World Health Organization, 2014. World Malaria Report 2014. Available at: http://www.who.int/malaria/publications/world_malaria_report_2014/report/en/. Accessed July 18, 2016.
Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD, 2007. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 7: 93–104.
Menéndez C, Ferenchick E, Roman E, Bardají A, Mangiaterra V, 2015. Malaria in pregnancy: challenges for control and the need for urgent action. Lancet Glob Health 3: e433–e434.
Shankar AH, 2000. Nutritional modulation of malaria morbidity and mortality. J Infect Dis 1: S37–S53.
Davis TM, Skinner-Adams TS, Beilby J, 1998. In vitro growth inhibition of Plasmodium falciparum by retinol at concentrations present in normal human serum. Acta Trop 69: 111–119.
Hamzah J, Davis TM, Skinner-Adams TS, Beilby J, 2004. Characterization of the effect of retinol on Plasmodium falciparum in vitro. Exp Parasitol 107: 136–144.
Stürchler D, Tanner M, Hanck A, Betschart B, Gautschi K, Weiss N, Burnier E, Del Guidice G, Degremont A, 1987. A longitudinal study on relations of retinol with parasitic infections and the immune response in children of Kikwawila village, Tanzania. Acta Trop 44: 213–227.
Das BS, Thurnham DI, Das DB, 1996. Plasma alpha-tocopherol, retinol, and carotenoids in children with falciparum malaria. Am J Clin Nutr 64: 94–100.
Chevion M, Chuang L, Golenser J, 1995. Effects of zinc-desferrioxamine on Plasmodium falciparum in culture. Antimicrob Agents Chemother 39: 1902–1905.
Shankar AH, Genton B, Semba RD, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Tielsch JM, Alpers MP, West KP Jr, 1999. Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua New Guinea: a randomized trial. Lancet 354: 203–209.
Nankabirwa V, Tylleskar T, Nankunda J, Engebretsen IM, Sommerfelt H, Tumwine JK; PROMISE EBF Research Consortium, 2011. Malaria parasitaemia among infants and its association with breastfeeding peer counselling and vitamin A supplementation: a secondary analysis of a cluster randomized trial. PLoS One 6: e21862.
Owusu-Agyei S, Newton S, Mahama E, 2013. Impact of vitamin A with zinc supplementation on malaria morbidity in Ghana. Nutr J 12: 131.
Shankar AH, Genton B, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Bannon D, Tielsch JM, West KP Jr, Alpers MP, 2000. The influence of zinc supplementation on morbidity due to Plasmodium falciparum: a randomized trial in preschool children in Papua New Guinea. Am J Trop Med Hyg 62: 663–669.
Müller O, Becher H, van Zweeden AB, Ye Y, Diallo DA, Konate AT, Gbangou A, Kouyate B, Garenne M, 2001. Effect of zinc supplementation on malaria and other causes of morbidity in west African children: randomized double blind placebo controlled trial. BMJ 322: 1567.
Zeba AN, Sorgho H, Rouamba N, Zongo I, Rouamba J, Guiguemdé RT, Hamer DH, Mokhtar N, Ouedraogo JB, 2008. Major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children in Burkina Faso: a randomized double blind trial. Nutr J 7: 7.
Veenemans J, Milligan P, Prentice AM, Schouten LR, Inja N, van der Heijden AC, de Boer LC, Jansen EJ, Koopmans AE, Enthoven WT, Kraaijenhagen RJ, Demir AY, Uges DR, Mbugi EV, Savelkoul HF, Verhoef H, 2011. Effect of supplementation with zinc and other micronutrients on malaria in Tanzanian children: a randomised trial. PLoS Med 8: e1001125.
Cox SE, Staalsoe T, Arthur P, Bulmer JN, Tagbor H, Hviid L, Frost C, Riley EM, Kirkwood BR, 2005. Maternal vitamin A supplementation and immunity to malaria in pregnancy in Ghanaian primigravids. Trop Med Int Health 10: 1286–1297.
Saaka M, Oosthuizen J, Beatty S, 2009. Effect of joint iron and zinc supplementation on malarial infection and anaemia. East Afr J Public Health 6: 55–62.
Ota E, Mori R, Middleton P, Tobe-Gai R, Mahomed K, Miyazaki C, Bhutta ZA, 2015. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev 2: CD000230.
Thorne-Lyman AL, Fawzi W, 2012. Vitamin A and carotenoids during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 26: 36–54.
The United Republic of Tanzania Ministry of Health and Social Welfare, 2007. Standard Treatment Guidelines (STG) and the National Essential Medicines List (NEMLIT) for Mainland Tanzania. Available at: http://www.who.int/medicines/areas/coordination/tanzania_stgs_eml.pdf. Accessed July 18, 2016.
Rosanas-Urgell A, Mueller D, Betuela I, Barnadas C, Iga J, Zimmerman PA, del Portillo HA, Siba P, Mueller I, Felger I, 2010. Comparison of diagnostic methods for the detection and quantification of the four sympatric Plasmodium species in field samples from Papua New Guinea. Malar J 9: 361.
Kamau E, Tolbert LS, Kortepeter L, Pratt M, Nyakoe N, Muringo L, Oguto B, Waitumbi JN, Ockenhouse CF, 2011. Development of a highly sensitive genus-specific quantitative reverse transcriptase real-time PCR assay for detection and quantitation of Plasmodium by amplifying RNA and DNA of the 18S rRNA genes. J Clin Microbiol 49: 2946–2953.
Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M, 1996. A United States national reference for fetal growth. Obstet Gynecol 87: 163–168.
Villar J, Cheikh Ismail L, Victoria CG, Ohuma EO, Bertino E, Altman DG, Lambert A, Papageorghiou AT, Carvalho M, Jaffer YA, Gravett MG, Purwar M, Frederick IO, Noble AJ, Pang R, Barros FC, Chumlea C, Bhutta ZA, Kennedy SH; International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st), 2014. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet 384: 857–868.
Robins JM, Hernán MÁ, Brumback B, 2000. Marginal structural models and causal inference in epidemiology. Epidemiology 11: 550–560.
Spiegelman D, Hertzmark E, 2005. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol 162: 199–200.
Ogbe AE, Ekwempu CC, Musa J, Anzaku AS, 2015. A comparison of the accuracy of the use of last menstrual period and symphisio-fundal height for gestational age determination among Nigerian women. Int J Trop Dis Health 7: 32–39.
Mayor A, Moro L, Aguilar R, Bardají A, Cisteró P, Serra-Casas E, Sigaúque B, Alonso PL, Ordi J, Menéndez C, 2012. How hidden can malaria be in pregnant women? Diagnosis by microscopy, placental histology, polymerase chain reaction and detection of histidine-rich protein 2 in plasma. Clin Infect Dis 54: 1561–1568.
Ferguson EL, Gadowsky SL, Huddle JM, Cullinan TR, Lehrfeld J, Gibson RS, 1995. An interactive 24-h recall technique for assessing the adequacy of trace mineral intakes of rural Malawian women; its advantages and limitations. Eur J Clin Nutr 49: 565–578.
Rwebembera AA, Munubhi EK, Manji KP, Mpembeni R, Philip J, 2006. Relationship between infant birth weight ≤2000 g and maternal zinc levels at Muhimbili National Hospital, Dar es Salaam, Tanzania. J Trop Pediatr 52: 118–125.
Shankar AH, Prasad AS, 1998. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr 68: 447S–463S.
Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, Ezzati M, Grantham-McGregor S, Katz J, Martorell R, Uauy R; Maternal and Child Nutrition Study Group, 2013. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 382: 427–451.
Roll Back Malaria Partnership, 2012. Focus on Mainland Tanzania. Available at: http://www.rollbackmalaria.org/microsites/ProgressImpactSeries/docs/report10-en.pdf. Accessed April 15, 2012.
Past two years | Past Year | Past 30 Days | |
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Abstract Views | 83 | 83 | 17 |
Full Text Views | 944 | 457 | 2 |
PDF Downloads | 372 | 70 | 1 |
Vitamin A and zinc are important for immune function and may improve host defense against malaria and reduce the risk of adverse pregnancy outcomes. Our objective was to determine whether daily oral supplementation with either or both nutrients starting in the first trimester reduces the risk of placental malaria and adverse pregnancy outcomes. We undertook a randomized, double-blind placebo-controlled trial with a factorial design among 2,500 human immunodeficiency virus–negative primigravid or secundigravid pregnant women in their first trimester of pregnancy in Dar es Salaam, Tanzania. We randomly allocated equal numbers of participants to 2,500 IU of vitamin A, 25 mg of zinc, both 2,500 IU of vitamin A and 25 mg of zinc, or a placebo until delivery. A total of 625 participants were allocated to each treatment group. Our primary outcome, placental malaria infection (past or current), was assessed in all randomized participants for whom placental samples were obtained at delivery (N = 1,404), which represents 56% of total participants and 62% of all pregnancies lasting 28 weeks or longer (N = 2,266). Birth outcomes were obtained for 2,434 of the 2,500 randomized participants. Secondary outcomes included small for gestational age (SGA) births and prematurity. All analyses were intent to treat. Those who received zinc had a lower risk of histopathology-positive placental malaria compared with those who did not receive zinc (risk ratio = 0.64, 95% confidence interval = 0.44, 0.91), but neither nutrient had an effect on polymerase chain reaction–positive malaria, SGA, or prematurity. No safety concerns were identified. We recommend additional studies in other geographic locations to confirm these findings.
Financial support: This study was supported by grants from the National Institute of Child Health and Human Development (NICHD R01 HD057941-01 and K24 HD 058795 [Christopher Duggan]).
Authors' addresses: Anne Marie Darling, Analee J. Etheredge, Nilupa S. Gunaratna, Ajibola Ibraheem Abioye, and Wafaie W. Fawzi, Department of Global Health and Population, Harvard TH Chan School of Public Health, Boston, MA, E-mails: adarling@hsph.harvard.edu, aetheredge@gmail.com, ngunarat@hsph.harvard.edu, drabioye@gmail.com, and mina@hsph.harvard.edu. Ferdinand M. Mugusi, Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, E-mail: fm.mugusi@gmail.com. Said Aboud, Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, E-mail: aboudsaid@yahoo.com. Christopher Duggan, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA, E-mail: christopher.duggan@childrens.harvard.edu. Robert Mongi, Department of Parasitology/Medical Entomology, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, E-mail: rmongi@hotmail.com. Donna Spiegelman, Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, E-mail: stdls@hsph.harvard.edu. Drucilla Roberts, Department of Pathology, Massachusetts General Hospital, Boston, MA, E-mail: djroberts@mgh.harvard.edu. Davidson H. Hamer, Department of Global Health, Boston University School of Public Health, Boston, MA, E-mail: dhamer@bu.edu. Kevin C. Kain, Department of Medicine, University of Toronto, Toronto, Canada, E-mail: kevin.kain@uhn.ca.
World Health Organization, 2014. World Malaria Report 2014. Available at: http://www.who.int/malaria/publications/world_malaria_report_2014/report/en/. Accessed July 18, 2016.
Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD, 2007. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 7: 93–104.
Menéndez C, Ferenchick E, Roman E, Bardají A, Mangiaterra V, 2015. Malaria in pregnancy: challenges for control and the need for urgent action. Lancet Glob Health 3: e433–e434.
Shankar AH, 2000. Nutritional modulation of malaria morbidity and mortality. J Infect Dis 1: S37–S53.
Davis TM, Skinner-Adams TS, Beilby J, 1998. In vitro growth inhibition of Plasmodium falciparum by retinol at concentrations present in normal human serum. Acta Trop 69: 111–119.
Hamzah J, Davis TM, Skinner-Adams TS, Beilby J, 2004. Characterization of the effect of retinol on Plasmodium falciparum in vitro. Exp Parasitol 107: 136–144.
Stürchler D, Tanner M, Hanck A, Betschart B, Gautschi K, Weiss N, Burnier E, Del Guidice G, Degremont A, 1987. A longitudinal study on relations of retinol with parasitic infections and the immune response in children of Kikwawila village, Tanzania. Acta Trop 44: 213–227.
Das BS, Thurnham DI, Das DB, 1996. Plasma alpha-tocopherol, retinol, and carotenoids in children with falciparum malaria. Am J Clin Nutr 64: 94–100.
Chevion M, Chuang L, Golenser J, 1995. Effects of zinc-desferrioxamine on Plasmodium falciparum in culture. Antimicrob Agents Chemother 39: 1902–1905.
Shankar AH, Genton B, Semba RD, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Tielsch JM, Alpers MP, West KP Jr, 1999. Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua New Guinea: a randomized trial. Lancet 354: 203–209.
Nankabirwa V, Tylleskar T, Nankunda J, Engebretsen IM, Sommerfelt H, Tumwine JK; PROMISE EBF Research Consortium, 2011. Malaria parasitaemia among infants and its association with breastfeeding peer counselling and vitamin A supplementation: a secondary analysis of a cluster randomized trial. PLoS One 6: e21862.
Owusu-Agyei S, Newton S, Mahama E, 2013. Impact of vitamin A with zinc supplementation on malaria morbidity in Ghana. Nutr J 12: 131.
Shankar AH, Genton B, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Bannon D, Tielsch JM, West KP Jr, Alpers MP, 2000. The influence of zinc supplementation on morbidity due to Plasmodium falciparum: a randomized trial in preschool children in Papua New Guinea. Am J Trop Med Hyg 62: 663–669.
Müller O, Becher H, van Zweeden AB, Ye Y, Diallo DA, Konate AT, Gbangou A, Kouyate B, Garenne M, 2001. Effect of zinc supplementation on malaria and other causes of morbidity in west African children: randomized double blind placebo controlled trial. BMJ 322: 1567.
Zeba AN, Sorgho H, Rouamba N, Zongo I, Rouamba J, Guiguemdé RT, Hamer DH, Mokhtar N, Ouedraogo JB, 2008. Major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children in Burkina Faso: a randomized double blind trial. Nutr J 7: 7.
Veenemans J, Milligan P, Prentice AM, Schouten LR, Inja N, van der Heijden AC, de Boer LC, Jansen EJ, Koopmans AE, Enthoven WT, Kraaijenhagen RJ, Demir AY, Uges DR, Mbugi EV, Savelkoul HF, Verhoef H, 2011. Effect of supplementation with zinc and other micronutrients on malaria in Tanzanian children: a randomised trial. PLoS Med 8: e1001125.
Cox SE, Staalsoe T, Arthur P, Bulmer JN, Tagbor H, Hviid L, Frost C, Riley EM, Kirkwood BR, 2005. Maternal vitamin A supplementation and immunity to malaria in pregnancy in Ghanaian primigravids. Trop Med Int Health 10: 1286–1297.
Saaka M, Oosthuizen J, Beatty S, 2009. Effect of joint iron and zinc supplementation on malarial infection and anaemia. East Afr J Public Health 6: 55–62.
Ota E, Mori R, Middleton P, Tobe-Gai R, Mahomed K, Miyazaki C, Bhutta ZA, 2015. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev 2: CD000230.
Thorne-Lyman AL, Fawzi W, 2012. Vitamin A and carotenoids during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 26: 36–54.
The United Republic of Tanzania Ministry of Health and Social Welfare, 2007. Standard Treatment Guidelines (STG) and the National Essential Medicines List (NEMLIT) for Mainland Tanzania. Available at: http://www.who.int/medicines/areas/coordination/tanzania_stgs_eml.pdf. Accessed July 18, 2016.
Rosanas-Urgell A, Mueller D, Betuela I, Barnadas C, Iga J, Zimmerman PA, del Portillo HA, Siba P, Mueller I, Felger I, 2010. Comparison of diagnostic methods for the detection and quantification of the four sympatric Plasmodium species in field samples from Papua New Guinea. Malar J 9: 361.
Kamau E, Tolbert LS, Kortepeter L, Pratt M, Nyakoe N, Muringo L, Oguto B, Waitumbi JN, Ockenhouse CF, 2011. Development of a highly sensitive genus-specific quantitative reverse transcriptase real-time PCR assay for detection and quantitation of Plasmodium by amplifying RNA and DNA of the 18S rRNA genes. J Clin Microbiol 49: 2946–2953.
Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M, 1996. A United States national reference for fetal growth. Obstet Gynecol 87: 163–168.
Villar J, Cheikh Ismail L, Victoria CG, Ohuma EO, Bertino E, Altman DG, Lambert A, Papageorghiou AT, Carvalho M, Jaffer YA, Gravett MG, Purwar M, Frederick IO, Noble AJ, Pang R, Barros FC, Chumlea C, Bhutta ZA, Kennedy SH; International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st), 2014. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet 384: 857–868.
Robins JM, Hernán MÁ, Brumback B, 2000. Marginal structural models and causal inference in epidemiology. Epidemiology 11: 550–560.
Spiegelman D, Hertzmark E, 2005. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol 162: 199–200.
Ogbe AE, Ekwempu CC, Musa J, Anzaku AS, 2015. A comparison of the accuracy of the use of last menstrual period and symphisio-fundal height for gestational age determination among Nigerian women. Int J Trop Dis Health 7: 32–39.
Mayor A, Moro L, Aguilar R, Bardají A, Cisteró P, Serra-Casas E, Sigaúque B, Alonso PL, Ordi J, Menéndez C, 2012. How hidden can malaria be in pregnant women? Diagnosis by microscopy, placental histology, polymerase chain reaction and detection of histidine-rich protein 2 in plasma. Clin Infect Dis 54: 1561–1568.
Ferguson EL, Gadowsky SL, Huddle JM, Cullinan TR, Lehrfeld J, Gibson RS, 1995. An interactive 24-h recall technique for assessing the adequacy of trace mineral intakes of rural Malawian women; its advantages and limitations. Eur J Clin Nutr 49: 565–578.
Rwebembera AA, Munubhi EK, Manji KP, Mpembeni R, Philip J, 2006. Relationship between infant birth weight ≤2000 g and maternal zinc levels at Muhimbili National Hospital, Dar es Salaam, Tanzania. J Trop Pediatr 52: 118–125.
Shankar AH, Prasad AS, 1998. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr 68: 447S–463S.
Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, Ezzati M, Grantham-McGregor S, Katz J, Martorell R, Uauy R; Maternal and Child Nutrition Study Group, 2013. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 382: 427–451.
Roll Back Malaria Partnership, 2012. Focus on Mainland Tanzania. Available at: http://www.rollbackmalaria.org/microsites/ProgressImpactSeries/docs/report10-en.pdf. Accessed April 15, 2012.
Past two years | Past Year | Past 30 Days | |
---|---|---|---|
Abstract Views | 83 | 83 | 17 |
Full Text Views | 944 | 457 | 2 |
PDF Downloads | 372 | 70 | 1 |