Undernutrition and malaria in pregnancy – a dangerous dyad?

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Background:
In low-resource settings, malaria and macronutrient undernutrition are major health problems in pregnancy, contributing significantly to adverse pregnancy outcomes such as preterm birth and fetal growth restriction. Affected pregnancies may result in stillbirth and neonatal death, and surviving children are at risk of poor growth and infection in infancy, and of non-communicable diseases in adulthood. Populations exposed to macronutrient undernutrition frequently reside in malaria-endemic areas, and seasonal peaks of low food supply and malaria transmission tend to coincide. Despite these geographic and temporal overlaps, integrated approaches to these twin challenges are infrequent.

Discussion:
This opinion article examines the current evidence for malaria-macronutrition interactions and discusses possible mechanisms whereby macronutrient undernutrition and malaria may interact to worsen pregnancy outcomes. Macronutrient undernutrition dysregulates the immune response. In pregnant women, undernutrition may worsen the already increased susceptibility to malarial infection and could impair development of protective immunity to malaria, and is likely to exacerbate the impact of placental malaria on fetal growth. Malarial infection, in turn, can drive nutritional depletion; poor gestational weight gain and weight loss in pregnancy increases the risk of adverse pregnancy outcomes. Despite a commendable number of studies and trials that, in isolation, attempt to address the challenges of malaria and undernutrition in pregnancy, few dare to venture beyond the ‘single disease – single solution’ paradigm. We believe that this may be a lost opportunity: researching malaria–nutrition interactions, and designing and implementing integrated interventions to prevent and treat these commonly co-existing and intertwining conditions, may markedly reduce the high burden of preterm birth and fetal growth restriction in affected areas.

Conclusion:
We call for more collaboration between researchers studying malaria and nutrition in pregnancy, and propose a research agenda to address this important twin health problem.

Keywords:
Pregnancy, Malaria, Nutrition, Low birthweight, Fetal growth restriction

Autoři: Holger W. Unger ^1,2; Per Ashorn ^3,4,5; Jordan E. Cates ⁶; Kathryn G. Dewey ⁷; Stephen J. Rogerson ^1*
Působiště autorů: Department of Medicine at the Doherty Institute, The University of Melbourne, Melbourne, Victoria, Australia. ¹; Simpson Centre for Reproductive Health, Edinburgh Royal Infirmary, Edinburgh, UK. ²; Department of Paediatrics, University of Tampere School of Medicine, Tampere, Finland. ³; Department for International Health, University of Tampere School of Medicine, Tampere, Finland. ⁴; Department of Paediatrics, Tampere University Hospital, Tampere, Finland. ⁵; Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA. ⁶; Program in International and Community Nutrition and Department of Nutrition, University of California, Davis, CA, USA. ⁷
Vyšlo v časopise: BMC Medicine 2016, 14:142
Kategorie: Opinion
prolekare.web.journal.doi_sk: https://doi.org/10.1186/s12916-016-0695-2

© 2016 The Author(s).

Open access
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The electronic version of this article is the complete one and can be found online at: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0695-2

Souhrn

Conclusion:
We call for more collaboration between researchers studying malaria and nutrition in pregnancy, and propose a research agenda to address this important twin health problem.

Keywords:
Pregnancy, Malaria, Nutrition, Low birthweight, Fetal growth restriction

Zdroje

1. Christian P, Mullany LC, Hurley KM, Katz J, Black RE. Nutrition and maternal, neonatal, and child health. Semin Perinatol. 2015;39(5):361–72.

2. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, Ezzati M, Grantham-McGregor S, Katz J, Martorell R, et al. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013;382(9890):427–51.

3. Walker PG, Ter Kuile FO, Garske T, Menendez C, Ghani AC. Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study. Lancet Glob Health. 2014;2(8):e460–7.

4. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007;7(2):93–104.

5. Hanson MA, Gluckman PD. Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev. 2014;94(4):1027–76.

6. World Health Organization. Global Strategy for Women's, Children's and Adolescents' Health 2016–2030. Geneva: WHO; 2015.

7. Sustainable Development Goals. http://www.un.org/sustainabledevelopment/sustainable-development-goals/. Accessed 16 Sept 2016.

8. Dellicour S, Tatem AJ, Guerra CA, Snow RW, ter Kuile FO. Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study. PLoS Med. 2010;7(1):e1000221.

9. Katona P, Katona-Apte J. The interaction between nutrition and infection. Clin Infect Dis. 2008;46(10):1582–8.

10. Raiten DJ, Sakr Ashour FA, Ross AC, Meydani SN, Dawson HD, Stephensen CB, Brabin BJ, Suchdev PS, van Ommen B. Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE). J Nutr. 2015;145(5):1039S–108S.

11. Maternal anthropometry and pregnancy outcomes. A WHO Collaborative Study. Bull World Health Organ. 1995;73 Suppl:1–98.

12. Unger HW, Wangnapi RA, Ome-Kaius M, Boeuf P, Karl S, Mueller I, Rogerson SJ. Azithromycin-containing intermittent preventive treatment in pregnancy affects gestational weight gain, an important predictor of birthweight in Papua New Guinea - an exploratory analysis. Matern Child Nutr. 2015. Ahead of print.

13. Rayco-Solon P, Fulford AJ, Prentice AM. Differential effects of seasonality on preterm birth and intrauterine growth restriction in rural Africans. Am J Clin Nutr. 2005;81(1):134–9.

14. Ceesay SM, Prentice AM, Cole TJ, Foord F, Weaver LT, Poskitt EM, Whitehead RG. Effects on birth weight and perinatal mortality of maternal dietary supplements in rural Gambia: 5 year randomised controlled trial. BMJ. 1997; 315(7111):786–90.

15. Shankar AH. Nutritional modulation of malaria morbidity and mortality. J Infect Dis. 2000;182 Suppl 1:S37–53.

16. Ferreira E, Alexandre MA, Salinas JL, de Siqueira AM, Benzecry SG, de Lacerda MV, Monteiro WM. Association between anthropometry-based nutritional status and malaria: a systematic review of observational studies. Malar J. 2015;14(1):346.

17. Nyakeriga AM, Troye-Blomberg M, Chemtai AK, Marsh K, Williams TN. Malaria and nutritional status in children living on the coast of Kenya. Am J Clin Nutr. 2004;80(6):1604–10.

18. Landis SH, Lokomba V, Ananth CV, Atibu J, Ryder RW, Hartmann KE, Thorp JM, Tshefu A, Meshnick SR. Impact of maternal malaria and under-nutrition on intrauterine growth restriction: a prospective ultrasound study in Democratic Republic of Congo. Epidemiol Infect. 2009;137(2):294–304.

19. Lovel HJ, Newby RM, Hillier VF. Severe placental malaria and maternal shortness, thinness, and small skeletal size in rural Congo: cohort study. BMJ. 2005;331(7530):1439–40.

20. Griffin JB, Lokomba V, Landis SH, Thorp Jr JM, Herring AH, Tshefu AK, Rogerson SJ, Meshnick SR. Plasmodium falciparum parasitaemia in the first half of pregnancy, uterine and umbilical artery blood flow, and foetal growth: a longitudinal Doppler ultrasound study. Malar J. 2012;11(1):319.

21. McClure EM, Meshnick SR, Lazebnik N, Mungai P, King CL, Hudgens M, Goldenberg RL, Siega-Riz AM, Dent AE. A cohort study of Plasmodium falciparum malaria in pregnancy and associations with uteroplacental blood flow and fetal anthropometrics in Kenya. Int J Gynaecol Obstet. 2014;126(1):78–82.

22. Umbers AJ, Aitken EH, Rogerson SJ. Malaria in pregnancy: small babies, big problem. Trends Parasitol. 2011;27(4):168–75.

23. Moore SE, Fulford AJ, Wagatsuma Y, Persson LA, Arifeen SE, Prentice AM. Thymus development and infant and child mortality in rural Bangladesh. Int J Epidemiol. 2014;43(1):216–23.

24. Borgella S, Fievet N, Huynh BT, Ibitokou S, Hounguevou G, Affedjou J, Sagbo JC, Houngbegnon P, Guezo-Mevo B, Massougbodji A, et al. Impact of pregnancy-associated malaria on infant malaria infection in southern Benin. PLoS One. 2013;8(11):e80624.

25. Walther B, Miles DJ, Crozier S, Waight P, Palmero MS, Ojuola O, Touray E, van der Sande M, Whittle H, Rowland-Jones S, et al. Placental malaria is associated with reduced early life weight development of affected children independent of low birth weight. Malar J. 2010;9:16.

26. Kozuki N, Katz J, Lee AC, Vogel JP, Silveira MF, Sania A, Stevens GA, Cousens S, Caulfield LE, Christian P, et al. Short maternal stature increases the risk of small-for-gestational-age and preterm births in low- and middle-income countries: individual participant data meta-analysis and population attributable fraction. J Nutr. 2015;145(11):2542–50.

27. Luxemburger C, McGready R, Kham A, Morison L, Cho T, Chongsuphajaisiddhi T, White NJ, Nosten F. Effects of malaria during pregnancy on infant mortality in an area of low malaria transmission. Am J Epidemiol. 2001;154(5):459–65.

28. Moore SE. Early life nutritional programming of health and disease in The Gambia. J Dev Orig Health Dis. 2016;7(2):123–31.

29. Rytter MJ, Kolte L, Briend A, Friis H, Christensen VB. The immune system in children with malnutrition–a systematic review. PLoS One. 2014;9(8):e105017.

30. Fabrizi F, Dixit V, Martin P, Jadoul M, Messa P. Meta-analysis: the impact of nutritional status on the immune response to hepatitis B virus vaccine in chronic kidney disease. Dig Dis Sci. 2012;57(5):1366–72.

31. Fillol F, Cournil A, Boulanger D, Cisse B, Sokhna C, Targett G, Trape JF, Simondon F, Greenwood B, Simondon KB. Influence of wasting and stunting at the onset of the rainy season on subsequent malaria morbidity among rural preschool children in Senegal. Am J Trop Med Hyg. 2009;80(2):202–8.

32. Fillol F, Sarr JB, Boulanger D, Cisse B, Sokhna C, Riveau G, Simondon KB, Remoue F. Impact of child malnutrition on the specific anti-Plasmodium falciparum antibody response. Malar J. 2009;8:116.

33. Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis. 2007;7(2):105–17.

34. Duffy PE, Fried M. Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are associated with increased birth weight and the gestational age of newborns. Infect Immun. 2003;71(11):6620–3.

35. Teo A, Hasang W, Randall LM, Feng G, Bell L, Unger H, Langer C, Beeson JG, Siba PM, Mueller I, et al. Decreasing malaria prevalence and its potential consequences for immunity in pregnant women. J Infect Dis. 2014;210(9): 1444–55.

36. Chandrasiri UP, Fowkes FJ, Richards JS, Langer C, Fan YM, Taylor SM, Beeson JG, Dewey KG, Maleta K, Ashorn P, et al. The impact of lipid-based nutrient supplementation on anti-malarial antibodies in pregnant women in a randomized controlled trial. Malar J. 2015;14:193.

37. Munson D, Franco D, Arbeter A, Velez H, Vitale JJ. Serum levels of immunoglobulins, cell-mediated immunity, and phagocytosis in proteincalorie malnutrition. Am J Clin Nutr. 1974;27(6):625–8.

38. Cumberland P, Shulman CE, Maple PA, Bulmer JN, Dorman EK, Kawuondo K, Marsh K, Cutts FT. Maternal HIV infection and placental malaria reduce transplacental antibody transfer and tetanus antibody levels in newborns in Kenya. J Infect Dis. 2007;196(4):550–7.

39. Atwell JE, Thumar B, Robinson LJ, Tobby R, Yambo P, Ome-Kaius M, Siba PM, Unger HW, Rogerson SJ, King CL, et al. Impact of placental malaria and hypergammaglobulinemia on transplacental transfer of respiratory syncytial virus antibody in Papua New Guinea. J Infect Dis. 2015;213(3):423–31.

40. Malhotra I, McKibben M, Mungai P, McKibben E, Wang X, Sutherland LJ, Muchiri EM, King CH, King CL, LaBeaud AD. Effect of antenatal parasitic infections on anti-vaccine IgG levels in children: a prospective birth cohort study in Kenya. PLoS Negl Trop Dis. 2015;9(1):e0003466.

41. Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today. 1997;18(10):478–82.

42. Gerriets VA, MacIver NJ. Role of T cells in malnutrition and obesity. Front Immunol. 2014;5:379.

43. Chico RM, Mayaud P, Ariti C, Mabey D, Ronsmans C, Chandramohan D. Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub-Saharan Africa: a systematic review. JAMA. 2012;307(19):2079–86.

44. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760–5.

45. Boeuf P, Aitken EH, Chandrasiri U, Chua CL, McInerney B, McQuade L, Duffy M, Molyneux M, Brown G, Glazier J, et al. Plasmodium falciparum malaria elicits inflammatory responses that dysregulate placental amino acid transport. PLoS Pathog. 2013;9(2):e1003153.

46. Gaccioli F, Lager S, Powell TL, Jansson T. Placental transport in response to altered maternal nutrition. J Dev Orig Health Dis. 2013;4(2):101–15.

47. Huynh BT, Cottrell G, Cot M, Briand V. Burden of malaria in early pregnancy: a neglected problem? Clin Infect Dis. 2014;60(4):598–604.

48. Hambidge KM, Krebs NF, Westcott JE, Garces A, Goudar SS, Kodkany BS, Pasha O, Tshefu A, Bose CL, Figueroa L, et al. Preconception maternal nutrition: a multi-site randomized controlled trial. BMC Pregnancy Childbirth. 2014;14:111.

49. Gernand AD, Christian P, Paul RR, Shaikh S, Labrique AB, Schulze KJ, Shamim AA, West Jr KP. Maternal weight and body composition during pregnancy are associated with placental and birth weight in rural Bangladesh. J Nutr. 2012;142(11):2010–6.

50. Umbers AJ, Stanisic DI, Ome M, Wangnapi R, Hanieh S, Unger HW, Robinson LJ, Lufele E, Baiwog F, Siba PM, et al. Does malaria affect placental development? Evidence from in vitro models. PLoS One. 2013;8(1):e55269.

51. Schulz LC, Widmaier EP. The effect of leptin on mouse trophoblast cell invasion. Biol Reprod. 2004;71(6):1963–7.

52. Conroy AL, Silver KL, Zhong K, Rennie M, Ward P, Sarma JV, Molyneux ME, Sled J, Fletcher JF, Rogerson S, et al. Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria. Cell Host Microbe. 2013;13(2):215–26.

53. Palmer AC. Nutritionally mediated programming of the developing immune system. Adv Nutr. 2011;2(5):377–95.

54. Bartz S, Mody A, Hornik C, Bain J, Muehlbauer M, Kiyimba T, Kiboneka E, Stevens R, Bartlett J, St Peter JV, et al. Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality. J Clin Endocrinol Metab. 2014; 99(6):2128–37.

55. Conroy AL, Liles WC, Molyneux ME, Rogerson SJ, Kain KC. Performance characteristics of combinations of host biomarkers to identify women with occult placental malaria: a case-control study from Malawi. PLoS One. 2012; 6(12):e28540.

56. Soliman AT, ElZalabany MM, Salama M, Ansari BM. Serum leptin concentrations during severe protein-energy malnutrition: correlation with growth parameters and endocrine function. Metabolism. 2000;49(7):819–25.

57. Bouyou-Akotet MK, Issifou S, Meye JF, Kombila M, Ngou-Milama E, Luty AJ, Kremsner PG, Mavoungou E. Depressed natural killer cell cytotoxicity against Plasmodium falciparum-infected erythrocytes during first pregnancies. Clin Infect Dis. 2004;38(3):342–7.

58. Belkacemi L, Nelson DM, Desai M, Ross MG. Maternal undernutrition influences placental-fetal development. Biol Reprod. 2010;83(3):325–31.

59. Phillips DI, Matthews SG. Is perinatal neuroendocrine programming involved in the developmental origins of metabolic disorders? World J Diabetes. 2011;2(12):211–6.

60. Brabin L, Brabin BJ, Gies S. Influence of iron status on risk of maternal or neonatal infection and on neonatal mortality with an emphasis on developing countries. Nutr Rev. 2013;71(8):528–40.

61. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, Othman MK, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006; 367(9505):133–43.

62. Senga EL, Harper G, Koshy G, Kazembe PN, Brabin BJ. Reduced risk for placental malaria in iron deficient women. Malar J. 2011;10:47.

63. Pena-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;7:CD004736.

64. Etheredge AJ, Premji Z, Gunaratna NS, Abioye AI, Aboud S, Duggan C, Mongi R, Meloney L, Spiegelman D, Roberts D, et al. Iron supplementation in iron-replete and nonanemic pregnant women in Tanzania: a randomized clinical trial. JAMA Pediatr. 2015;169(10):947–55.

65. Mwangi MN, Roth JM, Smit MR, Trijsburg L, Mwangi AM, Demir AY, Wielders JP, Mens PF, Verweij JJ, Cox SE, et al. Effect of daily antenatal iron supplementation on Plasmodium infection in Kenyan women: a randomized clinical trial. JAMA. 2015;314(10):1009–20.

66. Boel M, Carrara VI, Rijken M, Proux S, Nacher M, Pimanpanarak M, Paw MK, Moo O, Gay H, Bailey W, et al. Complex interactions between soiltransmitted helminths and malaria in pregnant women on the Thai-Burmese border. PLoS Negl Trop Dis. 2010;4(11):e887.

67. Hall A, Zhang Y, Macarthur C, Baker S. The role of nutrition in integrated programs to control neglected tropical diseases. BMC Med. 2012;10:41.

68. van Eijk AM, Ouma PO, Williamson J, Ter Kuile FO, Parise M, Otieno K, Hamel MJ, Ayisi JG, Kariuki S, Kager PA, et al. Plasma folate level and high-dose folate supplementation predict sulfadoxine-pyrimethamine treatment failure in pregnant women in Western Kenya who have uncomplicated malaria. J Infect Dis. 2008;198(10):1550–53.

69. Haider BA, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev. 2015;11:CD004905.

70. Cox SE, Staalsoe T, Arthur P, Bulmer JN, Tagbor H, Hviid L, Frost C, Riley EM, Kirkwood BR. Maternal vitamin A supplementation and immunity to malaria in pregnancy in Ghanaian primigravids. Trop Med Int Health. 2005;10(12): 1286–97.

71. World Health Organization. WHO Antenatal Care Randomized Trial: Manual for the Implementation of the New Model. Geneva: WHO; 2002.

72. Ververs MT, Antierens A, Sackl A, Staderini N, Captier V. Which anthropometric indicators identify a pregnant woman as acutely malnourished and predict adverse birth outcomes in the humanitarian context? PLoS Curr. 2013;5. doi:10.1371/currents.dis.54a8b618c1bc031ea140e3f2934599c8.

73. World Health Organization. WHO policy brief for the implementation of intermittent preventive treatment in malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP). Geneva: WHO; 2014.

74. Bhutta ZA, Das JK, Rizvi A, Gaffey MF, Walker N, Horton S, Webb P, Lartey A, Black RE. Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet. 2013;382(9890): 452–77.

75. Dewey KG. Reducing stunting by improving maternal, infant and young child nutrition in regions such as South Asia: evidence, challenges and opportunities. Matern Child Nutr. 2016;12 Suppl 1:27–38.

76. Girard AW, Olude O. Nutrition education and counselling provided during pregnancy: effects on maternal, neonatal and child health outcomes. Paediatr Perinat Epidemiol. 2012;26 Suppl 1:191–204.

77. Imdad A, Bhutta ZA. Maternal nutrition and birth outcomes: effect of balanced protein-energy supplementation. Paediatr Perinat Epidemiol. 2012; 26 Suppl 1:178–90.

78. Toe LC, Bouckaert KP, De Beuf K, Roberfroid D, Meda N, Thas O, Van Camp J, Kolsteren PW, Huybregts LF. Seasonality modifies the effect of a lipidbased nutrient supplement for pregnant rural women on birth length. J Nutr. 2015;145(3):634–9.

79. Adu-Afarwuah S, Lartey A, Okronipa H, Ashorn P, Zeilani M, Peerson JM, Arimond M, Vosti S, Dewey KG. Lipid-based nutrient supplement increases the birth size of infants of primiparous women in Ghana. Am J Clin Nutr. 2015;101(4):835–46.

80. Ashorn P, Alho L, Ashorn U, Cheung YB, Dewey KG, Harjunmaa U, Lartey A, Nkhoma M, Phiri N, Phuka J, et al. The impact of lipid-based nutrient supplement provision to pregnant women on newborn size in rural Malawi: a randomized controlled trial. Am J Clin Nutr. 2015;101(2):387–97.

81. Althabe F, Moore JL, Gibbons L, Berrueta M, Goudar SS, Chomba E, Derman RJ, Patel A, Saleem S, Pasha O, et al. Adverse maternal and perinatal outcomes in adolescent pregnancies: The Global Network's Maternal Newborn Health Registry study. Reprod Health. 2015;12 Suppl 2:S8.

82. Luntamo M, Kulmala T, Mbewe B, Cheung YB, Maleta K, Ashorn P. Effect of repeated treatment of pregnant women with sulfadoxine-pyrimethamine and azithromycin on preterm delivery in Malawi: a randomized controlled trial. Am J Trop Med Hyg. 2010;83(6):1212–20.

83. Unger HW, Ome-Kaius M, Wangnapi RA, Umbers AJ, Hanieh S, Suen CS, Robinson LJ, Rosanas-Urgell A, Wapling J, Lufele E, et al. Sulphadoxinepyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial. BMC Med. 2015;13:9.

84. Angelakis E, Merhej V, Raoult D. Related actions of probiotics and antibiotics on gut microbiota and weight modification. Lancet Infect Dis. 2013;13(10): 889–99.

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2016 Číslo 142

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Undernutrition and malaria in pregnancy – a dangerous dyad?

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