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RESEARCH: Siddhartha Gogia and Harshpal Singh Sachdev Neonatal vitamin A supplementation for prevention of mortality and morbidity in infancy: systematic review of randomised controlled trials BMJ 2009; 338: b919 [Abstract] [Full text]

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A Central Question Not Answered: Can Newborn Vitamin A Reduce Infant Mortality in South Asia?

Keith P. West, Jr., Alfred Sommer, James M. Tielsch, Joanne Katz, Parul Christian, Rolf D.W. Klemm   (2 April 2009)

Academic Nihilism and Vitamin A

Laurence E Wood   (4 April 2009)

Vitamin A supplements in newborns in South asia

Dr.Umesh Kapil   (11 May 2009)

A Central Question Not Answered: Can Newborn Vitamin A Reduce Infant Mortality in South Asia? 2 April 2009
Keith P. West, Jr., Professor Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA 21205, Alfred Sommer, James M. Tielsch, Joanne Katz, Parul Christian, Rolf D.W. Klemm Send response to journal: Re: A Central Question Not Answered: Can Newborn Vitamin A Reduce Infant Mortality in South Asia?	Dear Editor, The recent systematic review by Gogia and Sachdev (1) on efficacy of newborn vitamin A supplementation in reducing infant mortality illustrates how inappropriate adherence to a popular analytical tool can frame the wrong question and produce misleading findings. At issue is the central question of whether vitamin A, given to newborns in South Asia, can reduce infant mortality? This issue should have been addressed because it arises from findings of improved infant survival following newborn vitamin A receipt in three, double-masked, randomized, controlled trials in Indonesia (2), India (3) and Bangladesh (4) designed to address this question. It is unfortunate the authors confused the issue by including in their analysis older neonates from an earlier study never designed to reach newborns (5). Secondly, their insistence to pool studies from South Asia and Africa suggests both regions pose homogeneous risks, an assumption belied by long-known differences in maternal, infant and child health (6), vitamin A deficiency (7), and infant feeding practices (6) which would anticipate geographic variation in impact. Third, despite claiming to include trials irrespective of maternal vitamin A supplementation status, they in fact excluded two-thirds of ~8000 placebo newborns in Bangladesh, whose mothers received weekly vitamin A or beta-carotene as part of a larger trial into which the newborn study was nested (4), leaving their rationale wanting. The exclusion does not materially alter the effect estimate, but reduces sample size and weakens this major trial’s contribution to the analysis. Gogia and Sachdev emphatically conclude that ”no justification” exists for neonatal vitamin A supplementation, in direct conflict with all available data in Asia relevant to this question, while calling for additional trials in Africa and Asia to define regional differences. Additional African trials are needed, but programming that awaits a fourth Asian trial will condemn a million Asian infants to die during the five years needed to complete it. References 1. 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 2. Humphrey JH, Agoestina T, Wu LSF, Julianti A, Septian S, Ichord RN, Widjaja H, Cerreto MC, Katz J, West KP Jr. Neonatal vitamin A supplementation: Effect on development and growth at 3 years of age. Am J Clin Nutr 1998;68:109-117. 3. Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, John R, Prakash K, Sadanand AV, Edwin N, Kamaraj C. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India. BMJ 2003;327:254-259 4. Klemm RDW, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, Sommer A, West KP Jr. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 2008;122:242-250. 5. West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK, Pradhan EK, Adhikari R, Wu LS, Pokhrel RP, Sommer A. Mortality of infants <6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr 1995;62:143-148. 6. Ramalingaswami V, Johnson U, Rohde J. Commentary: The Asian enigma. In: The Progress of Nations 1996: Nutrition. New York, NY: UNICEF, 1997 http://www.unicef.org/pon96/nuenigma.htm. (accessed 31 March 2009) 7. West KP Jr. Extent of vitamin A deficiency among preschool children and women of reproductive age. J Nutr 2002;132:2857S-2866S. Competing interests: None declared
Academic Nihilism and Vitamin A 4 April 2009
Laurence E Wood, Lead Obstetrician UHCW, Coventry, CV2 2DX Send response to journal: Re: Academic Nihilism and Vitamin A	Nihilism means a tendency to negate, to the point of rejection of possibility, (from 'nihil', meaning 'nothing'). Academic nihilism is a modern contagious disease, which has infected NICE and Cochrane, and now finally has filtered into the editorial rooms of the BMJ. Gogia and Singh's analysis of neonatal vitamin A supplementation is a case in point (1). They conclude: "There is thus no justification for initiating (Vit A) supplementation as a public health intervention in developing countries for reducing infant mortality and morbidity". The correct conclusion is: "Vitamin A deficiency is known to be important for immune function, (2), and is common in some developing countries (3). Thus treatment with Vitamin A to those who need it can be important, (4). Nevertheless, supplementing vitamin A to healthy neonates at birth produces only a nonsignificant reduction in mortality, with confidence limits which include harm. Possible explanations for these conflicting results include poor trial quality or numbers, inadequate contribution of Vit A to all-cause mortality, infrequency of Vit-A deficiency in some populations, and counterbalancing harmful effect of supplementation in those who do not need it. Because this analysis does not support routine vitamin A supplementation for all neonates in the populations studied, future research needs to establish ways of identifying more easily those at need, and to clarify the putative benefits and harms in such individuals. Meanwhile, addressing vitamin A deficiency remains important in certain common situations, such as measles." Such accuracy makes for less eye-popping headlines, but also less inappropriate debasement of important interventions. refs: 1. Gogia, S., Sachdev, H.S., "Neonatal vitamin A supplementation for prevention of mortality and morbidity in infancy: systematic review of randomised controlled trials" BMJ 2009;338:b919 2. Stephenson CB Vitamin A, infection and immune function, Annu Rev Nutr 2001;21:167-92. 3. Busie, B.M-D. et al, "Vitamin A Deficiency Is Prevalent in Children Less Than 5 y of Age in Nigeria" J. Nutr. 136:2255-2261 4. D'Souza RM, D'Souza R, "Vitamin A for the Treatment of Children with Measles—A Systematic Review" Journal of Tropical Pediatrics 2002 48(6):323-327 Competing interests: None declared
Vitamin A supplements in newborns in South asia 11 May 2009
Dr.Umesh Kapil, Professor, Public Health Nutrition AIIMS, New Delhi,India,110029 Send response to journal: Re: Vitamin A supplements in newborns in South asia	The systematic review by Gogia and Sachdev (1) is a lucid illustration of posing an appropriate question, which examines the relevant evidence in entirety to aid policy formulation. Their approach reflects conventional methodology and wisdom, and is in sharp contrast to framing a misleading question solely on the basis of positive trials (three of the four trials in South Asia rather than all global trials). Sub-group analyses, especially those based on region rather than biological plausibility, are at best exploratory in nature and never definitive to frame policy. Further, a regional policy cannot be adopted on the basis of only three trials from the most deprived settings in South Asia. At issue is the central biological question of whether vitamin A given to newborns (neonates) at risk of developing vitamin A deficiency can reduce infant mortality? The issue is not whether Vitamin A supplementation acts as a “magic bullet” in selected regions. The systematic review (1) elegantly illustrates that there are no biological predictors of heterogeneity for the mortality effect amongst the entire global trials, which has also been described in detail earlier (2,3). The authors had also meticulously discussed their rationale for methodological criteria including the comparator group and the effect of varying assumptions on the pooled estimates and conclusions. Their results and conclusions remain robust despite varying the assumptions (1). Even after excluding the Nepal trial (4) and comparing intervention with a control group irrespective of maternal vitamin A supplementation status in the Bangladesh trial (5), there was no evidence of a reduced risk of mortality in infancy for intervention within the first 48 hours (RR 0.89, 95% CI 0.73 to 1.09; P=0.256) or seven days (RR 0.88, 95% CI 0.73 to 1.07; P=0.196). Also, if the choice of a control group in one trial alters the conclusion of a pooled analysis radically, the evidence is considerably weak to justify a translation into policy. Thus West et al.’s insistence on raising these issues again is only an attempt to confuse the reader and create doubts about the credibility of the systematic review. The declaration of no competing interest by West et al. is not only perplexing but could also deceive the readers because in earlier publications an institutional link with a leading manufacturer of vitamin A had been revealed (6). In their final bid to compel South Asian populations to adopt a doubtful intervention immediately, they advocate a “holier than thou attitude” by stating “programming that awaits a fourth Asian trial will condemn a million Asian infants to die during the five years needed to complete it”. The call of the hour is that policy should primarily be framed by representatives of those who will have to live with the recommendations (7). The policy makers and scientists of these South Asian populations have ample qualities of head and heart to decide what is best for their people! References 1 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. 2 Benn CS, Whittle H, Fisker A, Aaby P. Neonatal vitamin A supplementation in South Asia: Rapid implementation or understanding the variation. bmj.com, 11 Jul 2008. http://www.bmj.com/cgi/eletters/336/7658/1385#198676 accessed on April 21, 2009. 3 Gogia S, Sachdev HS. Vitamin A supplements in newborns and child survival. bmj.com, 10 Jul 2008. http://www.bmj.com/cgi/eletters/336/7658/1385#198607 accessed on April 21, 2009. 4 West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK, Pradhan EK, Adhikari R, Wu LS, Pokhrel RP, Sommer A. Mortality of infants <6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr 1995; 62:143-148. 5 Klemm RDW, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, Sommer A, West KP Jr. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 2008; 122: 242-250. 6 Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: a community-based randomized trial in southern India. BMJ 2003; 327: 254. 7 Oxman AD, Lavis JN, Fretheim A. Use of evidence in WHO recommendations. Lancet 2007; 369: 1883-89. Competing interests: None declared