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EDITORIALS: James M Tielsch Vitamin A supplements in newborns and child survival BMJ 2008; 336: 1385-1386 [Full text]

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Supplements to improve newborn and child survival, why not nutrition education ?

sudershan kumari   (27 June 2008)

Vitamin A Supplements in Newborns and Child Survival

Siddhartha Gogia, Harshpal S Sachdev   (10 July 2008)

Neonatal vitamin A supplementation in South Asia: Rapid implementation or understanding the variation?

Christine S Benn, Hilton Whittle, Ane Fisker, and Peter Aaby   (11 July 2008)

It May Not be Appropriate to Recommend the Vitamin A Supplements in Newborns

Umesh Kapil   (12 July 2008)

Supplements to improve newborn and child survival, why not nutrition education ? 27 June 2008
sudershan kumari, neonatologist sunderlal jain hospital,ashok vihar, delhi 110052, India Send response to journal: Re: Supplements to improve newborn and child survival, why not nutrition education ?	The article highlights the role of vitamin A supplements in newborns in reducing neonatal and child mortality.The two studies show contradictory results,while Indian study showed improved infant survival with neonatal vitamin A supplementation, other study from africa failed to show any benefit on survival. Longitudinal studies involve funds, personnel and take a lot of time. I wonder why there is paucity of studies of health and nutrition education to mothers during antenatal /postnatal period. The fact is that during first 6 months a mother with her baby has a contact with health personnel at least 4-5 times for immunisations,which are now accepted by majority of populations.A short time,say about 5-10 minutes, given individually to mother at first contact (hospital, home or clinic)can resolve the problems of breast feeding and keeping baby warm. At the same time she can be informed about danger signs in the newborn and when to contact health personnel, which has long term survival benefits also. emphasing to eat for two in early infancy with whatever diet is affordable helps better lactation. In my personal experience , a study of nutrition education and its implications in malnutrition carried out in a busy underfive clinic in Northern India(Kumari S.Jour Trop Peditr 1982; 28; 216-17)it was seen that nutrition education was more effective in improving nutritional status at follow up than in supplemented group.In Northern India ,there is a custom of giving a diet rich in fats, protein and nuts with cereals and sugar to breast feeding mothers in postpartun period. It was observed that mothers who consmed more than 5 kg of extra fat in addition to family diet , their babies weighed 300gm nore at 3 months than when fat intake was less than 4 kg(unpublished data). Public health programmes should emphasize the role of educating adolescent girls and young mothers about breast feeding, pregnacy risk factors, nutrition and basic neonatal care, which will hopefully reduce incidence of mortality and low birth weight as well. How long and how many supplements to infants,there is no limit, they are difficult to reach to all infants. May be at some time, such simple trials can be undetaken and tried. Competing interests: None declared
Vitamin A Supplements in Newborns and Child Survival 10 July 2008
Siddhartha Gogia, Attending Consultant, Department of Pediatrics and Clinical Epidemiology Sitaram Bhartia Institute of Science and Reasearch, Delhi 110016, Harshpal S Sachdev Send response to journal: Re: Vitamin A Supplements in Newborns and Child Survival	Exceptional care is needed when interpreting data that may create policy for an annual birth cohort of over 50 million. We disagree with Tielsch’s conclusion1 that for populations in Asia who are deficient in vitamin A, the evidence for child survival benefit of newborn (neonatal) vitamin A supplementation (VAS) is convincing enough to warrant implementation for the following reasons. Data showing no evidence of survival benefit following neonatal VAS in Nepal, Asia (RR 1.07, 95% CI 0.66 to 1.72)2 were not included in Tielsch’s assessment. There are three compelling arguments to restrict the evaluation of the VAS effect to the neonates in the maternal placebo group in the factorial-designed Bangladesh study3, which again shows no evidence of survival benefit (RR 0.87; 95% CI 0.67 to 1.12): (i) Postpartum VAS given to HIV positive mothers whose infants remained polymerase chain reaction-negative at 6 weeks increased their mortality by 2 years of age (HR 1.82, 95% CI 0.99, 3.31; P=0.05)4. Other trials of antenatal and/or postnatal maternal VAS5, 6 have also shown increased risk of mortality in the offspring (RRs 1.05 to 1.26; P>0.05). It is possible that inclusion of maternal vitamin A or beta-carotene supplementation groups could inflate survival benefit by increasing mortality in the neonatal placebo group; (ii) The most satisfactory comparison for policy should replicate programmatic intervention, and no country in Asia is resorting to prolonged antenatal and postnatal weekly vitamin A or beta-carotene supplementation; and (iii) The trial was planned to detect a minimum reduction of 15% in 6-month infant mortality with 80% power for the effect pooled across the three maternal supplementation arms (vitamin A, beta-carotene and placebo). A significant survival benefit was inferred from the pooled estimate, which was justified by post-hoc subgroup analyses that showed no significant interaction between maternal and newborn supplementation. However, such analyses are underpowered to reveal realistic interactions; the power was only 10% to detect an interaction term (0.88) equivalent to the observed effect size in the maternal placebo subgroup. Trials with 80% power for the overall effect have only 29% power to detect an interaction effect of the same magnitude, and even less power for the smaller interactions that are more likely to occur in practice7. There is no plausible biological explanation for variation in outcomes amongst trials. Data from study subjects do not suggest that differences in outcomes between Asian and African trials can be explained by the baseline mortality and maternal vitamin A status of these populations (Table) 2, 3, 6, 8-12. Notably, the study9 with maximum survival benefit was an urban, hospital-based study with maternal serum retinol concentrations comparable to those of US residents. Conversely the rural trial2 with the worst baseline mortality and high maternal vitamin A deficiency had no beneficial effect. There is also no consistent pattern of other speculated predictors of response including gender, gestation, vaccination status, and low birth weight. However, evaluation of seven potential subgroup analyses in 6 trials amounts to an avoidable “fishing expedition”. Biological plausibility must also be considered in the context of no evidence of survival benefit for pooled estimates of all neonatal VAS trials13, for vitamin A administered through breast milk (maternal VAS) 5, 6, and for VAS commencing at 6 weeks of age14. In the literature and from a programmatic perspective, the terms newborn and neonate are used interchangeably to denote an age below 1 month. Tielsch’s reference to “vitamin A supplements to newborns within the first few days of life” is ambiguous with respect to the exact time frame. There is no evidence of significant survival benefit, even for the pooled effect in the Bangladesh trial3, if the time frame refers to 2 or 7 days of life. Tielsch’s declaration of no competing interest is perplexing because in an earlier paper10 he had revealed an institutional link with a leading manufacturer of vitamin A. In view of the serious concerns in this context15, 16, an editorial from an academic with no conflict of interest would have been preferable. Considering the current evidence, we are in total agreement with Benn and colleagues’8 conclusion that a global or regional recommendation of newborn VAS is unwarranted. References Tielsch JM. Vitamin A supplements in newborns and child survival. BMJ 2008; 336:1385-6. Epub 2008 Jun 16. West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK, Pradhan EK, et al. Mortality of infants under six months of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr 1995;62:143-8. Klemm RDW, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, et al. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 2008; 122 No. 1 July 2008, pp. e242-e250 (doi:10.1542/peds.2007-3448). Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton LH, Chidawanyika H, 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, infection-free survival, and mortality. J Infect Dis 2006; 193:860–71. Katz J, West KP Jr, Khatry SK, Pradhan EK, LeClerq SC, Christian P, et al. Maternal low-dose vitamin A or beta-carotene supplementation has no effect on fetal loss and early infant mortality: a randomized cluster trial in Nepal. Am J Clin Nutr. 2000;71:1570-6. Malaba LC, Iliff PJ, Nathoo KH, Marinda E, Moulton LH, Chidawanyika H, et al. Effect of post-partum 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. Brookes ST, Whitely E, Egger M, Davey Smith G, Mulheran PA, Peters TJ. Subgroup analyses in randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test. J Clin Epidemiol 2004; 57: 229-36. Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, et al. Effect of 50 000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial. BMJ 2008 doi: 10.1136/bmj.39542.509444.AE. Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996; 128: 489-96. 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. United Nations, Department of Economic and Social Affairs, Population Division 2007. World Population Prospects: The 2006 Revision, Highlights, Working Paper No. ESA/P/WP.202. West KP Jr, Rice A, Sugimoto J. Tables on the Global Burden of Vitamin A Deficiency and Xerophthalmia among Preschool Aged Children and Low Vitamin A Status, Vitamin A Deficiency and Maternal Night Blindness among Pregnant Women by WHO Region. Http://www.jhsph.edu/CHN/GlobalVAD.pdf (updated August 2002) Sachdev HPS. Neonatal vitamin A supplementation and infant survival in Asia. Lancet 2008; 371: 1746. WHO/CDD Immunization Linked Vitamin A Supplementation Study Group. Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunization in early infancy. Lancet 1998; 352: 1257-63. Yngve A, Margetts B, Sachdev HPS. Guidance on publishing results and how we operate evidence-based policy. Public Health Nutr 2008; 11: 655-6. Godlee F. Key opinion leaders, your time is up. BMJ 2008; 336 (21 June), doi:10.1136/bmj.a413 Table: Summary of important characteristics of newborn VAS trials. Study Benn8 (Africa) Malaba6^ (Africa) West2* (Asia) Humphrey9 (Asia) Rahmathullah10 (Asia) Klemm3^ (Asia) Country Guinea- Bissau Zimbabwe Nepal Indonesia India Bangladesh Prevalence of xerophthalmia† 9.4 9.6 31.5 10.2 4.8 6.0 Prevalence of low vitamin A ‡ 20.4 35.4 54.0 34.2 22.8 22.5 VAD status (study subjects) <1 % mothers had low serum RBP, 27% children with RBP corresponding to values below 0.7 µmol/l retinol 37.1% mothers with serum retinol <1.05µmol/l, MNB 0% MNB 8.4% Mean maternal serum retinol 1.77 µmol/l MNB 5.5% MNB 9.6%. Mean maternal serum retinol 1.15 µmol/l National IMR ₤ 121.2 64.4 64.5 34.2 62.5 61.3 Placebo mortality $ 45.7 17 132.3 19.8 69.1 43.7# Follow up (months) 12 12 4 12 6 6 Study RR/ HR (95% CI) 1.07 (0.79-1.44) 1.18 (0.76-1.83) 1.07 (0.66-1.72) 0.36 (0.16-0.87) 0.78 (0.63-0.96) 0.87 (0.67, 1.12) Other Results Study excluded LBW babies, significant -ve effect of vitamin A among girls with normal / high ponderal index 12% LBW, benefitted small infants but harmed large subjects 10% LBW, benefitted normal birth weight subjects and boys 31% LBW, benefitted only low birth weight subjects and boys Benefitted normal birth weight subjects > LBW, girls > boys, term > preterm † National prevalence of xerophthalmia among pregnant women 11 ‡ National prevalence of low vitamin A status among pregnant women12 ₤ National infant mortality rate (2001-2005) 11 $ Placebo group mortality rate per 1000 person years # Placebo group mortality rate per 1000 live births * Data extracted from Table 2 of the published paper ^ Data from neonatal VAS group and placebo LBW – Low birth weight; MNB – Maternal night blindness; RBP – Retinol binding protein Competing interests: Both authors have conducted a systematic review entitled “Benefits and safety of vitamin A supplementation in the first half of infancy” supported by WHO, Geneva.
Neonatal vitamin A supplementation in South Asia: Rapid implementation or understanding the variation? 11 July 2008
Christine S Benn, Senior researcher Bandim Health Project, Statens Serum Institut, 2300 Copenhagen S, Denmark, Hilton Whittle, Ane Fisker, and Peter Aaby Send response to journal: Re: Neonatal vitamin A supplementation in South Asia: Rapid implementation or understanding the variation?	Neonatal vitamin A supplementation in South Asia: Rapid implementation or understanding the variation? Five trials of neonatal vitamin A supplementation (VAS) have now been published. Three trials from South Asia showed beneficial effects on mortality of neonatal VAS (1-3). Two trials from Africa found no overall beneficial effect, the estimates going in the other direction (4-6).   When some trials have found a positive effect of neonatal VAS and others no effect, a subgroup VAS policy is only acceptable if there is convincing evidence that the subgroup encompasses the children who benefit, and not those who might be harmed. Apparently, many seem to accept the geographical area “South Asia” as a reasonable definition of such a subgroup. Several voices have been raised in favour of recommending blanket neonatal VAS in South Asia (7,8). Recently, as a comment to our neonatal VAS trial from Guinea-Bissau (6), Professor Tielsch wrote “For populations in Asia who are deficient in vitamin A the evidence for benefit is convincing” (9).   We think it might be premature to implement neonatal VAS in South Asia before we understand the background for the contradictory effects in existing trials (6,10). As argued below, there may be factors other than vitamin A deficiency that explain the effects of neonatal VAS.   According to Professor Tielsch differences in vitamin A status and baseline mortality in the five neonatal VAS trials is the best way of reconciling the contradiction between the trials. It is the common understanding that VAS has the greatest benefit in populations with endemic vitamin A deficiency (VAD) and high mortality, and intuitively it is a very appealing explanation. However, this may not fit the data very well. Even in the early studies of VAS to older children, there is no evidence for such associations (11). The five neonatal VAS trials do not support a strong association between vitamin A status and baseline mortality and the effect of VAS either. First, it is not easy to assess the vitamin A status since the trials have provided very different measurements of VAD (Table). We agree with Dr. Tielsch that the Indian and Bangladeshi trials probably had the highest degree of VAD and found a good effect of neonatal VAS (2). It is also noteworthy that none of the women in the African trials suffered from night blindness. However, it should be also noted – not dismissed as an outlier among five trials – that the Indonesian trial had a good vitamin A status for the mothers and a very good effect of VAS (1). Also, one of the Zimbabwean subgroups of 4,495 HIV positive women presumably suffered from VAD and neonatal VAS had no beneficial effect in that group; it even had a significantly negative effect in the large majority of the children who remained HIV-negative (5). Second, it is easier to assess the mortality level in the five trials though they had variable length of follow-up and this could have affected the mortality level (Table). Mortality was reduced in the Guinea-Bissau trial due to exclusion of low birth weight infants and free drugs and treatment of trial participants (9). However, the infant mortality rate in Guinea-Bissau was still higher than in the trials from Bangladesh and Indonesia. A plot of the effect of neonatal VAS as a function of baseline mortality in the placebo groups reveals no association (Figure available upon request). Hence, though it may seem illogical, the existing evidence does not convincingly support that “Benefit depends on the setting, baseline infant mortality, and vitamin A deficiency “(9). The effect of VAS can not be predicted based alone on the level of VAD and baseline mortality, and there is no reason why it should be predicted based on the setting. This is not to say that VAS does not prevent or treat VAD and prevent deaths for that reason. However, other environmental factors may modify the effect of VAS on mortality, making it impossible to predict its effect based on pre-existing degree of VAD and baseline mortality. Identifying such environmental factors could lead to optimised use of VAS. Importantly, VAS has been associated with increased mortality in some situations (5, 12-15). Identifying the underlying mechanisms is crucial in order to prevent the worst thinkable scenario: intervention-induced increased mortality.   We have proposed that the divergent results may be explained by differences in vaccination intensity in the five trials (10). Accumulating data suggests that VAS may interact negatively with DTP vaccine in girls (12-15). We have found that DTP has a negative effect for girls in areas with herd immunity to pertussis (16) and VAS may amplify this negative effect. In our trial from Guinea-Bissau, all children received BCG at the same time as VAS or placebo (6). Having received VAS tended to be beneficial as long as BCG was the last vaccine to be received, the mortality rate ratio being 0.86 (0.48-1.54). However, a post hoc analysis showed that once children received DTP vaccine, mortality in girls who had received VAS at birth was significantly 2-fold higher compared with girls who had received placebo at birth (14). Hence, in our experience VAS has a beneficial effect as long as BCG is the last vaccine but may have a negative effect for girls once they receive DTP (14). As a consequence the survival curves of VAS and placebo recipients should cross over once they start receiving DTP around two months of age if the coverage for DTP is high. This pattern is seen both in Guinea-Bissau and in Zimbabwe (4). An important question for further research is what happens when BCG and DTP are administered simultaneously as often happen in rural areas. We suspect that VAS in this situation will be more beneficial for girls since we have previously experienced that combined BCG and DTP vaccinations are better for girls than for boys (17).   Such vitamin A-vaccine interactions could help explain the variation in trial results. Vaccination intensity was high in Guinea-Bissau (14, Table) and probably also in Zimbabwe as judged by the national coverage data (18). This was not the case in the trials from India and Bangladesh, which were the only trials to provide data on vaccination coverage (Table). The trial from Indonesia was conducted 15 years ago when vaccination coverage may have been lower. Hence, existing data are compatible with the hypothesis that early DTP vaccination might interfere with the beneficial effect of neonatal VAS. Importantly, neonatal VAS-DTP interactions would be most important in settings which have high mortality throughout infancy. The Indian and Bangladeshi trials tended to have nearly all mortality concentrated in the first 1-2 months of life (Table), which would not be affected by a negative interaction between VAS and DTP. In contrast, the African trials continued to have high mortality throughout the 12-24 months of follow-up. High neonatal mortality combined with little mortality in the subsequent months may be a better indicator of populations in which neonatal VAS may be beneficial than “South Asia”. However, it would seem important to conduct trials with longer follow-up than 6 months to make sure that the effect does not cease to be beneficial and/or becomes negative.   If our hypothesis is correct and neonatal VAS is made a general policy in South Asia, the intervention may cease to be beneficial or even become detrimental as the DTP coverage increases and more children are vaccinated early in life, especially in populations in which mortality is not limited to the first months of life. However, there will be no way of knowing because it is considered unethical to conduct further trials once an intervention has become policy.   It will be up to the WHO to weigh the evidence for and against a neonatal VAS policy in South Asia. Hopefully, in the process, a consensus will be reached on how VAD data should be reported, and which potential effect modifiers should be examined. Based on our experience data on vitamin A effects should always be reported by sex and by vaccination status. So far there is limited scientific evidence for the interpretation that neonatal VAS is most beneficial in areas with highest degree of VAD and baseline mortality. We need better explanations for the contradictory results before we make subgroup policies.   References 1.      Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996; 128:489-96. 2.      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: community based randomised trial in southern India. BMJ 2003; 327:254. 3.      Klemm R, Labrique A, Christian P, Rashid M, Shamim AA, Wu L, et al. Efficacy of newborn vitamin A supplementation in reducing infant mortality in rural Bangladesh: The JIVITA-2 trial. Pediatrics 2008; 4.      Malaba LC, Iliff PJ, Nathoo KJ, Marinda E, Moulton LH, Zijenah LS, 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. 5.      Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton LH, Chidawanyika H, 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. 6.      Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM, Whittle H, Rodrigues A, Yazdanbakhsh M, Aaby P. Randomised trial of the effect on mortality of 50,000 IU vitamin A given with BCG vaccine to infants in Guinea-Bissau, West-Africa BMJ 2008; 336(7658):1416-20. 7.      West Jr K, Sommer A. Newborn vitamin A dosing: Policy implications for Southern Asia and Africa. Abstract presented at the 1st Micronutrient Forum Meeting in Istanbul, Turkey, April 2007. (http://www.micronutrientforum.org/Meeting2007/MN%20Forum%20Program%20Part%20II_Abstracts.pdf, abstract T116). 8.      Bhutta ZA, Ahmed T, Black RE, Cousens S, Dewey K, Giugliani E, et al; Maternal and Child Undernutrition Study Group. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417-40. 9.      Tielsch JM.  Editorial. Vitamin A supplements in newborns and child survival. BMJ 2008; 336(7658): 1385-1386. 10.  Benn CS, Fisker AB, Jřrgensen MJ, Aaby P. Conflicting evidence for neonatal vitamin A supplementation. Vaccine 2008 Apr 30. [Epub ahead of print] 11.  Beaton GH, Martorell R, Aronson KJ, Edmonston B, McCabe G, Ross AC, et al. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries. International Nutrition Program. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto. Toronto, Ontario, Canada. 1993. 12.  Benn CS, Balé C, Sommerfelt H, Friis H, Aaby P. Vitamin A supplementation and childhood mortality: Amplification of the non-specific effects of vaccines? Int J Epidemiol 2003; 32:822-8.  13.  Benn CS, Martins C, Rodrigues A, Fisker AB, Christoffersen D, Aaby P. The effect of vitamin A supplementation administered with missing vaccines during national immunisation days in Guinea-Bissau (Int J Epidemiol, in review) 14.  Benn CS, Rodrigues A, Yazdanbakhsh M, Fisker AB, Ravn H, Whittle H, Aaby P. The effect of high-dose vitamin A supplementation administered with BCG vaccine at birth may be modified by subsequent DTP vaccination (Int J Epidemiol, in review) 15.  Benn CS, Fisker AB, Jřrgensen MJ, Aaby P. Why worry: Vitamin A with DTP vaccine? Vaccine 2007; 25: 777-779. 16.  Aaby P,Jensen H, Samb B, Cisse B, Sodeman M, Jakobsen M, Poulsen A, Rodrigues A, Lisse IM, Simondon F, Whittle H. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: a re-analysis of the West African studies. Lancet 2003;361: 2183-88 17.  Aaby P, Jensen H, Rodrigues A, Garly ML, Benn CS, Lisse IM, Simondon F. Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs. Int J Epidemiol 2004;33:367-73 18.  http://www.who.int/vaccines/globalsummary/immunization/countryprofileselect.cfm 19.  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 Intern Health 2005;10:1-9.     Table. Overview of the neonatal vitamin A supplementation (VAS) trials.   Partici-pants Maternal supplement Age at follow-up Mortality rate /1000 pyrs in control group % deaths  during the first mo in control group Level of vitamin A deficiency Vaccine coverage information Effect of VAS on mortality ALL Effect of VAS on mortality BOYS Effect of VAS on mortality GIRLS ASIAN TRIALS   Indonesia (1) 2,067 No 12 mo 20 (12 mo) 21 (1 mo) @ 48 (2 mo) & MMSR: 1.77 umol/L   0.36 (0.16-0.87) 0.15 (0.03-0.68) 0.84 (0.26-2.77) India (2) 11,619 No 6 mo 69* (6 mo) 61 (1 mo) & 70 (2 mo) & 5-6% NB in pregnancy BCG: 59% DTP1: 66% DTP3: 17% (6 mo)(19) 0.78 (0.63-0.97) 0.70 (0.52-0.94) 0.87 (0.65-1.17) Bangladesh (3) 15,937 Yes (3*2 factorial) 5˝ mo 45 (5˝ mo) 69 (1 mo) @ 82 (2 mo) &   MMSR in first trimester: 1.15 umol/L. 10% NB in last pregnancy BCG: 72% DTP1: 65% (5˝ mo**) 0.87 (0.67-1.12) $ 0.89 (0.72-1.10) 0.81 (0.65-1.00) AFRICAN TRIALS   Zimbabwe (4) HIV negative mothers 9,208 Yes (2*2 factorial) 12 mo 17 (12 mo) 53 (1 mo) & 65 (2 mo) &   MSR: 6%<1.05 umol/L (6 wks) No NB   1.18 (0.76-1.83) N/A N/A Zimbabwe (5) HIV positive mothers 4,495 Yes (2*2 factorial) 24 mo 155 (2 yrs (all children)) 28 (6 wks) ¤     MMSR: ~1.00 umol/L after delivery, No NB 1.21 (0.99-1.46) $ HIV positive: 0.88 (0.58-1.32) HIV negative: 1.89 (1.05-3.40) N/A N/A Zimbabwe (5) combined 14,110 Yes (2*2 factorial) N/A N/A N/A No NB 1.16 (0.98-1.38) N/A N/A Guinea-Bissau (6) 4,345 No 12 mo 47 (12 mo) 53 (6 mo) 23 (1mo) 30 (2mo) MMSR at 4 mo: 1.66 umol/L Mean child SR: 0.95 umol/L (6 wks) 1.07 umol/L (4 mo) BCG: 100%  DTP1: 97% DTP3: 90% (6 mo) (17) 1.07 (0.79-1.44) 0.84 (0.55-1.27)   1.39 (0.90-2.14) MMSR= Mean maternal serum retinol. NB=night blindness * Note, mortality per 1000 live births **Estimates presented in the paper without any indication of when collected - presumably at age 5˝ months. @ Presented in paper & Based on extrapolation from mortality curves in papers ¤ 6 weeks, calculated from table 3 in paper, those without HIV infection $ Effect in maternal placebo groups   Competing interests: None declared
It May Not be Appropriate to Recommend the Vitamin A Supplements in Newborns 12 July 2008
Umesh Kapil, Professor, Public Health, Oman Medical College, Oman Send response to journal: Re: It May Not be Appropriate to Recommend the Vitamin A Supplements in Newborns	The editorial entitled Vitamin A supplements in newborns and child survival documented that giving vitamin A supplements to newborns within the first few days of life significantly reduces early infant mortality in Asian populations with endemic maternal vitamin A deficiency and high infant mortal¬ity (1). This strategy has been advocated as a core intervention to reduce the mortality in young children in developing countries , particularly in Asia, in a recent publication in Lancet.(2) The core health care interventions are the one which are based on compelling new scientific evidence, relevant to micronutrient policies and programs, warrants the attention of the nutrition and public health communities. The core interventions are based on scientific evidence of the most rigorous and definitive , particularly when they are generated by replicated, well-designed, rigorously conducted randomized trials carried-out in appropriate populations. However , the studies on which have Vitamin A supplements in newborns has been advocated , have neither been replicated nor carried out in the different population groups. If we scrutinize carefully , we have data only from three studies (3-5 ). Of the three studies at least two , were carried under one leadership of one institute (though at different locations). An association between high prevalence of clinical signs of vitamin A deficiency in a community of pregnant mothers and relatively high rates of mortality among their children may be expected. Mothers and children with clinical signs of vitamin A deficiency generally belong to the poor deprived sections of the community and suffer from several inadequacies besides deficiency of vitamin A; these inadequacies are the inevitable attributes of their poverty syndrome. Their diets are generally inadequate not just in vitamin A but in calories and other nutrients as well; they live in highly unsanitary surroundings and they have poor access to basic health care. Relatively high mortality observed in children of such poor communities is probably attributable to a multiplicity of synergistic causative factors. Indeed, in view of the fact that these factors coexist in the same environment and the metabolic effects of some of them are closely interrelated, it will be hazardous to attempt to quantify with any precision the actual contribution of any single causative factor to the prevailing mortality profile. Do we have deficiency of Vitamin A in newborns ? No data is available on this aspect as it is difficult to interpret because all infants are born with low reserves of vita¬min A, especially those born prematurely. Newborns depend on adequate supplies from breast milk or appropriate substitutes to satisfy physiological demands in early life. If there is an biological impact of VA administration , then both in the newborns of Asia and Africa should have reduction in mortality. Policy makers and planners of developing countries, who because of their resource constraints, are desperately looking for easy remedies, simple solutions and soft options, should not be misled to believe that better child survival and child health and nutrition can be largely achieved by such instant devices and shortcuts as distribution of a pill or capsule once in six months. Scientists and health administrators of developing countries should not let themselves be confused, overawed and misled by these seemingly weighty pronouncements. Promises of miracle drugs and magic bullets should not distract from the real jobs that lie ahead and should not be allowed to distort their primary health care programmes. Recommending public health interventions like giving Vitamin A supplements to 50 million new born in Asia, should not be based on the evidence obtained from efficacy trials , in which a large number of field workers are employed who are supervised by monitors who under take personal visits in every home in the villages. We should generate more scirntifric evidence before we jump onm conclusions of recommending the Vitamin A supplements in newborns . 1. Bhutta ZA, Ahmed T, Black RE, Cousens S, Dewey K, Giugliani E, et al; Maternal and Child Undernutrition Study Group. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417-40. 2. Tielsch JM. Vitamin A supplements in newborns and child survival. BMJ 2008; 336:1385-6. Epub 2008 Jun 16. 3.Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128:489-96. 4. Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, et 5 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. 5.Klemm RDW, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J, 6 et al. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics (in press). Competing interests: None declared