

World Health Organization. Promoting optimal fetal development. Report of a technical consultation. Geneva: WHO, 2006.

78.

Ashworth

. Effects of intrauterine growth retardation on mortality and morbidity in infants and young children. Eur J Clin Nutr 1998;52(suppl 1):S34–41.

79.

Richards

Hardy

Kuh

Wadsworth

. Birth weight and cognitive function in the British 1946 birth cohort: Longitudinal population based study. BMJ 2001;322:199–203.

80.

Kusin

Kardjati

Houtkooper

Renqvist

. Energy supplementation during pregnancy and postnatal growth. Lancet 1992;340:623–6.

81.

Alderman

Behrman

. Reducing the incidence of low birth weight in low-income countries has substantial economic benefits. World Bank Res Obs 2006;21:25–48.

82.

Victora

Adair

Fall

Hallal

Martorell

Richter

Sachdev

. Maternal and child undernutrition: Consequences for adult health and human capital. Lancet 2008;371:340–57.

83.

Barker

Hales

Fall

Osmond

Phipps

Clark

. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): Relation to reduced fetal growth. Diabetologia 1993;36:62–7.

84.

Katz

Christian

Dominici

Zegery

. Treatment effects of maternal micronutrient supplementation vary by percentiles of the birth weight distribution in rural Nepal. J Nutr 2006;136:1389–94.

85.

Christian

Darmstadt

Khatry

Leclerq

Katz

West

Jr Adhikari

. The effect of maternal micronutrient supplementation on early neonatal morbidity in rural Nepal: A randomized, controlled, community trial. Arch Dis Child 2008;93:660–4.

86.

Stewart

Katz

Khatry

LeClerq

Shrestha

West

Jr Christian

. Preterm delivery but not intrauterine growth retardation is associated with young maternal age among primiparae in rural Nepal. Matern Child Nutr 2007;3:174–85.

87.

Sharma

Katz

Mullany

Khatry

LeClerq

Shrestha

Darmstadt

Tielsch

. Young maternal age and the risk of neonatal mortality in rural Nepal. Arch Pediatr Adolesc Med 2008;162:828–35.

88.

Titaley

Dibley

Agho

Roberts

Hall

. Determinants of neonatal mortality in Indonesia. BMC Public Health 2008;8:232. 1–15.

89.

Vangen

Stoltenberg

Skjaerven

Magnus

Harris

Stray-Pedersen

. The heavier the better? Birthweight and perinatal mortality in different ethnic groups. Int J Epidemiol 2002;31:654–60.

90.

Ceesay

Prentice

Cole

Foord

Poskitt

EME

Weaver

Whitehead

. Effects on birth weight and perinatal mortality of maternal dietary supplements in rural Gambia: 5 year randomised controlled trial. BMJ 1997;315:786–90.

91.

Ministry of Health and Population (MOHP) [Nepal], New ERA, Macro International. Nepal Demographic and Health Survey 2006. Kathmandu: Ministry of Health and Population, New ERA, and Calverton, Md, USA: Macro International, 2007.

92.

National Institute of Population Research and Training (NIPORT), Mitra and Associates, and Macro International. Bangladesh Demographic and Health Survey 2007. Dhaka: National Institute of Population Research and Training, Mitra and Associates, and Calverton, Md, USA: Macro International, 2009.

93.

Institut National de la Statistique et de la Démographie (INSD) and ORC Macro. Enquête Démographique de Santé du Burkina Faso 2003. Calverton, Md, USA: INSD and ORC Macro, 2004.

94.

World Health Organization/UNICEF. Global strategy on infant and young child feeding. Geneva: WHO, 2003.

95.

World Health Organization. Physical status: The use and interpretation of anthropometry. WHO Technical Report Series No. 854. Geneva: WHO, 2005.

96.

World Health Organization. Reproductive health strategy. Geneva: WHO, 2004.

97.

Podja

Kelly

, eds. Low birthweight. Nutrition Policy Paper No. 18. Geneva: UN Standing Committee on Nutrition, 2004.

98.

Morris SS, Cogil B, Uauy R; Child Undernutrition Study Group. Effective international action against undernutrition: Why has it proven so difficult and what can be done to accelerate progress? Lancet 2008;371:608–21.

99.

Marmot M, Friel S, Bell R, Houweling TA, Taylor S; Commission on Social Determinants of Health. Closing the gap in a generation: Health equity through action on the social determinants of health. Lancet 2008;372:1661–9.