- Email: [email protected]
Vitamin A supplementation in Indian children
Correspondence
Shally Awasthi and colleagues’ DEVTA investigation (published online March 14)1 purports to have studied 1–2 million children in Uttar Pradesh, India, from 1999 to 2004, half in villages in which vitamin A supplementation reached 86% of the children every 6 months for 5 years and half in which coverage was assumed to be low. About 25 000 deaths were reported; no difference in child mortality was found between the vitamin A group and the control group. But this was neither a rigorously conducted nor acceptably executed efficacy trial: children were not enumer ated, consented, formally enrolled, or carefully followed up for vital events, which is the reason there is no CONSORT diagram. Coverage was ascertained from logbooks of overworked government community workers (anganwadi workers), and verified by a small number of supervisors who periodically visited randomly selected anganwadi workers to question and examine children who these workers gathered for them. Both anganwadi worker self-reports, and the validation procedures, are fraught with potential bias that would inflate the actual coverage. To achieve 96% coverage in Uttar Pradesh in children found in the anganwadi workers’ registries would have been an astonishing feat; covering 72% of children not found in the anganwadi workers’ registries seems even more improbable. In 2005–06, shortly after DEVTA ended, only 6·1% of children aged 6–59 months in Uttar Pradesh were reported to have received a vitamin A supplement in the previous 6 months according to results from the National Family Health Survey,2 a national household survey representative at national and state levels. The level of contact between anganwadi workers and children has www.thelancet.com Vol 382 August 17, 2013
historically been very low. Although 76% of children aged 0–71 months in 2005–06 lived in areas covered by an anganwadi worker, only 22% of children received any service from the anganwadi worker. Thus, it is hard to understand how DEVTA ramped up coverage to extremely high levels (and if it did, why so little of this effort was sustained). DEVTA provided the anganwadi workers with less than half a day’s training and minimal if any incentive.3 Each of their 18 study monitors was responsible for overseeing the work of 463 anganwadi workers and the status of 55 000 children. Their alleged coverage reached or exceeded that of intensive efficacy trials, yet the researchers spent substantially less than US$1 million.3 That comes to $0·02 in field research costs per child per year ($1 million per 1 million children per 5 years)—roughly a thousandth what a rigorously done field efficacy trial costs.4 Although an expensive trial does not guarantee quality, a trial that does not spend adequately raises serious questions about its validity. We are also concerned that Awasthi and colleagues included the results from this study, which is really a programme evaluation, in a meta-analysis in which all of the positive studies were rigorously designed and conducted efficacy trials and thus represented a much higher level of evidence. Compounding the problem, Awasthi and colleagues used a fixed-effects analytical model, which dramatically overweights the results of their negative findings from a single population setting. The size of a study says nothing about the quality of its data or the generalisability of its findings. At best, DEVTA is but one unorthodox study, done in one remote population of one country. If, for argument’s sake, the DEVTA results were wrong, and Awasthi and colleagues had studied 4 million children instead of 1 million, their meta-analytical approach would have virtually nullified, erroneously, all six previous rigorous trials, from four different countries,
that showed significant reductions in mortality of 19–54%.4 We declare that we have no conflicts of interest. Amy Toensing/National Geographic Society/Corbis
Vitamin A supplementation in Indian children
*Alfred Sommer, Keith P West Jr, Reynaldo Martorell [email protected] Johns Hopkins University, Baltimore, MD 21205, USA (AS, KPW); and Emory University, Atlanta, GA, USA (RM) 1
2
3
4
Awasthi S, Peto R, Read S, Clark S, Pande V, Bundy D, and the DEVTA (Deworming and Enhanced Vitamin A) team. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet 2013; published online March 14. http:// dx.doi.org/10.1016/S1040-6736(12)62125-4. International Institute for Population Sciences and Macro International. National family health survey (NFHS-3), India, 2005–06: Uttar Pradesh. Mumbai: IIPS, 2008. University of Oxford Clinical Trials Service Unit. Workshop on the DEVTA study. Worcester College, Oxford, UK; Nov 3–4, 2008. Sommer A, West KP Jr. Vitamin A deficiency: health, survival and vision. Oxford: Oxford University Press, 1996: 19–61.
The results of the DEVTA study presented by Shally Awasthi and colleagues (April 27, p 1469)1 show a surprisingly low effect of vitamin A supplementation on mortality in pre-school children in Uttar Pradesh, India. The study draws attention to the challenges of ensuring optimum delivery and adequacy in evaluation of efficacious interventions in a programmatic setting. It calls on programme implementers to undertake measures to achieve and sustain high coverage for optimum delivery and outcome of such interventions. The latest WHO guidelines 2 for vitamin A supplementation in infants and children aged 6–59 months reaffirm that it is one of the most costeffective child survival interventions available. In settings in which vitamin A deficiency is a public health problem, supplementation is recommended for infants and children aged 6–59 months as a public health intervention to reduce nutritional blindness, morbidity, and mortality. Public health policy on vitamin A supplementation has been set through
Published Online March 21, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)60645-5 This online publication has been corrected. The corrected version first appeared at thelancet.com on August 16, 2013
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
591
Correspondence
a rigorous analysis of available efficacy data from randomised controlled trials from different settings, which informed the delivery of vitamin A in deficient populations.3,4 Members of our three agencies attended a 2 day consultation in 2008, in Oxford, UK, which reviewed the DEVTA study, provided constructive comments, and discussed globally relevant lessons on the challenges facing large delivery programmes and their assessment, in terms of design, implementation, and resources needed. Many concerns were raised that, in our opinion, have not been fully addressed, either in the Article1 or in the Comment.5 It was agreed that these proceedings would be made publically available and so we call on the authors to share the proceedings in order to have a fully informed and ethical public debate. We concur with the authors of the Comment5 that science should inform policy. We therefore call on the appropriate normative bodies to take account of both the DEVTA study and the Oxford proceedings when assessing what, if any, adjustments should be made in the estimation of the expected effect of vitamin A supplementation on child mortality, and to provide any appropriate changes to vitamin A supplementation policy. As representatives of agencies dedicated to saving children’s lives, we are gravely concerned by the call in the Comment5 for new controlled trials of such supplementation. Any further controlled trials would inherently deprive those children assigned to control groups of a proven, life-saving intervention. We urge decision makers in national governments and donor agencies to continue to provide strong support for vitamin A supplementation as a core, evidence-based child survival intervention that has been used so effectively in the past decade in combination with other proven interventions to address underlying determinants of vitamin A deficiency, including food-based approaches. 592
VM is President of the Micronutrient Initiative, which has been supporting the inclusion of vitamin A supplementation in child survival programming for 20 years. WS is the Chief of Nutrition at UNICEF, which has been supporting the scale-up of vitamin A supplementation in more than 70 countries around the world for the past 20 years. KS is President and Chief Executive Officer of Helen Keller International, which has been supporting vitamin A supplementation delivery for decades.
*Venkatesh Mannar, Werner Schultink, Kathy Spahn [email protected] The Micronutrient Initative, Ottawa, ON K2P 2K3, Canada (VM); UNICEF, New York, NY, USA (WS); and Helen Keller International, New York, NY, USA (KS) 1
2
3
4
5
Awasthi S, Peto R, Read S, Clark S, Pande V, Bundy D, and the DEVTA (Deworming and Enhanced Vitamin A) team. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet 2013; 381: 1469–77. WHO. Guideline: vitamin A supplementation in infants and children 6–59 months of age. 2011. http://whqlibdoc.who.int/ publications/2011/9789241501767_eng.pdf (accessed March 14, 2013). Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011; 343: d5094. 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. Garner P, Taylor-Robinson D, Sachdev HS. DEVTA: results from the biggest clinical trial ever. Lancet 2013; 381: 1439–41.
and therefore careful documentation of what takes place at all levels in such chains is essential.3 These questions were only partly addressed in a nonrandom opportunistic subsample of 2106 of the million children in the study, who were likely to be easily reached and therefore received both the supplement and the validation visits. There is thus no plausible evidence that the intervention was or was not given to those who could most benefit. Programme assessments must address complex causal pathways, including bottlenecks to delivery and use. 4 By contrast, biological efficacy studies must concentrate on establishing that vitamin A is actually ingested by most, if not all, children. As a consequence, these different types of study should never be included together in meta-analyses, no matter how well they are done. Both biological efficacy and programme studies are important, so we heartily concur with the recommendation that “funders should invest—and invest heavily—in such studies”.5 We declare that we have no conflicts of interest.
Jean-Pierre Habicht, *Cesar Victora [email protected]
The results of the DEVTA study of vitamin A supplementation delivered through an Indian Government programme show that this particular programme did not reduce mortality. This could be a worthwhile finding if the reasons for the failure were elucidated—eg, were supply chains properly set up and implemented and was the supplement delivered to those who could most benefit? Sommer and colleagues2 addressed the methodological shortcomings of the trial, but in our view the most important issue is that programme assessments need more complex designs than do biological efficacy trials. Causal chains in large-scale programmes are long and complex, 1
Cornell University, 129 Eastlake Road, Ithaca, NY, USA (J-PH); and Federal de Pelotas, CP 464, Pelotas, RS 96001, Brazil (CV) 1
2
3
4
5
Awasthi S, Peto R, Read S, Clark S, Pande V, Bundy D, and the DEVTA (Deworming and Enhanced Vitamin A) team. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet 2013; 381: 1469–77. Sommer A, West KP, Martorell R. Vitamin A supplementation in Indian children. Lancet 2013; 382: 591. Arifeen SE, Hoque DME, Akter T, et al. Effect of the Integrated Management of Childhood Illness strategy on childhood mortality and nutrition in a rural area in Bangladesh: a cluster randomised trial. Lancet 2009; 374: 393–403. Habicht JP, Pelto GH, Lapp J. Doing impact evaluation 13. Methodologies to evaluate the impact of large scale nutrition programs. Washington DC: World Bank, 2009. Garner P, Taylor-Robinson D, Sachdev HS. DEVTA: results from the biggest clinical trial ever. Lancet 2013; 381: 1439–41.
www.thelancet.com Vol 382 August 17, 2013
Shally Awasthi and colleagues’ DEVTA investigation (published online March 14)1 purports to have studied 1–2 million children in Uttar Pradesh, India, from 1999 to 2004, half in villages in which vitamin A supplementation reached 86% of the children every 6 months for 5 years and half in which coverage was assumed to be low. About 25 000 deaths were reported; no difference in child mortality was found between the vitamin A group and the control group. But this was neither a rigorously conducted nor acceptably executed efficacy trial: children were not enumer ated, consented, formally enrolled, or carefully followed up for vital events, which is the reason there is no CONSORT diagram. Coverage was ascertained from logbooks of overworked government community workers (anganwadi workers), and verified by a small number of supervisors who periodically visited randomly selected anganwadi workers to question and examine children who these workers gathered for them. Both anganwadi worker self-reports, and the validation procedures, are fraught with potential bias that would inflate the actual coverage. To achieve 96% coverage in Uttar Pradesh in children found in the anganwadi workers’ registries would have been an astonishing feat; covering 72% of children not found in the anganwadi workers’ registries seems even more improbable. In 2005–06, shortly after DEVTA ended, only 6·1% of children aged 6–59 months in Uttar Pradesh were reported to have received a vitamin A supplement in the previous 6 months according to results from the National Family Health Survey,2 a national household survey representative at national and state levels. The level of contact between anganwadi workers and children has www.thelancet.com Vol 382 August 17, 2013
historically been very low. Although 76% of children aged 0–71 months in 2005–06 lived in areas covered by an anganwadi worker, only 22% of children received any service from the anganwadi worker. Thus, it is hard to understand how DEVTA ramped up coverage to extremely high levels (and if it did, why so little of this effort was sustained). DEVTA provided the anganwadi workers with less than half a day’s training and minimal if any incentive.3 Each of their 18 study monitors was responsible for overseeing the work of 463 anganwadi workers and the status of 55 000 children. Their alleged coverage reached or exceeded that of intensive efficacy trials, yet the researchers spent substantially less than US$1 million.3 That comes to $0·02 in field research costs per child per year ($1 million per 1 million children per 5 years)—roughly a thousandth what a rigorously done field efficacy trial costs.4 Although an expensive trial does not guarantee quality, a trial that does not spend adequately raises serious questions about its validity. We are also concerned that Awasthi and colleagues included the results from this study, which is really a programme evaluation, in a meta-analysis in which all of the positive studies were rigorously designed and conducted efficacy trials and thus represented a much higher level of evidence. Compounding the problem, Awasthi and colleagues used a fixed-effects analytical model, which dramatically overweights the results of their negative findings from a single population setting. The size of a study says nothing about the quality of its data or the generalisability of its findings. At best, DEVTA is but one unorthodox study, done in one remote population of one country. If, for argument’s sake, the DEVTA results were wrong, and Awasthi and colleagues had studied 4 million children instead of 1 million, their meta-analytical approach would have virtually nullified, erroneously, all six previous rigorous trials, from four different countries,
that showed significant reductions in mortality of 19–54%.4 We declare that we have no conflicts of interest. Amy Toensing/National Geographic Society/Corbis
Vitamin A supplementation in Indian children
*Alfred Sommer, Keith P West Jr, Reynaldo Martorell [email protected] Johns Hopkins University, Baltimore, MD 21205, USA (AS, KPW); and Emory University, Atlanta, GA, USA (RM) 1
2
3
4
Awasthi S, Peto R, Read S, Clark S, Pande V, Bundy D, and the DEVTA (Deworming and Enhanced Vitamin A) team. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet 2013; published online March 14. http:// dx.doi.org/10.1016/S1040-6736(12)62125-4. International Institute for Population Sciences and Macro International. National family health survey (NFHS-3), India, 2005–06: Uttar Pradesh. Mumbai: IIPS, 2008. University of Oxford Clinical Trials Service Unit. Workshop on the DEVTA study. Worcester College, Oxford, UK; Nov 3–4, 2008. Sommer A, West KP Jr. Vitamin A deficiency: health, survival and vision. Oxford: Oxford University Press, 1996: 19–61.
The results of the DEVTA study presented by Shally Awasthi and colleagues (April 27, p 1469)1 show a surprisingly low effect of vitamin A supplementation on mortality in pre-school children in Uttar Pradesh, India. The study draws attention to the challenges of ensuring optimum delivery and adequacy in evaluation of efficacious interventions in a programmatic setting. It calls on programme implementers to undertake measures to achieve and sustain high coverage for optimum delivery and outcome of such interventions. The latest WHO guidelines 2 for vitamin A supplementation in infants and children aged 6–59 months reaffirm that it is one of the most costeffective child survival interventions available. In settings in which vitamin A deficiency is a public health problem, supplementation is recommended for infants and children aged 6–59 months as a public health intervention to reduce nutritional blindness, morbidity, and mortality. Public health policy on vitamin A supplementation has been set through
Published Online March 21, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)60645-5 This online publication has been corrected. The corrected version first appeared at thelancet.com on August 16, 2013
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
591
Correspondence
a rigorous analysis of available efficacy data from randomised controlled trials from different settings, which informed the delivery of vitamin A in deficient populations.3,4 Members of our three agencies attended a 2 day consultation in 2008, in Oxford, UK, which reviewed the DEVTA study, provided constructive comments, and discussed globally relevant lessons on the challenges facing large delivery programmes and their assessment, in terms of design, implementation, and resources needed. Many concerns were raised that, in our opinion, have not been fully addressed, either in the Article1 or in the Comment.5 It was agreed that these proceedings would be made publically available and so we call on the authors to share the proceedings in order to have a fully informed and ethical public debate. We concur with the authors of the Comment5 that science should inform policy. We therefore call on the appropriate normative bodies to take account of both the DEVTA study and the Oxford proceedings when assessing what, if any, adjustments should be made in the estimation of the expected effect of vitamin A supplementation on child mortality, and to provide any appropriate changes to vitamin A supplementation policy. As representatives of agencies dedicated to saving children’s lives, we are gravely concerned by the call in the Comment5 for new controlled trials of such supplementation. Any further controlled trials would inherently deprive those children assigned to control groups of a proven, life-saving intervention. We urge decision makers in national governments and donor agencies to continue to provide strong support for vitamin A supplementation as a core, evidence-based child survival intervention that has been used so effectively in the past decade in combination with other proven interventions to address underlying determinants of vitamin A deficiency, including food-based approaches. 592
VM is President of the Micronutrient Initiative, which has been supporting the inclusion of vitamin A supplementation in child survival programming for 20 years. WS is the Chief of Nutrition at UNICEF, which has been supporting the scale-up of vitamin A supplementation in more than 70 countries around the world for the past 20 years. KS is President and Chief Executive Officer of Helen Keller International, which has been supporting vitamin A supplementation delivery for decades.
*Venkatesh Mannar, Werner Schultink, Kathy Spahn [email protected] The Micronutrient Initative, Ottawa, ON K2P 2K3, Canada (VM); UNICEF, New York, NY, USA (WS); and Helen Keller International, New York, NY, USA (KS) 1
2
3
4
5
Awasthi S, Peto R, Read S, Clark S, Pande V, Bundy D, and the DEVTA (Deworming and Enhanced Vitamin A) team. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet 2013; 381: 1469–77. WHO. Guideline: vitamin A supplementation in infants and children 6–59 months of age. 2011. http://whqlibdoc.who.int/ publications/2011/9789241501767_eng.pdf (accessed March 14, 2013). Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011; 343: d5094. 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. Garner P, Taylor-Robinson D, Sachdev HS. DEVTA: results from the biggest clinical trial ever. Lancet 2013; 381: 1439–41.
and therefore careful documentation of what takes place at all levels in such chains is essential.3 These questions were only partly addressed in a nonrandom opportunistic subsample of 2106 of the million children in the study, who were likely to be easily reached and therefore received both the supplement and the validation visits. There is thus no plausible evidence that the intervention was or was not given to those who could most benefit. Programme assessments must address complex causal pathways, including bottlenecks to delivery and use. 4 By contrast, biological efficacy studies must concentrate on establishing that vitamin A is actually ingested by most, if not all, children. As a consequence, these different types of study should never be included together in meta-analyses, no matter how well they are done. Both biological efficacy and programme studies are important, so we heartily concur with the recommendation that “funders should invest—and invest heavily—in such studies”.5 We declare that we have no conflicts of interest.
Jean-Pierre Habicht, *Cesar Victora [email protected]
The results of the DEVTA study of vitamin A supplementation delivered through an Indian Government programme show that this particular programme did not reduce mortality. This could be a worthwhile finding if the reasons for the failure were elucidated—eg, were supply chains properly set up and implemented and was the supplement delivered to those who could most benefit? Sommer and colleagues2 addressed the methodological shortcomings of the trial, but in our view the most important issue is that programme assessments need more complex designs than do biological efficacy trials. Causal chains in large-scale programmes are long and complex, 1
Cornell University, 129 Eastlake Road, Ithaca, NY, USA (J-PH); and Federal de Pelotas, CP 464, Pelotas, RS 96001, Brazil (CV) 1
2
3
4
5
Awasthi S, Peto R, Read S, Clark S, Pande V, Bundy D, and the DEVTA (Deworming and Enhanced Vitamin A) team. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet 2013; 381: 1469–77. Sommer A, West KP, Martorell R. Vitamin A supplementation in Indian children. Lancet 2013; 382: 591. Arifeen SE, Hoque DME, Akter T, et al. Effect of the Integrated Management of Childhood Illness strategy on childhood mortality and nutrition in a rural area in Bangladesh: a cluster randomised trial. Lancet 2009; 374: 393–403. Habicht JP, Pelto GH, Lapp J. Doing impact evaluation 13. Methodologies to evaluate the impact of large scale nutrition programs. Washington DC: World Bank, 2009. Garner P, Taylor-Robinson D, Sachdev HS. DEVTA: results from the biggest clinical trial ever. Lancet 2013; 381: 1439–41.
www.thelancet.com Vol 382 August 17, 2013