Neonatal vitamin A supplementation and infant survival in Asia – Authors' reply
Authors: Zulfiqar A Bhutta, Batool A Haider, Simon Cousens, Betty R Kirkwood, Robert E Black
Journal: The Lancet (2008)

We note H P S Sachdev's concerns with regard to neonatal vitamin A supplementation. Had they been raised before publication, we would have had an opportunity to debate this issue and our recommendation. We took his agreement to coauthor the paper as an indication of his concurrence with the consensus. Concerns about the varied nature of previous studies led us to assess the existing evidence base for early neonatal vitamin A supplementation (within 3 days of birth) and its effect on mortality in early infancy (later in or after the neonatal period). Supplementation after 6 months was treated as a separate intervention and recommended for universal implementation. There are several reasons for excluding these alternative delivery points and older age-groups, including variability in dosing via breast milk and the possible existence of a critical postnatal time window for development of immunity. We also agreed that an appropriate estimate to include in any meta-analysis of the effect of neonatal dosing would be that for mortality at 6 months. Our protocol and basis for undertaking this analysis is published and a formal Cochrane review is in preparation.1Haider BA Irfan FB Bhutta ZA Neonatal vitamin A supplementation for the prevention of mortality and morbidity in term neonates in developing countries (Protocol).Cochrane Database Syst Rev. 2008; 1 (CD006980.)Google Scholar In our analysis we included data from all published studies of early newborn dosing.2Humphrey JH Agoestina T Wu L et al.Impact of neonatal vitamin A supplementation on infant morbidity and mortality.J Pediatr. 1996; 12: 489-496Summary Full Text Full Text PDF Scopus (204) Google Scholar, 3Rahmathullah L Tielsch JM Thulasiraj RD et al.Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India.BMJ. 2003; 327: 254Crossref PubMed Google Scholar, 4Malaba 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: 454-460PubMed Scopus (122) Google Scholar The study by West and colleagues5West KP Katz J Shrestha SR et al.Mortality of infants <6 months of age supplemented with vitamin A: a randomized, double-masked trial in Nepal.Am J Clin Nutr. 1995; 62: 143-148PubMed Scopus (112) Google Scholar from Nepal was not included because, out of 11 198 infants, only 13·6% received vitamin A within the neonatal period, mostly after the first 48 h, and no outcome data on mortality for that subgroup were provided. We had access to the two abstracts from the Micronutrient Forum that Sachdev cites,6Benn CS Diness BR Roth A et al.Effect of 50 000 IU vitamin A given to newborns and infants in Guinea-Bissau, West-Africa.http://www.micronutrientforum.org/Meeting2007/MN%20Forum%20Program%20Part%20II_Abstracts.pdfGoogle Scholar, 7Klemm R Labrique A Christian P et al.Efficacy of newborn vitamin A supplementation in reducing infant mortality in rural Bangladesh: The JiVitA-2 Trial.http://www.micronutrientforum.org/Meeting2007/MN%20Forum%20Program%20Part%20II_Abstracts.pdfGoogle Scholar but desisted from including these preliminary findings because they have not undergone full peer-review and full details of methods are not available. Klemm and colleagues7Klemm R Labrique A Christian P et al.Efficacy of newborn vitamin A supplementation in reducing infant mortality in rural Bangladesh: The JiVitA-2 Trial.http://www.micronutrientforum.org/Meeting2007/MN%20Forum%20Program%20Part%20II_Abstracts.pdfGoogle Scholar did a secondary analysis with the full data for mortality outcomes at 6 months of age at our request, and these were reported as a personal communication. We took the general finding from the study by Benn and colleagues6Benn CS Diness BR Roth A et al.Effect of 50 000 IU vitamin A given to newborns and infants in Guinea-Bissau, West-Africa.http://www.micronutrientforum.org/Meeting2007/MN%20Forum%20Program%20Part%20II_Abstracts.pdfGoogle Scholar into account in our recommendation, since this added to the evidence that newborn vitamin A dosing might be acting differently in sub-Saharan Africa. We caution against reporting meta-analysis findings without adequate access to trial information and would welcome a full analysis of the effects on mortality (all-cause as well as cause-specific) once these data are published and truly in the public domain after peer review. However, given the issues raised by Sachdev, we have done a meta-analysis (figure) of the effect estimates of neonatal dosing on mortality estimates at 6 months, incorporating the results of these two unpublished studies. We consider inappropriate the way Sachdev has incorporated the data from the Malaba trial.4Malaba 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: 454-460PubMed Scopus (122) Google Scholar The trial was a factorial design and the authors clearly report no evidence of interaction between maternal and neonatal supplementation. Thus if all children are to be included in the meta-analysis, the appropriate single estimate to include would be that comparing mortality at 6 months in the two groups who received newborn vitamin A dose with or without maternal supplementation, with the two groups who did not (relative risk 1·11, 95% CI 0·80–1·55). Use of these figures in the meta-analyses alters the results very slightly from those shown in the figure to give a relative risk of 0·88 (0·73–1·06; p=0·19). It can be seen from the figure that most, if not all, of the between-study heterogeneity can be explained by region. After accounting for region, the proportion of the variation in between-study estimates due to heterogeneity between studies (rather than sampling variation) is estimated to be 0%. Region-specific analyses suggest strong evidence of a benefit in south Asia, but no benefit in Africa. Vitamin A supplementation during late infancy and beyond is an accepted core intervention that saves lives, and extending it to cover early infancy in areas of endemic maternal and childhood vitamin A deficiency, where more than 60–70% of child deaths occur in the first 6 months of life, makes sense. However, with the exception of early neonatal doses, vitamin A supplementation in early infancy seems to have no effect on mortality.8Kirkwood B Supplementation of infants and/or their mothers with vitamin A during the first six months of life.Food Nutr Bull. 2002; 22: 285-294Google Scholar The disparate findings concerning the benefits of early newborn dosing from Africa and Asia without current biological explanation do concern us. These would merit further large-scale assessments in vitamin-A-deficient populations, to investigate the importance of potential effect modifiers such as HIV and malaria. On the basis of evidence available at the time of our analyses, our study group chose to make the cautious recommendation that neonatal vitamin A dosing be considered for scaling up in at-risk populations in Asia, with recommendations for other areas of the world being revisited as more information becomes available. We declare that we have no conflict of interest. Neonatal vitamin A supplementation and infant survival in AsiaThe paper by Zulfiqar Bhutta and colleagues (Feb 2, p 417)1 concludes that neonatal vitamin A supplementation is associated with reduced mortality in infants younger than 6 months in Asia, and includes it as a core intervention for that region. Such a recommendation will create pressure for its adoption. I was the credited coauthor for the vitamin A review in the same paper, but did not do the specific meta-analysis leading to this recommendation. Since my concerns with such a recommendation were overruled, it is my duty to caution stakeholders. Full-Text PDF