An enigma: Why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality

International Journal of Epidemiology

Volumn 44, Issue 3, 2015, Pages 906-918

  Benn, Christine S ^a,b   Aaby, Peter ^a,c   Arts, Rob J W ^d   Jensen, Kristoffer J ^a   Netea, Mihai G ^d   Fisker, Ane B ^a,c  

^a STATENS SERUM INSTITUT   (Denmark)

^b UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^c Studies of the Epidemiology of Epilepsy in Demographic Surveillance Systems   (Guinea-Bissau)

^d RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Child mortality; Heterologous effects; Vaccines; Vitamin A

Indexed keywords

DIPHTHERIA PERTUSSIS TETANUS VACCINE; MEASLES VACCINE; ORAL POLIOMYELITIS VACCINE; RETINOL;

AGE CLASS; CHILD HEALTH; FOOD SUPPLEMENTATION; HETEROGENEITY; IMMUNE RESPONSE; INFANT MORTALITY; SEX-RELATED DIFFERENCE; VACCINE; VITAMIN; VITAMIN DEFICIENCY; WORLD HEALTH ORGANIZATION;

ARTICLE; BIRTH WEIGHT; CHILDHOOD MORTALITY; CLINICAL INDICATOR; DRUG MEGADOSE; FOLLOW UP; GROUPS BY AGE; GUINEA-BISSAU; HEALTH CARE POLICY; HUMAN; INFANT MORTALITY; INNATE IMMUNITY; META ANALYSIS; NIGHT BLINDNESS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REPEATED DRUG DOSE; RETINOL DEFICIENCY; SEASONAL VARIATION; SEX DIFFERENCE; TH1 TH2 BALANCE; VACCINATION; VITAMIN SUPPLEMENTATION; XEROPHTHALMIA; DIETARY SUPPLEMENT; INFANT; VITAMIN A DEFICIENCY;

DIETARY SUPPLEMENTS; HUMANS; INFANT; INFANT MORTALITY; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SEX FACTORS; VACCINATION; VITAMIN A; VITAMIN A DEFICIENCY;

EID: 84939619752     PISSN: 03005771     EISSN: 14643685     Source Type: Journal    
DOI: 10.1093/ije/dyv117     Document Type: Article

References (74)

1. Semba RD. Vitamin A as "anti-infective" therapy, 1920-1940. J Nutr 1999;129:783-91.
2. Beaton GH, Martorell R, McCabe G, L'abbe KA, Edmonston B, Ross AC. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. University of Toronto, 1993.
3. Rahmathullah L, Underwood BA, Thulasiraj RD et al. Reduced mortality among children in Southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990;323:929-35.
4. Muhilal, Permeisih D, Idjradinata YR, Muherdiyantiningsih, Karyadi D. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. Am J Clin Nutr 1988;48:1271-76.
5. Vijayaraghavan K, Radhaiah G, Prakasam BS, Sarma KV, Reddy V. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Lancet 1990;336:1342-45.
6. Herrera MG, Nestel P, El Amin A, Fawzi WW, Mohamed KA, Weld L. Vitamin A supplementation and child survival. Lancet 1992; 340:267-71.
7. WHO/UNICEF. Vitamin A Supplements: A Guide to Their Use in the Treatment and Prevention of Vitamin A Deficiency and Xerophthalmia. Geneva: WHO, 1997.
8. UNICEF. Vitamin A Supplementation. A Decade of Progress. New York, NY: UNICEF, 2007.
9. Benn CS, Bale C, Sommerfelt H, Friis H, Aaby P. Hypothesis: Vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines? Int J Epidemiol 2003; 32:822-28.
10. Gogia S, Sachdev HS. Vitamin A supplementation for the prevention of morbidity and mortality in infants six months of age or less. Cochrane Database Syst Rev 2011;10:CD007480.
11. Edmond KM, Newton S, Shannon C et al. Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomized, double-blind, placebo-controlled trial. Lancet 2015;385:1315-23.
12. Masanja H, Smith ER, Muhihi A et al. Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomized, double-blind, placebo-controlled trial. Lancet 2015;385:1324-32.
13. Mazumder S, Taneja S, Bhatia K et al. Efficacy of early neonatal supplementation with vitamin A to reduce mortality in infancy in Haryana, India (Neovita): a randomized, double-blind, placebo-controlled trial. Lancet 2015;385:1333-42.
14. Fisker AB, Bale C, Rodrigues A et al. High-dose Vitamin A with vaccination after 6 months of age: a randomized trial. Pediatrics 2014;134:e739-48.
15. Awasthi S, Peto R, Read S, Clark S, Pande V, Bundy D. Vitamin A supplementation every 6 months with retinol in 1 million preschool children in north India: DEVTA, a cluster-randomized trial. Lancet 2013;381:1469-77.
16. Ross DA. Vitamin A and childhood mortality. Ghana Vitamin A Supplementation Trials Study Team. Lancet 1993;342:861.
17. Agarwal DK, Pandey CM, Agarwal KN. Vitamin A administration and preschool child mortality. Nutr Res 1995;15:669-80.
18. Pant CR, Pokharel GP, Curtale F et al. Impact of nutrition education and mega-dose vitamin A supplementation on the health of children in Nepal. BullWorld Health Organ 1996;74:533-45.
19. Danneskiold-Samsoe N, Fisker AB, JorgensenMJ et al. Determinants of vitamin A deficiency in children between 6 months and 2 years of age in Guinea-Bissau. BMC Public Health 2013;13:172.
20. Benn CS, Diness BR, Balde I et al. Two different doses of supplemental vitamin A did not affect mortality of normal-birth-weight neonates in Guinea-Bissau in a randomized controlled trial. J Nutr 2014;144:1474-79.
21. Fisker AB, Lisse IM, Aaby P et al. Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age. Am J Clin Nutr 2007;86:1032-39.
22. Humphrey JH, Agoestina T, Wu L, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128:489-96.
23. Rahmathullah L, Tielsch JM, Thulasiraj RD, et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomized trial in southern India. BMJ 2003; 327:254.
24. Kirkwood B, Humphrey J, Moulton L, Martines J. Neonatal vitamin A supplementation and infant survival. Lancet 2010; 376:1643-44.
25. Humphrey JH, Iliff PJ, Marinda ET et al. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. J Infect Dis 2006; 193:860-71.
26. Malaba LC, Iliff PJ, Nathoo KJ et al. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. Am J Clin Nutr 2005;81:454-60.
27. Benn CS, Fisker A, Aaby P. Heterogeneous effects on child survival in neonatal vitamin A supplementation trials. Lancet 2011; 377:1314-15.
28. Benn CS, Lund S, Fisker A, Jorgensen MJ, Aaby P. Should infant girls receive micronutrient supplements? Int J Epidemiol 2009; 38:586-90.
29. Aaby P, Martins CL, GarlyML et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomized controlled trial. BMJ 2010;341:c6495.
30. Benn CS, Netea MG, Selin LK, Aaby P. A small jab-a big effect: nonspecific immunomodulation by vaccines. Trends Immunol 2013;34:431-39.
31. WHO. Meeting of the strategic advisory group of experts on immunization, April 2014-conclusions and recommendations. Wkly Epidemiol Rec 2014;89:221-36.
32. Aaby P, Benn C, Nielsen J, Lisse IM, Rodrigues A, Ravn H. Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open 2012;2(3).
33. Benn CS, Aaby P, Nielsen J, Binka FN, Ross DA. Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana Vitamin A Supplementation Trial. Am J Clin Nutr 2009;90:629-39.
34. Benn CS, Martins C, Rodrigues A et al. The effect of vitamin A supplementation administered with missing vaccines during national immunization days in Guinea-Bissau. Int J Epidemiol 2009;38:304-11.
35. Fisker AB, Aaby P, Bale C et al. Does the effect of vitamin A supplements depend on vaccination status? An observational study from Guinea-Bissau. BMJ Open 2012;2:e000448.
36. Benn CS, Diness BR, Roth A et al. Effect of 50 000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomized placebo controlled trial. BMJ 2008;336:1416-20.
37. Benn CS, Fisker AB, Napirna BM et al. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomized controlled trial. BMJ 2010; 340:c1101.
38. Benn CS, Rodrigues A, Yazdanbakhsh M et al. The effect of high-dose vitamin A supplementation administered with BCG vaccine at birth may be modified by subsequent DTP vaccination. Vaccine 2009;27:2891-98.
39. Aaby P, Nielsen J, Benn CS, Trape JF. Sex-differential and nonspecific effects of routine vaccinations in a rural area with low vaccination coverage: an observational study from Senegal. Trans R Soc Trop Med Hyg 2015;109:77-84.
40. Aaby P, Ravn H, Roth A et al. Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomized trial. Arch Dis Child 2012;97:685-91.
41. WHO/SAGE. http://www.who.int/immunization/sage/meetings/2014/april/3_NSE_Epidemiology_review_Report_to_SAGE_14_Mar_FINAL.pdf.
42. Moulton LH, Rahmathullah L, Halsey NA, Thulasiraj RD, Katz J, Tielsch JM. Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population. Trop Med Int Health 2005;10:947-55.
43. Benn CS, Martins CL, Fisker AB et al. Interaction between neonatal vitamin A supplementation and timing of measles vaccination: a retrospective analysis of three randomized trials from Guinea-Bissau. Vaccine 2014;32:5468-74.
44. Fisker AB, Aaby P, Rodrigues A, Frydenberg M, Bibby BM, Benn CS. Vitamin A supplementation at birth might prime the response to subsequent vitamin A supplements in girls. Three year follow-up of a randomized trial. PLoS One 2011;6: e23265.
45. Yakymenko D, Benn CS, Martins C et al. The impact of different doses of vitamin A supplementation on male and female mortality. A randomized trial from Guinea-Bissau. BMC Pediatr 2011; 11:77.
46. West KP Jr, Pokhrel RP, Katz J et al. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991;338: 67-71.
47. Klemm RDW, Labrique AB, Christian P et al. Newborn Vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 2008;122:e242-e50.
48. Lund N, Biering-Sorensen S, Andersen A et al. Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomized trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth. BMC Pediatr 2014;14:214.
49. Benn CS. Combining Vitamin A and vaccines: convenience or conflict? Dan Med J 2012;59:B4378.
50. Wada Y, Hisamatsu T, Kamada N, Okamoto S, Hibi T. Retinoic acid contributes to the induction of IL-12-hypoproducing dendritic cells. Inflamm Bowel Dis 2009;15:1548-56.
51. Raverdeau M, Mills KH. Modulation of T cell and innate immune responses by retinoic acid. J Immunol 2014;192: 2953-58.
52. Tsai YC, Chang HW, Chang TT, Lee MS, Chu YT, Hung CH. Effects of all-trans retinoic acid on Th1-and Th2-related chemokines production in monocytes. Inflammation 2008;31: 428-33.
53. Arts RJ, Blok BA, van Crevel R et al. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes. J Leukoc Biol 2015, May 1. pii: jlb.6AB0914-416R. [Epub ahead of print.].
54. Gudas LJ. Retinoids induce stem cell differentiation via epigenetic changes. Semin Cell Dev Biol 2013;24:701-05.
55. Fazi F, Travaglini L, Carotti D et al. Retinoic acid targets DNA-methyltransferases and histone deacetylases during APL blast differentiation in vitro and in vivo. Oncogene 2005;24: 1820-30.
56. Cheong HS, Lee HC, Park BL et al. Epigenetic modification of retinoic acid-treated human embryonic stem cells. BMB Rep 2010;43:83035.
57. Kleinnijenhuis J, Quintin J, Preijers F et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 2012;109:17537-42.
58. Biering-Sorensen S, Aaby P, Napirna BM et al. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guerin vaccination at first health center contact. Pediatr Infect Dis J 2012;31(3):306-08.
59. Aaby P, Roth A, Ravn H et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204:245-52.
60. Quintin J, Cheng SC, van der Meer JW, Netea MG. Innate immune memory: towards a better understanding of host defense mechanisms. Curr Opin Immunol 2014;29C:1-7.
61. Raiten DJ, Ashour FA, Ross AC et al. Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE). J Nutr 2015;145:1039S-108S.
62. Jørgensen MJ, Hein-Kristensen L, Hempel C et al. The effect of vitamin A supplementation and diphtheria-tetanus-pertussis vaccination on parasitaemia in an experimental murine malaria model. Scand J Infect Dis 2011;43:296-303.
63. Jørgensen MJ, Fisker AB, Sartono E et al. The effect of at-birth vitamin A supplementation on differential leucocyte counts and in vitro cytokine production: an immunological study nested within a randomized trial in Guinea-Bissau. Br J Nutr 2013;109: 467-77.
64. Jensen KJ, Sondergaard M, Andersen A et al. A randomized trial of an early measles vaccine at 4(1/2) months of age in Guinea-bissau: sex-differential immunological effects. PLoS One 2014;9:e97536.
65. Mason J, Greiner T, Shrimpton R, Sanders D, Yukich J. Vitamin A policies need rethinking. Int J Epidemiol 2015;44: 283-98.
66. http://www.sightandlife.org/fileadmin/data/Magazine/2013/27_1_2013/Congress_report_a_framework_for_shifting_from_universal_vitamin_a_supplementation.pdf.
67. GAVA. http://wphna.org/wp-content/uploads/2014/12/2014-11-GAVA-rebuttal-of-IJE-commentary-here.pdf.
68. Benn CS, Fisker AB, Aaby P. Response to: J Mason et al. Vitamin A policies need rethinking. Int J Epidemiol 2015;44: 366-67.
69. Thorne-Lyman A, Fawzi WW. Improving child survival through vitamin A supplementation. BMJ 2011;343:d5294.
70. West KP Jr, Katz J, Shrestha SR et al. Mortality of infants < 6 mo of age supplemented with vitamin A: a randomized, doublemasked trial in Nepal. Am J Clin Nutr 1995;62:143-48.
71. Patwardhan VN, Kamel WW, Pharaon H. Studies on Vitamin A Deficiency in Infants and Young Children in Jordan. WHO report. Geneva: WHO, 1966.
72. Sommer A, Tarwotjo I, Djunaedi E et al. Impact of vitamin A supplementation on childhood mortality. A randomized controlled community trial. Lancet 1986;1:1169-73.
73. Mahalanabis D, Rahman MM, Wahed MA, Islam MA, Habte D. Vitamin A megadoses during early infancy on serum retinol concentration and acute side effects and residual effects on 6 month follow-up. Nutr Res 1997;17:649-59.
74. Daulaire NM, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A in a high risk population. BMJ 1992;304:207-10.