Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial
Shally Awasthi, Richard Peto, Simon Read, Sarah Clark, Vinod Pande, Donald Bundy, DEVTA (Deworming and Enhanced Vitamin A) team, Lakshmi Ayyar, Atul Chandra, Vipin Chandra Joshi, Nisha Narang, Hasibur Rehman, Nikhil Saxena, Naveen Prakash, Anuradha Sharma, Monika Sharma, Manish Tripathi, Deepak Kumar Upreti, Rohini Das, Anupama Lal, Tuhina Rastogi, S S Mani, Dheeraj Chitransh, Lalit Pandey, Amit Tandon, Durgesh Bajpai, Umesh Chandra, Arunesh Dwivedi, P K Pant, Vivekanand Shukla, Amir Ahmad, Hafeez Ahmad, Jitendra Bahadur, Harish Chandra, Ramesh Chandra, Anil Chaturvedi, Shailesh Dwivedi, Amar Kumar, Digant Kumar, Mahesh Kumar, Neelu Kumar, Rajesh Kumar, Sudheer Kumar, Sunil Kumar 1st, Sunil Kumar 2nd, Chandra Pal, Mahesh Prasad, Rakesh Kumar 1st, Rakesh Kumar 2nd, Zafar Rashid, Hitler Singh, Hanslal Shukla, Kunj Bihari Shukla, Shiv Shanker Shukla, Vipin Bihari Shukla, Sangram Singh, Satyawan Singh, Shiv Shankar Verma, Shiv Singh Verma, Ramesh Chandra, Inamul Haq, Mohd Kazi, Ajay Kumar, Keshav Kumar, Manoj Kumar, Sharawan Kumar, Bansi Lal, Ashok Kumar Tiwari, Shrawan Awasthi, Alpana Maseeh, Safia Najeeb, Lalji Neetu, Shahnaaz Parween, B Rai, Tuhina Rastogi, Ajay Sharma, Reetu Shukla, Sudha Shukla, Lalji Shukla, Anuj Srivastava, Vinay Kumar Srivastava, Shally Awasthi, Richard Peto, Simon Read, Sarah Clark, Vinod Pande, Donald Bundy, DEVTA (Deworming and Enhanced Vitamin A) team, Lakshmi Ayyar, Atul Chandra, Vipin Chandra Joshi, Nisha Narang, Hasibur Rehman, Nikhil Saxena, Naveen Prakash, Anuradha Sharma, Monika Sharma, Manish Tripathi, Deepak Kumar Upreti, Rohini Das, Anupama Lal, Tuhina Rastogi, S S Mani, Dheeraj Chitransh, Lalit Pandey, Amit Tandon, Durgesh Bajpai, Umesh Chandra, Arunesh Dwivedi, P K Pant, Vivekanand Shukla, Amir Ahmad, Hafeez Ahmad, Jitendra Bahadur, Harish Chandra, Ramesh Chandra, Anil Chaturvedi, Shailesh Dwivedi, Amar Kumar, Digant Kumar, Mahesh Kumar, Neelu Kumar, Rajesh Kumar, Sudheer Kumar, Sunil Kumar 1st, Sunil Kumar 2nd, Chandra Pal, Mahesh Prasad, Rakesh Kumar 1st, Rakesh Kumar 2nd, Zafar Rashid, Hitler Singh, Hanslal Shukla, Kunj Bihari Shukla, Shiv Shanker Shukla, Vipin Bihari Shukla, Sangram Singh, Satyawan Singh, Shiv Shankar Verma, Shiv Singh Verma, Ramesh Chandra, Inamul Haq, Mohd Kazi, Ajay Kumar, Keshav Kumar, Manoj Kumar, Sharawan Kumar, Bansi Lal, Ashok Kumar Tiwari, Shrawan Awasthi, Alpana Maseeh, Safia Najeeb, Lalji Neetu, Shahnaaz Parween, B Rai, Tuhina Rastogi, Ajay Sharma, Reetu Shukla, Sudha Shukla, Lalji Shukla, Anuj Srivastava, Vinay Kumar Srivastava
Abstract
Background: In north India, vitamin A deficiency (retinol <0·70 μmol/L) is common in pre-school children and 2-3% die at ages 1·0-6·0 years. We aimed to assess whether periodic vitamin A supplementation could reduce this mortality.
Methods: Participants in this cluster-randomised trial were pre-school children in the defined catchment areas of 8338 state-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks (clusters) were cluster-randomly allocated in Oxford, UK, between 6-monthly vitamin A (retinol capsule of 200,000 IU retinyl acetate in oil, to be cut and dripped into the child's mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of retinol effects are by block (36 vs 36 clusters). The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6-72 months. Annually, one centre per block was randomly selected and visited by a study team 1-5 months after any trial vitamin A to sample blood (for retinol assay, technically reliable only after mid-study), examine eyes, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100,000 visits, 25,000 deaths at ages 1·0-6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547.
Findings: Estimated compliance with 6-monthly retinol supplements was 86%. Among 2581 versus 2584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0·72 [SE 0·01] vs 0·62 [0·01] μmol/L, increase 0·10 [SE 0·01] μmol/L) and the prevalence of severe deficiency was halved (retinol <0·35 μmol/L 6%vs 13%, decrease 7% [SE 1%]), as was that of Bitot's spots (1·4%vs 3·5%, decrease 2·1% [SE 0·7%]). Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0-6·0 years during the 5-year study were 3·01 retinol versus 3·15 control (absolute reduction 0·14 [SE 0·11], mortality ratio 0·96, 95% CI 0·89-1·03, p=0·22), suggesting absolute risks of death between ages 1·0 and 6·0 years of approximately 2·5% retinol versus 2·6% control. No specific cause of death was significantly affected.
Interpretation: DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20-30%, but cannot rule out some more modest effect. Meta-analysis of DEVTA plus eight previous randomised trials of supplementation (in various different populations) yielded a weighted average mortality reduction of 11% (95% CI 5-16, p=0·00015), reliably contradicting the hypothesis of no effect.
Funding: UK Medical Research Council, USAID, World Bank (vitamin A donated by Roche).
Copyright © 2013 Elsevier Ltd. All rights reserved.
Figures
References
- Sommer A, Tarwotjo I, Djunaedi E. The Aceh Study Group. Impact of vitamin A supplementation on childhood mortality: a randomised controlled community trial. Lancet. 1986;1:1169–1173.
- Vijayaraghavan K, Radhaiah G, Prakasam BS, Sarma KVR, Reddy V. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Lancet. 1990;336:1342–1345.
- Rahmathullah L, Underwood BA, Thulasiraj RD. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med. 1990;323:929–935.
- West KP, Jr, Pokhrel RP, Katz J. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Lancet. 1991;338:67–71.
- Daulaire NMP, Starabuck 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;304:207–210.
- Herrera MG, Nestel P, El Amin A, Fawzi WW, Mohamed KA, Weld L. Vitamin A supplementation and child survival. Lancet. 1992;340:267–271.
- Arthur P, Kirkwood B, Ross D. Impact of vitamin A supplementation on childhood morbidity in northern Ghana. Lancet. 1992;339:361–362.
- Ghana VAST Study Team Vitamin A supplementation in northern Ghana: effects on clinic attendances, hospital admissions, and child mortality. Lancet. 1993;342:7–12.
- 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;48:1271–1276.
- Tonascia JA. Public health significance of vitamin A deficiency and its control—proceedings of the Bellagio meeting on vitamin A deficiency and childhood mortality. Helen Keller International; New York: 1993. Meta-analysis of published community trials: impact of vitamin A on mortality.
- Beaton GH, Martorell R, Aronson KA. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. Final report of the Canadian International Development Agency. University of Toronto; Toronto: 1993.
- Beaton GH, Martorell R, Aronson KA, et al. Effectiveness of Vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN State of the Art Series, Nutrition Policy Discussion United Nations, Paper No. 13, 1993.
- Fawzi WW, Chalmers TC, Herrera G, Mosteller F. Vitamin A supplementation and child mortality: a meta-analysis. JAMA. 1993;269:898–903.
- Glasziou PP, Mackerras DEM. Vitamin A supplementation in infectious diseases: a meta-analysis. BMJ. 1993;306:366–370.
- Conclusions and Recommendations. Ministry of Health & Family Welfare; New Delhi, India: 2000. A Report on the National Consultation on the Benefits and Safety of Vitamin A Administration to Pre-school Children and Pregnant and Lactating Women.
- Gragnolati M, Shekar M, Das Gupta M, Bredenkamp C, Lee Y-K. India's undernourished children: a call for reform and action. Health, Nutrition and Population Division, World Bank, Washington, DC, 2006. (accessed July 13, 2012).
- Awasthi S, Peto R, Read S, Richards SM, Pande V, Bundy D, the DEVTA (Deworming and Enhanced Vitamin A) team Population deworming every 6 months with albendazole in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet. 2013 published online March 14.
- Awasthi S, Peto R, Read S, Bundy D. Six-monthly vitamin A from 1 to 6 years of age—DEVTA: cluster randomised trial in 1 million children in North India. Powerpoints and abstract of a talk presentated at 2007 micronutrient forum, Istanbul (accessed July 13, 2012), plus short 1998 DEVTA protocol. (accessed July 13, 2012).
- Gogia S, Sachdev HS. Neonatal vitamin A supplementation for prevention of mortality and morbidity in infancy: systematic review of randomised controlled trials. BMJ. 2009;338:b919.
- What works? Interventions for maternal and child undernutrition and survival. Lancet. 2008;371:417–440.
- Imdad A, Herzer K, Mayo-Wilson E, Yakoob MY, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database Syst Rev. 2010;12:CD008524.
- Imdad A, Yakoob MW, Sudfeld C, Haider BA, Black RE, Bhutta ZA. Impact of vitamin A supplementation on infant and childhood mortality. BMC Public Health. 2011;11(suppl 3):S20.
- Latham M. The great vitamin A fiasco. World Nutrition. 2010;1:12–45.
- West KP, Jr, Klemm RDW, Sommer A. Vitamin A saves lives. Sound science, sound policy. World Nutrition. 2010;1:211–229.
- Early Breast Cancer Trialists' Collaborative Group . Treatment of early breast cancer: worldwide evidence, 1985–1990. Oxford University Press; Oxford: 1990. (accessed July 13, 2012).
- Baigent C, Peto R, Gray R, Parish S, Collins R. Large-scale randomized evidence: trials and meta-analyses of trials. In: Warrell DA, Cox TM, Firth JD, editors. Oxford Textbook of Medicine. 5th edn. Oxford University Press; Oxford: 2010. pp. 31–45.
- Kapil U. Update on vitamin A-related deaths in Assam, India. Am J Clin Nutr. 2004;80:1082–1083.
- Anon In memoriam: Martin Frigg, 1943–2010. Sight and Life. 2010;3:64–66.
- Peto R, Beral V. Sir Richard Doll CH OBE 28 October 1912–24 July 2005. Biogr Mems Fell R Soc. 2010;56:63–83.
Source: PubMed