CSU 58/2010: VITAMIN A SUPPLEMENTS AND INFANT MORTALITY IN DEVELOPING COUNTRIES

Monday, 17th of May 2010

CSU 58/2010: VITAMIN A SUPPLEMENTS AND INFANT MORTALITY IN DEVELOPING COUNTRIES

As countries find that most of their remaining IMR is from neonatal causes, work like the following will be of great practical importance.

Many countries now give vitamin A from six months of age. Far fewer give it to newborns.

'In regions where at least 22% of pregnant women have vitamin A deficiency, giving neonates vitamin A supplements will have a protective effect against infant death.'

If the authors' conclusions are correct, should TBAs get vitamin A capsules?

Good reading.

BD

Bulletin of the World Health Organization

also at http://www.who.int/bulletin/volumes/88/9/09-068080.pdf

Michael Anthony Rotondi & Nooshin Khobzi

Vitamin A supplements and infant mortality in developing countries

Vitamin A supplementation and neonatal mortality in the developing world: a meta-regression of cluster randomized trials

Michael Anthony Rotondi

a & Nooshin Khobzia
a

University of Western Ontario, Room K201 Kresge Building, London, Canada, N6A 5C1.
Correspondence to Michael Anthony Rotondi (e-mail: mrotondi@uwo.ca).

(Submitted: 31 May 2009 – Revised version received: 4 December 2009 – Accepted: 15 February

2010 – Published online: 16 April 2010)

Abstract

Objective

To assess the relationship between the prevalence of vitamin A deficiency among pregnant women and the effect of neonatal vitamin A supplementation on infant mortality.
Methods

Studies of neonatal supplementation with vitamin A have yielded contradictory findings with regard to its effect on the risk of infant death, possibly owing to heterogeneity between studies. One source of that heterogeneity is the prevalence of vitamin A deficiency among pregnant women, which we examined using meta-regression techniques on eligible individual and cluster-randomized trials. Adapting standard techniques to control for the inclusion of a cluster randomized trial, we modelled the logarithm of the relative risk of infant death comparing vitamin A supplementation at birth to a standard treatment, as a linear function of the prevalence of vitamin A deficiency in pregnant women.
Findings

Meta-regression analysis revealed a statistically significant linear relationship between the prevalence of vitamin A deficiency in pregnant women and the observed effectiveness of vitamin A supplementation at birth. In regions where at least 22% of pregnant women have vitamin A deficiency, giving neonates vitamin A supplements will have a protective effect against infant death.
Conclusion

A meta-regression analysis is observational in nature and may suffer from confounding bias. Nevertheless, our study suggests that vitamin A supplementation can reduce infant mortality in regions where this micronutrient deficiency is common. Thus, neonatal supplementation programs may prove most beneficial in regions where the prevalence of vitamin A deficiency among pregnant women is high.
Introduction

Vitamin A deficiency is a public health concern in more than half of all countries, and most of the countries affected are in Africa or south-eastern Asia.
1 This deficiency, which is the main cause of blindness in undernourished children,2,3 contributes to morbidity and mortality from severe infections, including those common in childhood, such as diarrhoeal diseases and measles.4,5 Currently, an estimated 250 million preschool children in the world have vitamin A deficiency, and 250 000 to 500 000 of such children go blind every year. Of the children who go blind, half die within one year of losing their eyesight.1 International awareness of the role of vitamin A in improving and maintaining health has led to decades of supplementation being provided to preschool children.4
In children over 6 months of age, vitamin A supplementation has been shown to decrease all-cause mortality.

6–10 However, the benefits in children under 6 months of age are still unclear, even though young infants are especially vulnerable to vitamin A deficiency. In general, all infants are born with low stores of vitamin A and depend on external sources, including breast milk, to build body stores.11,12 The milk of lactating women in developing countries typically has lower concentrations of vitamin A than that of women in developed countries,12 which means that neonates may not obtain their daily requirements.11 Direct supplementation of neonates and infants younger than 6 months has shown promising results in terms of survival, yet findings have been contradictory.
Studies conducted in Bangladesh,

13 India11 and Indonesia12 have shown reductions in all cause mortality (15%, 22% and 63%, respectively) in infants who received vitamin A supplementation relative to controls. Giving neonates vitamin A has also been found to significantly reduce diarrhoea case–fatality rates and the incidence of fever.14 In contrast, trials in Guinea-Bissau,15 Nepal16 and Zimbabwe17 suggest a lack of benefit from vitamin A supplementation. The positive findings have led to different recommendations, but these are controversial15,18 and there is much disagreement throughout the world on the appropriate policy surrounding neonatal vitamin A supplementation.19,20 Clearly, further controlled trials with infants and neonates are needed.
To examine some of the systematic differences in the findings of conflicting studies, we performed a meta-regression analysis in which the logarithm of the relative risk (logRR) of infant death (measured at either 6 or 12 months of age) was modelled as a function of the prevalence of vitamin A deficiency among pregnant women in the general population. Unlike a simple meta-analysis, a meta-regression model attempts to explain the variation among studies in terms of a study-level characteristic. A meta-regression analysis is observational in nature and is thus not likely to put an end to the controversy surrounding neonatal supplementation, but it may provide some insight into effectiveness in subsequent trials, based on the prevalence of vitamin A deficiency. The inclusion of a cluster-randomized trial
13 in the meta-regression analysis entails a unique application of the proposed method, as discussed below.
Methods

Inclusion criteria

The fundamental question of interest was whether the log(RR) of death among infants who received vitamin A supplements at birth versus placebo or a standard treatment such as vaccination was related to the level of vitamin A deficiency among pregnant women in the general population. To reconcile the conflicting evidence from different studies, we developed inclusion criteria that took into account extraneous sources of heterogeneity, such as varying target populations and differences in the time when vitamin A supplementation was administered. The a priori inclusion criteria were that trials (i) be randomized; (ii) have an appropriate control group that did not receive any vitamin A supplements; (iii) be administered at the population level (i.e. no supplements provided to specific subgroups of interest, such as infants or mothers, with or without specific health concerns); and (iv) have the vitamin A supplements administered within the first two days of life. These criteria were designed to allow for a focused and comprehensive analysis of the efficacy of giving neonates vitamin A supplements in the general population. In addition, the criteria were set to ensure that the effect of vitamin A supplementation could be extrapolated to the general population by excluding subjects who may have received vitamin A supplements after the first two days of life or who may have belonged to specific groups treated with vitamin A. This is of primary concern, given the significant variability in vitamin A supplementation trials.

Two studies in Zimbabwe were excluded because their participants were either HIV

− or HIV+ mothers only.17,21 A study in Nepal was excluded because it provided vitamin A supplements every four months and hence was not designed to dose neonates.16 A fourth trial was excluded because it was designed to measure the efficacy of a smaller dose of vitamin A, rather than the standard dose.8 Characteristics of the included studies are presented in Table 1.
Statistical analysis

A traditional meta-analysis combines all estimates of an observed treatment effect into a single overall estimate of the efficacy of a particular intervention. In general, the observed treatment effects are obtained from individually-randomized clinical trials, which ensures that, on average, each estimate of the treatment effect is not confounded by other factors. Nonetheless, observed treatment effects may lead to differing conclusions stemming from varying inclusion criteria and study populations, variations in the study protocols (e.g. dose or length of follow-up) and random error. Differences in the observed treatment effects are often the result of between-study heterogeneity, or simply heterogeneity. While attempts to explore the impact of heterogeneity on a meta-analysis are important, a meta-analysis tacitly accepts heterogeneity by combining different studies in the search for a single underlying treatment effect.

23 Cluster-randomized design is becoming more common, and a meta-analysis may be influenced by the inclusion of one or more cluster-randomized trials.24 The greatest threat to statistical validity is the failure to incorporate the appropriate design effect in variance calculations.25 Failing to account for clustering in a meta-analysis will contribute to an underestimation of the within-study variance, resulting in an unrealistically high weight for that particular treatment effect. Furthermore, care must be taken when combining results from cluster-randomized and individually-randomized trials, because the intervention itself may interact with the unit of randomization.26
As explained above, meta-regression analysis attempts to relate the effect size to study-level characteristics. This approach not only acknowledges between-study heterogeneity but also attempts to explain it at the study level. Similar to a classical metaanalysis, a meta-regression employs weights (typically random effects

27) to account for larger or more accurate studies. Because meta-regression analysis is observational in nature, rigorous causal associations cannot be directly ascertained.27
The prevalence of vitamin A deficiency among pregnant women was the main explanatory variable in this meta-regression analysis. While different proxies for vitamin A deficiency

22 exist in the target infant populations, this measure was deemed the most appropriate because it was obtained by weighting the combined prevalences of low serum retinol and xerophthalmia reported by studies from the countries of interest. This approach to estimating national prevalences of vitamin A deficiency avoids potential bias resulting from restriction to women who are diagnosed with xerophthalmia, given that maternal vitamin A deficiency that is less than severe may also have a detrimental effect on infant survival. Estimates of the prevalence of vitamin A deficiency are subject to uncertainty because of the difficulty of obtaining accurate measurements.2 As such, prevalence estimates used for our analysis differ from those in other published reports.28
However, the included values represent the best estimates of the prevalence of vitamin A deficiency in pregnant women at the time individual subjects were enrolled in each study, while remaining consistent with the literature.

28
Infant mortality was the endpoint of interest; thus, RRs < 1 demonstrate the protective effect of vitamin A supplementation on infant mortality. Although vitamin A supplementation was administered to neonates, mortality was measured at either 6 or 12 months of age. In an attempt to reduce the skewness of the distribution of the RRs, we used the log(RR) as the dependent variable of interest. That is, we fitted the following weighted linear regression:

log(RR

i) = β0 + β1VADi + εi
where

VADi corresponds to the prevalence of vitamin A deficiency among pregnant women in study i (i = 1, 2, 3, 4, etc.) and Єi is an independently and identically distributed normal random variable with zero mean and fixed variance. Within the range of our explanatory variable, β1 represents the change in the log(RR) for each percentage increase in the prevalence of vitamin A deficiency among pregnant women and β0 represents the intercept.
The study weights used in a random effects meta-regression analysis are obtained as the inverse of the sum of the within-trial variance and the residual between-trial variance. By contrast, the fixed effects meta-regression analysis would simply weight each study by the inverse of its within-study variance. The fixed effects model is a special case of the random effects model in which the between-trial variance is estimated as zero.

Throughout the analysis, we applied the random effects model because it acknowledges the presence of residual heterogeneity.

27 Regardless of the model of choice, the appropriate weights in a meta-regression analysis should include an adjustment for the effect of clustering. This adjustment is easily incorporated into the within-trial variance by multiplying the standard estimate of the variance by the design effect, as correctly applied in the Bangladesh trial.13 In general, failing to adjust for the effect of clustering would result in the use of inaccurate weights, possibly leading to biases in the estimated covariates and standard errors.
Although unnecessary for the meta-regression analysis, a minor variation of Cochran's

Q statistic for heterogeneity, as well as the I2 statistic,29 are required to adjust for the inclusion of a cluster-randomized trial. Both of these statistics account for the clustering effect in the estimation of the within-study variance for any included clusterrandomized trials.
All statistical analyses were performed using the

R software package, with appropriate modifications to account for the incorporation of cluster-randomized trials.30 The between-study heterogeneity was estimated using restricted maximum likelihood and empirical Bayes techniques;27 the residual heterogeneity component was estimated as zero, and this reduced the random effects model to a fixed effects meta-regression.
Results

As a precursory analysis, a fixed effects meta-analysis model (adjusted for clustering) demonstrated an overall protective effect of vitamin A supplementation with respect to infant death using the generalized inverse method,

25 the fixed effects RR was 0.85 (95% confidence interval, CI: 0.75–0.95), which indicates a statistically significant overall reduction in mortality. To assess the impact of study heterogeneity on the meta-analysis, the Q statistic is often used as a basis for deciding between the fixed or random effects meta-analysis model.29 With this method, the null hypothesis of study homogeneity is rejected (i.e. the studies are found to be heterogeneous and the fixed effects model is invalidated) if the observed value of Q exceeds the 95% critical value of a χ2 distribution with degrees of freedom equal to the number of included studies minus one. This value is obtained from statistical tables or software. Within this framework, the Q statistic is calculated as 6.55, a value that does not exceed the 95% critical value of 7.81 (on three degrees of freedom). A simple method to quantify the between-study heterogeneity is through the I2 statistic. Using this method, the I2 value (adjusted for clustering) of 0.54 suggests the presence of moderate heterogeneity, despite the lack of statistical significance of the Q statistic. For the sake of completeness, the random effects metaanalysis estimates a RR of 0.84 (95% CI: 0.69–1.03), which does not suggest a statistically significant reduction of infant mortality as a result of neonatal vitamin A supplementation.
The results of the meta-regression analysis are presented graphically in Fig. 1, as well as the fitted and expected 95% confidence bands. Specifically, the intercept (

β0) is estimated as 1.66 (95 % CI: 0.20-3.13) and β1 is estimated as 0.08 (95% CI: 0.15 to 0.02). These findings suggest a statistically significant linear relationship between the prevalence of vitamin A deficiency among pregnant women in the study population and the observed effectiveness of neonatal vitamin A supplementation in preventing infant death (at 6 or 12 months of age) in a given study. The findings suggest that a study taking place in an area where the prevalence of vitamin A deficiency among pregnant woman is at least 22% would show a statistically significant, protective effect of vitamin A supplementation against infant death.
Discussion

Meta-regression analysis aims to relate the size of an effect to one or more characteristics of the studies involved.

27 More specifically, it investigates whether a covariate (potential “effect modifier”) explains the heterogeneity of treatment effects between studies.27 In our analysis, the study-level covariate of interest was the prevalence of vitamin A deficiency among pregnant women, and the outcome variable – overall infant mortality – represented the efficacy of neonatal vitamin A supplementation in developing countries.
We found a statistically significant relationship between the covariate and infant mortality, which suggests that vitamin A supplementation to neonates within the first two days of life confers a benefit in regions where vitamin A deficiency is common. This is an important finding given the current debate as to whether giving neonates vitamin A supplements helps reduce infant mortality in populations where endemic vitamin A deficiency and high infant mortality exist.

18,31
A recent meta-analysis suggests that there is insufficient evidence to support neonatal supplementation with vitamin A.

32 Although the study is methodologically sound and appropriate, its application of more general inclusion criteria may limit its ability to ascertain the role of the prevalence of vitamin A deficiency on infant mortality.
Furthermore, to calculate the prevalence of vitamin A deficiency the study employed maternal night blindness as a proxy, but the latter is associated only with the most severe cases of vitamin A deficiency. Also, the prevalence of maternal night blindness was dichotomized (

 5% versus < 5%) and this may have reduced its statistical power.33 This problem is avoided in the current study through the use of a continuous covariate.
The results of our analyses will be useful in predicting the benefits of providing neonates with vitamin A supplements in certain trials; that is, in trials conducted in regions with a prevalence of vitamin A deficiency of 22% or more among pregnant women. Some authors have advocated implementation of neonatal vitamin A supplementation in Asia but not in Africa until further trials are carried out.

18 However, our findings point to another plausible approach to the global problem of nutritional deficiency. In general, vitamin A supplementation may prove beneficial in regions where the prevalence of vitamin A deficiency among pregnant women is high. Therefore, both Asian and African countries experiencing nutritional deficiencies may benefit from vitamin A supplementation programs for infants.
In our meta-regression analysis, we controlled for a significant source of variation between studies (background prevalence of vitamin A deficiency); nevertheless, there is a possibility of residual heterogeneity.

27 For example, studies may differ with regard to the vitamin A content of supplementary foods, the rate of infant growth and the burden of infectious diseases, all of which may translate into different requirements or losses of vitamin A.12,31 In addition, we made no distinction between trials employing a single large dose of vitamin A or vitamin A supplements in regular but smaller amounts– a potentially valuable insight given that a higher-dose regimen has been shown safe but not more efficacious than a lower-dose regimen provided to infants.34,35 Differences in vaccination coverage among trials may further explain study heterogeneity. The protective effect of neonatal vitamin A supplementation may depend not only on the prevention of vitamin A deficiency, but also on a synergistic (positive) interaction with routine vaccinations.5 Vitamin A supplementation may strengthen ongoing immune reactions induced by vaccines; for example, when given with a live vaccine, vitamin A may further enhance the capacity of the antigen-presenting cells to deliver polarizing signals from helper to non-helper T cells, an essential component of cell-mediated immunity.5 The beneficial effects of vitamin A supplements when given with the vaccines against tuberculosis (bacille Calmette-Guérin or BCG vaccine) and measles can be attributed to this mechanism. In addition, vitamin A deficiency has been linked to iron and other micronutrient deficiencies.36,37 Thus, there may be a positive interaction between vitamin A supplementation and overall infant nutritional status.
The Indonesian study

12 was a leverage point in the meta-regression analysis (Fig. 1). Although meta-regression appropriately accounts for the lower precision of this study in comparison to the others, a sensitivity analysis conducted after removing the Indonesian trial yielded an estimate of β1 = 0.12 with a two-sided P-value of 0.09.
While statistical significance is lost with the omission of this study, estimates of

β1 remain consistent.
Our study had limitations, particularly owing to the use of meta-regression methods. A meta-regression describes an observational association across trials, even though the original studies may be randomized.

27 Thus, meta-regression does not have the benefit of randomization to make causal inferences and may introduce bias by confounding. Also, there is the possibility of residual heterogeneity, as mentioned earlier.
However, the prevalence of vitamin A deficiency explains much of the observed heterogeneity (supported by the estimate of zero for the between-study variance).

The observational analysis employed in this paper is unlikely to put an end to the controversy on the effectiveness of neonatal supplementation with vitamin A. However, we hope that it will contribute to continued debate in the literature and help to focus attention on the role of vitamin A supplementation, micronutrient deficiencies and nutrition in general on infant mortality.

Competing interests:
None declared.

References

1. World Health Organization:

Micronutrient deficiencies. Geneva: WHO; 2008. Available from: http://www.who.int/nutrition/topics/vad/en. [accessed 2 April 2010].
2. Brown E, Akre J, eds.

Indicators for assessing vitamin A deficiency and their application in monitoring and evaluating intervention programmes
(WHO/NUT/96.10). Geneva: World Health Organization; 1996.

3. Sommer A.
Vitamin A deficiency and its consequences: a field guide to their detection and control. Geneva: World Health Organization; 1995.
4. Bates CJ. Vitamin A.

Lancet 1995;345:31-5. doi:10.1016/S0140- 6736(95)91157-X PMID:7799706
5. Benn CS, Bale C, Sommerfelt H, Friis H, Aaby P. Hypothesis: vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines?

Int J Epidemiol 2003;32:822-8. doi:10.1093/ije/dyg208
PMID:14559758

6. Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A supplementation and child mortality: a meta-analysis. JAMA

1993;269:898-903.

7. Beaton GH, Martorell R, Aronson K, Edmonston B, McCabe G, Ross A, 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 Paper No. 13)

. Geneva: United Nations, Administrative Committee on Coordination, Subcommittee on Nutrition; 1993. Available from: http://www.unu.edu/unupress/food/8f154e/8F154E04.htm. [accessed 2 April 2010]
8. Benn CS, Martins C, Rodrigues A, Jensen H, Lisse IM, Aaby P. Randomised study of effect of different doses of vitamin A on childhood morbidity and mortality.

BMJ 2005;331:1428-32. doi:10.1136/bmj.38670.639340.55 PMID:16306060
9. Rahmathullah L, Underwook BA, Thulasiraj RD, Milton RC, Ramaswamy K, Rahmathullah R. Reduced mortality among children in south India receiving a small weekly dose of vitamin A.

N Engl J Med 1990;323:929- 35. PMID:2205798
10. West KP Jr, Pokhrel RP, Katz J, LeClerq SC, Khatry SK, Shrestha SR, et al. Efficacy of vitamin A in reducing preschool child mortality in Nepal.

Lancet 1991;338:67-71. doi:10.1016/0140-6736(91)92652-I PMID:1682730
11. 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: 10.1136/bmj.327.7409.254. doi:10.1136/bmj.327.7409.254 PMID:12896935

12. 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. doi:10.1016/S0022-3476(96)70359- 1 PMID:8618182
13. Klemm RD, 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:e242-50. doi:10.1542/peds.2007-3448 PMID:18595969
14. Tielsch JM, Rahmathullah L, Thulasiraj RD, Katz J, Coles C, Sheeladevi S, et al. Newborn vitamin A dosing reduces the case fatality but not incidence of common childhood morbidities in south India.

J Nutr 2007;137:2470-4. PMID:17951487
15. 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;336:1416-20. doi:10.1136/bmj.39542.509444.AE PMID:18558641
16. West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK, Pradhan EK, et al. Mortality of infants

< 6 mo of age supplemented with vitamin A: a randomized, double-masked trial in Nepal. Am J Clin Nutr 1995;62:143-8. PMID:7598058
17. 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. PMID:15699235
18. Tielsch JM. Vitamin A supplements in newborns and child survival.

BMJ 2008;336:1385-6. doi:10.1136/bmj.39575.486609.80 PMID:18558638
19. Benn CS, Fisker AB, Jorgensen MJ, Aaby P. Conflicting evidence for neonatal vitamin A supplementation.

Vaccine 2008;26:4111-2. doi:10.1016/j.vaccine.2008.04.021 PMID:18486284
20. Bhutta ZA, Haider BA, Cousens S, Black RE. Response to conflicting evidence for neonatal vitamin A supplementation (letter) by Benn et al.

Vaccine 2008;26:4304-5. doi:10.1016/j.vaccine.2008.06.007 PMID:18573293
21. Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton L, 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. doi:10.1086/500366 PMID:16479521
22. 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. Geneva: World Health Organization; 2002. Available from: http://www.jhsph.edu/CHN/GlobalVAD.pdf [accessed 2 April 2010].
23. Lau J, Ioannidis JP, Schmid CH. Summing up evidence: one answer is not always enough.

Lancet 1998;351:123-7. doi:10.1016/S0140-6736(97)08468-7 PMID:9439507
24. Laopaiboon M. Meta-analyses involving cluster randomization trials: a review of published literature in health care.

Stat Methods Med Res 2003;12:515- 30. doi:10.1191/0962280203sm347oa PMID:14653354
25. Darlington GA, Donner A. Meta-analysis of community-based cluster randomization trials with binary outcomes.

Clin Trials 2007;4:491-8. doi:10.1177/1740774507083389 PMID:17942465
26. Donner A, Klar N. Issues in the meta-analysis of cluster randomized trials.

Stat Med 2002;21:2971-80. doi:10.1002/sim.1301 PMID:12325113
27. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted?

Stat Med 2002;21:1559-73. doi:10.1002/sim.1187 PMID:12111920
28. World Health Organization.

Global prevalence of vitamin A deficiency in populations at risk 1995–2005: WHO global database on vitamin A deficiency. Geneva: World Health Organization; 2009.
29. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis.

Stat Med 2002;21:1539-58. doi:10.1002/sim.1186 PMID:12111919
30. R Development Core Team.

R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2007.
31. Villamor E, Fawzi WW. Vitamin A supplementation: Implications for morbidity and mortality in children.

J Infect Dis 2000;182;S122-33.
doi:10.1086/315921

32. 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. doi:10.1136/bmj.b919
33. Royston P, Altman D, Sauerbrei W. Dichotomizing continuous predictors in multiple regression: A bad idea.

Stat Med 2006;25:127-41.
doi:10.1002/sim.2331 PMID:16217841

34. Benn CS, Martins C, Rodrigues A, Jensen H, Lisse IM, Aaby P. Randomised study of effect of different doses of vitamin A on childhood morbidity and

mortality. BMJ 2005;331:1428-30. doi:10.1136/bmj.38670.639340.55
PMID:16306060

35. Idindili B, Masanja H, Urassa H, Bunini W, van Jaarsveld P, Aponte JJ, et al. Randomized controlled safety and efficacy trial of 2 vitamin A supplementation schedules in Tanzanian infants.

Am J Clin Nutr 2007;85:1312-9. PMID:17490968
36. Wieringa FT, Dijkhuizen MA, West CE, Thurnham DI. Muhilal, Van der Meer JW. Redistribution of vitamin A after iron supplementation in Indonesian infants.

Am J Clin Nutr 2003;77:651-7. PMID:12600856
37. Schmidt MK, Muslimatun S, West CE, Schultink W, Hautvast JGAJ. Vitamin A and iron supplementation of Indonesian pregnant women benefits vitamin A status of their infants.

Br J Nutr 2001;86:607-15.
doi:10.1079/BJN2001444 PMID:11737959

Table 1.[consult Internet version]