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An ongoing challenge to our ability to address the role of food and nutrition in health promotion and disease prevention is how to design and implement context-specific interventions and guidance that are safe, efficacious, and avoid unintended consequences. The integration to effective implementation (I-to-I) concept is intended to address the complexities of the global health context through engagement of the continuum of stakeholders involved in the generation, translation, and implementation of evidence to public health guidance/programs. The I-to-I approach was developed under the auspices of the Micronutrient Forum and has been previously applied to the question of safety and effectiveness of interventions to prevent and treat nutritional iron deficiency. The present article applies the I-to-I approach to questions regarding the safety and utility of large-dose vitamin A supplementation programs, and presents the authors' perspective on key aspects of the topic, including coverage of the basic and applied biology of vitamin A nutrition and assessment, clinical implications, and an overview of the extant data with regard to both the justification for and utility of available intervention strategies. The article includes some practical considerations based on specific country experiences regarding the challenges of implementing vitamin A-related programs. This is followed by an overview of some challenges associated with engagement of the enabling communities that play a critical role in the implementation of these types of public health interventions. The article concludes with suggestions for potential approaches to move this important agenda forward., (Copyright © American Society for Nutrition 2019.)

Background: Biannual vitamin A supplementation is a well-established survival tool for preschool children 6 months and older in vitamin A deficient populations but this schedule misses the opportunity to intervene on most young infant deaths. Randomised trials of neonatal vitamin A supplementation (NVAS) in the first few days of life to assess its impact on under 6-month mortality in low/middle-income countries have had varying results., Methods: Investigators of 11 published randomised placebo-controlled NVAS trials (n=163 567 children) reanalysed their data according to an agreed plan and pooled the primary outcomes of mortality from supplementation through 6 and 12 months of age using random effects models and meta-regression. One investigator withdrew but allowed use of the data., Findings: Overall there was no effect of NVAS on infant survival through 6 (risk ratio (RR) 0.97; 95% CI 0.89 to 1.06) or 12 months of age (RR 1.00; 95% CI 0.93 to 1.08) but results varied by study population characteristics.NVAS significantly reduced 6-month mortality among the trials conducted in Southern Asia (RR 0.87; 95% CI 0.77 to 0.98), in contexts with moderate or severe vitamin A deficiency (defined as 10% or higher proportion of women with serum retinol <0.7 µmol/L or 5% or more women with night blindness) (RR 0.87; 95% CI 0.80 to 0.94), early infant mortality was 30 or more per 1000 live births (RR 0.91; 95% CI 0.85 to 0.98), 75% or more of infant mortality occurred in the first 6 months of life (RR 0.92; 95% CI 0.84 to 1.01), or where >32% mothers had no schooling (RR 0.88; 95% CI 0.80 to 0.96). NVAS did not reduce mortality in the first 6 months of life in trials conducted in Africa, in contexts characterised by a low prevalence of vitamin A deficiency, lower rates of infant mortality and where maternal education was more prevalent. There was a suggestion of increased infant mortality in trials conducted in Africa (RR 1.07; 95% CI 1.00 to 1.15).Individual-level characteristics such as sex, birth weight, gestational age and size, age at dosing, parity, time of breast feeding initiation, maternal education and maternal vitamin A supplementation did not modify the impact of NVAS., Conclusion: NVAS reduced infant mortality in South Asia, in contexts where the prevalence of maternal vitamin A deficiency is moderate to severe and early infant mortality is high; but it had no beneficial effect on infant survival in Africa, in contexts where the prevalence of maternal vitamin A deficiency is lower, early infant mortality is low., Competing Interests: Competing interests: JMT received grants from USAID, other from Task Force Sight & Life, during the conduct of the study. JK received grants from Bill and Melinda Gates Foundation, USAID, and Task Force Sight and Life, during the conduct of the original study contributing to this pooled analysis. KPW received within the past 3 years an award from the Sight and Life Foundation and DSM to support scholarships and academic activities within the programme in Human Nutrition. DSM has prepared gratis nutrient supplement for research., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We previously compared the potential effects of different intervention strategies for achieving dietary vitamin A (VA) adequacy. The Lives Saved Tool (LiST) permits estimates of lives saved through VA interventions but currently only considers periodic VA supplements (VASs). Objective: We aimed to adapt the LiST method for estimating the mortality impact of VASs to estimate the impact of other VA interventions (e.g., food fortification) on child mortality and to estimate the number of lives saved by VA interventions in 3 macroregions in Cameroon. Methods: We used national dietary intake data to predict the effects of VA intervention programs on the adequacy of VA intake. LiST parameters of population affected fraction and intervention coverage were replaced with estimates of prevalence of inadequate intake and effective coverage (proportion achieving adequate VA intake). We used a model of liver VA stores to derive an estimate of the mortality reduction from achieving dietary VA adequacy; this estimate and a conservative assumption of equivalent mortality reduction for VAS and VA intake were applied to projections for Cameroon. Results: There were 2217-3048 total estimated VA-preventable deaths in year 1, with 58% occurring in the North macroregion. The relation between effective coverage and lives saved differed by year and macroregion due to differences in total deaths, diarrhea burden, and prevalence of low VA intake. Estimates of lives saved by VASs (the intervention common to both methods) were similar with the use of the adapted method (in 2012: North, 743-1021; South, 280-385; Yaoundé and Douala, 146-202) and the "usual" LiST method (North: 697; South: 381; Yaoundé and Douala: 147). Conclusions: Linking effective coverage estimates with an adapted LiST method permits estimation of the effects of combinations of VA programs (beyond VASs only) on child mortality to aid program planning and management. Rigorous program monitoring and evaluation are necessary to confirm predicted impacts., Competing Interests: Author disclosures: RE-S, AP, AC, NW, MJH, SAV, and KHB, no conflicts of interest., (© 2017 American Society for Nutrition.)

Background: Although vitamin A supplementation reduces child mortality, it remains unclear whether dosing frequency, total dose, or duration modifies effectiveness., Objective: Determine whether mortality effects of vitamin A vary by dosing frequency, total dose, or duration., Methods: Meta-analysis of randomized controlled trials, identified by systematic review and expert opinion, utilizing relatively standard World Health Organization doses in children <5 years. Meta-regression evaluated whether mortality effects varied by dosing frequency, total dose, or supplementation duration., Results: Identified 17 trials, including 1,180,718 children, mean (standard deviation [SD]) age 31.5 (15.4) months at baseline. Supplementation frequency ranged every 3 months-every 2 years, supplementation duration 4-60 months (mean = 15.4; SD = 12.8), and total dose 134,361-2,200,000 IU (mean = 667,132 IU; SD = 540,795). Compared with control, vitamin A reduced mortality 22% (95% confidence interval [CI] = 10-32; P = 0.002). This protective effect was not modified by increasing supplementation frequency (dose/year: relative risk [RR] = 1.02; 95% CI = 0.98-1.06; P = .22), total dose (per 200,000 IU: RR = 1.02; 95% CI = 0.97-1.06; P = .31), nor supplementation duration (per year: RR = 1.06; 95% CI = 0.97-1.15; P = 0.14). Multivariate meta-regression showed similar results. Sensitivity analyses excluding 1 controversial trial (Aswathi 2013) did not alter findings., Conclusion: Results confirm benefits of vitamin A supplementation in children <5 years in nations with vitamin A deficiency, without influence of frequency, total dose, or dosing duration within ranges evaluated. These findings inform design and efficiency of vitamin A supplementation policies.

Background: Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. Based on prior evidence and a previous version of this review, the World Health Organization has continued to recommend vitamin A supplementation for children aged 6 to 59 months. There are new data available from recently published randomised trials since the previous publication of this review in 2010, and this update incorporates this information and reviews the evidence., Objectives: To assess the effects of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years., Search Methods: In March 2016 we searched CENTRAL, Ovid MEDLINE, Embase, six other databases, and two trials registers. We also checked reference lists and contacted relevant organisations and researchers to identify additional studies., Selection Criteria: Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation., Data Collection and Analysis: For this update, two reviewers independently assessed studies for inclusion and abstracted data, resolving discrepancies by discussion. We performed meta-analyses for outcomes, including all-cause and cause-specific mortality, disease, vision, and side effects. We used the GRADE approach to assess the quality of the evidence., Main Results: We identified 47 studies (4 of which are new to this review), involving approximately 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most of the studies included equal numbers of girls and boys and lasted about a year. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for vitamin A compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-quality evidence). This result was sensitive to choice of model, and a random-effects meta-analysis showed a different summary estimate (24% reduction: RR 0.76, 95% CI 0.66 to 0.88); however, the confidence intervals overlapped with that of the fixed-effect model. Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 participants; high-quality evidence). There was no significant effect for VAS on mortality due to measles, respiratory disease, and meningitis. VAS reduced incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies; 77,946 participants; low-quality evidence) and measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies; 19,566 participants; moderate-quality evidence). However, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies; 10,541 participants; moderate-quality evidence)., Authors' Conclusions: Vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children. Therefore, we suggest maintaining the policy of universal supplementation for children under five years of age in populations at risk of VAD. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented vitamin A deficiency, it would be unethical to conduct placebo-controlled trials.

Background: Despite evidence for the benefits of vitamin A supplementation (VAS) among children 6 to 59 months of age, the feasibility of introduction and potential benefit of VAS in the neonatal period in public health programmes is uncertain., Objective: The primary objective was to evaluate the feasibility and effectiveness of early neonatal VAS (single dose of 50 000 international units within 48-72 hours after birth) delivered through the public sector Lady Health Worker (LHW) programme in rural Pakistan and to document its association with a reduction in mortality at 6 months of age., Methods: A community-based, cluster randomised, placebo-controlled trial was undertaken in two districts of rural Pakistan. LHWs dispensed vitamin A/placebo in identical capsules to newborn infants within 48-72 hours of birth. Follow-up visits were undertaken at 1 week of age and every 4 weeks thereafter until 6 months of age., Results: Of a total of 15 433 consecutive pregnancies among eligible women of reproductive age, 13 225 pregnancies were registered, 12 218 live births identified and 11 028 newborn infants reached by LHWs. Of these, 5380 (49%) received neonatal VAS and 5648 (51%) placebo. The LHWs successfully delivered the capsules to 79% of newborns within 72 hours of birth with no significant adverse effects. Although the proportion of days observed with symptoms of fever, diarrhoea or rapid breathing were lower with neonatal VAS, these differences were not statistically significant. Mortality rates in the two groups were comparable at 6 months of age., Conclusions: While our study demonstrated that neonatal VAS was safe and could be feasibly delivered by LHWs in Pakistan as part of their early postnatal visits, the overall lack of benefit on neonatal and 6-month morbidity and mortality in our population suggests the need for further evaluation of this intervention in populations at risk., Trial Registration Number: ClinicalTrials.gov NCT00674089., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Vitamin A deficiency is a risk factor for blindness and for mortality from measles and diarrhoea in children aged 6-59 months. We aimed to estimate trends in the prevalence of vitamin A deficiency between 1991 and 2013 and its mortality burden in low-income and middle-income countries., Methods: We collated 134 population-representative data sources from 83 countries with measured serum retinol concentration data. We used a Bayesian hierarchical model to estimate the prevalence of vitamin A deficiency, defined as a serum retinol concentration lower than 0·70 μmol/L. We estimated the relative risks (RRs) for the effects of vitamin A deficiency on mortality from measles and diarrhoea by pooling effect sizes from randomised trials of vitamin A supplementation. We used information about prevalences of deficiency, RRs, and number of cause-specific child deaths to estimate deaths attributable to vitamin A deficiency. All analyses included a systematic quantification of uncertainty., Findings: In 1991, 39% (95% credible interval 27-52) of children aged 6-59 months in low-income and middle-income countries were vitamin A deficient. In 2013, the prevalence of deficiency was 29% (17-42; posterior probability [PP] of being a true decline=0·81). Vitamin A deficiency significantly declined in east and southeast Asia and Oceania from 42% (19-70) to 6% (1-16; PP>0·99); a decline in Latin America and the Caribbean from 21% (11-33) to 11% (4-23; PP=0·89) also occurred. In 2013, the prevalence of deficiency was highest in sub-Saharan Africa (48%; 25-75) and south Asia (44%; 13-79). 94 500 (54 200-146 800) deaths from diarrhoea and 11 200 (4300-20 500) deaths from measles were attributable to vitamin A deficiency in 2013, which accounted for 1·7% (1·0-2·6) of all deaths in children younger than 5 years in low-income and middle-income countries. More than 95% of these deaths occurred in sub-Saharan Africa and south Asia., Interpretation: Vitamin A deficiency remains prevalent in south Asia and sub-Saharan Africa. Deaths attributable to this deficiency have decreased over time worldwide, and have been almost eliminated in regions other than south Asia and sub-Saharan Africa. This new evidence for both prevalence and absolute burden of vitamin A deficiency should be used to reconsider, and possibly revise, the list of priority countries for high-dose vitamin A supplementation such that a country's priority status takes into account both the prevalence of deficiency and the expected mortality benefits of supplementation., Fundin: Bill & Melinda Gates Foundation, Grand Challenges Canada, UK Medical Research Council., (© 2015 World Health Organization; licensee Elsevier. This is an Open Access article published without any waiver of WHO's privileges and immunities under international law, convention, or agreement. This Article should not be reproduced for use in association with the promotion of commercial products, services, or any legal entity. There should be no suggestion that WHO endorses any specific organisation or products. The use of the WHO logo is not permitted. This notice should be preserved along with the Article's original URL.)

Background: Supplementation of vitamin A in children aged 6-59 months improves child survival and is implemented as global policy. Studies of the efficacy of supplementation of infants in the neonatal period have inconsistent results. We aimed to assess the efficacy of oral supplementation with vitamin A given to infants in the first 3 days of life to reduce mortality between supplementation and 180 days (6 months)., Methods: We did an individually randomised, double-blind, placebo-controlled trial of infants born in the Morogoro and Dar es Salaam regions of Tanzania. Women were identified during antenatal clinic visits or in the labour wards of public health facilities in Dar es Salaam. In Kilombero, Ulanga, and Kilosa districts, women were seen at home as part of the health and demographic surveillance system. Newborn infants were eligible for randomisation if they were able to feed orally and if the family intended to stay in the study area for at least 6 months. We randomly assigned infants to receive one dose of 50,000 IU of vitamin A or placebo in the first 3 days after birth. Infants were randomly assigned in blocks of 20, and investigators, participants' families, and data analysis teams were masked to treatment assignment. We assessed infants on day 1 and day 3 after dosing, as well as at 1, 3, 6, and 12 months after birth. The primary endpoint was mortality at 6 months, assessed by field interviews. The primary analysis included only children who were not lost to follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12610000636055., Findings: Between Aug 26, 2010, and March 3, 2013, 31,999 newborn babies were randomly assigned to receive vitamin A (n=15,995) or placebo (n=16,004; 15,428 and 15,464 included in analysis of mortality at 6 months, respectively). We did not find any evidence for a beneficial effect of vitamin A supplementation on mortality in infants at 6 months (26 deaths per 1000 livebirths in vitamin A vs 24 deaths per 1000 livebirths in placebo group; risk ratio 1·10, 95% CI 0·95-1·26; p=0·193). There was no evidence of a differential effect for vitamin A supplementation on mortality by sex; risk ratio for mortality at 6 months for boys was 1·08 (0·90-1·29) and for girls was 1·12 (0·91-1·39). There was also no evidence of adverse effects of supplementation within 3 days of dosing., Interpretation: Neonatal vitamin A supplementation did not result in any immediate adverse events, but had no beneficial effect on survival in infants in Tanzania. These results strengthen the evidence against a global policy recommendation for neonatal vitamin A supplementation., Funding: Bill & Melinda Gates Foundation to WHO., (Copyright © 2015 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd. All rights reserved.)

Background: Vitamin A supplementation in children aged 6 months to 5 years has been shown to reduce mortality. The efficacy of neonatal supplementation with vitamin A to reduce mortality in the first 6 months of life is plausible but not established. We aimed to assess the efficacy of neonatal oral supplementation with vitamin A to reduce mortality between supplementation and 6 months of age., Methods: We undertook an individually randomised, double-blind, placebo-controlled trial in Haryana, India. We identified pregnant women through a surveillance programme undertaken every 3 months of all female residents in two districts of Haryana, India, aged 15-49 years, and screened every identified livebirth. Eligible participants were neonates whose parents consented to participate, were likely to stay in the study area until at least 6 months of age, and were able to feed orally at the time of enrolment. Participants were randomly assigned to receive oral capsules containing vitamin A (retinol palmitate 50,000 IU plus vitamin E 9·5-12·6 IU) or placebo (vitamin E 9·5-12·6 IU) within 72 h of birth. Randomisation was in blocks of 20 according to a randomisation list prepared by a statistician not otherwise involved with the trial. Investigators, participants' families, and the data analysis team were masked to treatment allocation. The primary outcome was mortality between supplementation and 6 months of age. Analysis included all participants assigned to study groups. This trial is registered with ClinicalTrials.gov, number NCT01138449, and the Indian Council of Medical Research Clinical Trial Registry, number CTRI/2010/091/000220., Findings: Between June 24, 2010, and July 1, 2012 we screened 47,777 neonates and randomly assigned 44,984 to receive vitamin A (22,493) or placebo (22,491). Between supplementation and 6 months of age, 656 infants died in the vitamin A group compared with 726 in the placebo group (29·2 per 1000 vs 32·3 per 1000; difference -3·1 per 1000, 95% CI -6·3 to 0·1; risk ratio 0·90, 95% CI 0·81 to 1·00). We noted no significant interactions between the intervention effect and sex on mortality at 6 months (p=0·409). Supplementation with 50,000 IU vitamin A within the first 72 h of life was generally safe and well tolerated, with the exception of a small excess risk of transient bulging fontanelle (205 cases in the vitamin A group confirmed by physician vs 80 cases in the placebo group, risk ratio 2·56 [95% CI 1·98-3·32])., Interpretation: The findings of this study, done in a population in which vitamin A deficiency is a moderate public health problem, are consistent with a modest reduction in mortality between supplementation and 6 months of age. These findings must be viewed together with similar trials in other populations to enable determination of appropriate public health policy., Funding: Bill & Melinda Gates Foundation to WHO., (Copyright © 2015 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd. All rights reserved.)

Background: Results of randomised controlled trials of newborn (age 1-3 days) vitamin A supplementation have been inconclusive. The WHO is coordinating three large randomised trials in Ghana, India, and Tanzania (Neovita trials). We present the findings of the Neovita trial in Ghana., Methods: This study was a population-based, individually randomised, double-blind, placebo-controlled trial in the Brong Ahafo region of Ghana. The trial participants were infants aged at least 2 h, identified at home or facilities on the day of birth or in the next 2 days, able to feed orally, and likely to stay in the study area for at least 6 months. They were randomly assigned (ratio 1:1) to receive either one oral dose of vitamin A (50,000 IU) or placebo immediately after recruitment. The research team and parents of the infants were masked to treatment assignment. Follow-up home visits were undertaken every 4 weeks, when data were recorded for deaths, facility use, and care seeking. The primary outcome was post-supplementation mortality to 6 months of age. Analysis was by intention to treat. Potential adverse events were recorded at 1 and 3 days after supplementation. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR)CTRN12610000582055., Findings: We assessed 26,414 livebirths for eligibility between Aug 16, 2010, and Nov 7, 2011. We recruited 22,955 newborn infants, with 11,474 randomly assigned to receive vitamin A and 11,481 to receive placebo. Loss to follow-up was low with vital status at 6 months of age reported for 22,698 (98·9%) infants. We recorded 278 post-supplementation deaths to 6 months of age in the vitamin A group (mortality risk 24·5 in 1000 supplemented infants) and 248 deaths in the placebo group (mortality risk 21·8 per 1000 supplemented infants), relative risk (RR) 1·12 (95% CI 0·95-1·33; p=0·183) and risk difference (RD) 2·66 (95% CI -1·25 to 6·57; p=0·18). Adverse events within 3 days of supplementation did not differ by trial group. 122 infants died in the first 3 days after supplementation; 70 (0·6%) in the vitamin A and 52 (0·5%) in the placebo group (risk ratio [RR] 1·35, 95% CI 0·94-1·93, p=0·102). 53 infants were reported to have a bulging fontanelle; 32 (0·3%) in the vitamin A group and 21 (0·2%) in the placebo group (RR 1·53, 0·88-2·62, p=0·130)., Interpretation: The results of this trial do not support inclusion of newborn vitamin A supplementation as a child survival strategy in Ghana., Funding: Bill & Melinda Gates Foundation grant to the WHO., (Copyright © 2015 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd. All rights reserved.)

WHO recommends high-dose vitamin A supplementation (VAS) to children from 6 months to 5 years of age in low-income countries, in order to prevent and treat vitamin A deficiency-associated morbidity and mortality. The current policy does not discriminate this recommendation either by sex or vaccination status of the child. There is accumulating evidence that the effects of VAS on morbidity, mortality and immunological parameters depend on concomitant vaccination status. Moreover, these interactions may manifest differently in males and females. Certain vaccines administered through the Expanded Program on Immunization have been shown to alter all-cause mortality from infections other than the vaccine-targeted disease. This review summarizes the evidence from observational studies and randomized-controlled trials of the effects of VAS on these so-called heterologous or non-specific effects of vaccines, with a focus on sex differences. In general, VAS seems to enhance the heterologous effects of vaccines, particularly for diphtheria-tetanus-pertussis and live measles vaccines, where some studies, although not unanimously, show a stronger interaction between VAS and vaccination in females. We suggest that vaccination status and sex should be considered when evaluating the effects of VAS in early life., (© The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Preventive vitamin A supplementation (VAS) is an essential child survival intervention. In India, VAS program coverage has remained relatively low, with wide interstate variation., Objective: To review the VAS program in India, particularly in Bihar and Odisha, the two states that have had the most successful VAS programs, to define best practices and identify critical success factors., Methods: A thorough review of existing relevant literature was carried out, supplemented by field visits and interviews with selected partners., Results: Both states have adopted a biannual approach to reach out to children 1 to 5 years of age with VAS every 6 months, while infants below 1 year of age receive their first VAS dose with the measles immunization at 9 months. The critical success factors for the VAS program in the two states include strong leadership and ownership by the state government; close coordination between the two departments that are involved in the VAS program; effective microplanning prior to each biannual round; flexible dosing mechanisms that enhance coverage in hard-to-reach areas; a stable procurement and distribution mechanism to ensure an adequate, timely, and sustainable supply of VAS; intensive social mobilization and communication; and appropriate training and supervision of staff., Conclusions: The governments of Bihar and Odisha have demonstrated that it is feasible to implement a successful and inclusive VAS program in India. The challenge now is to reach out to the remaining 30% to 40% of children who are undoubtedly the hardest to reach and potentially the most vulnerable.

Purpose: Vitamin A deficiency is among major health problems worldwide that leads to blindness, retarded growth and death, particularly in developing countries. In these countries, vitamin A deficiency largely affects pre-school children, pregnant and lactating mothers, and the rural poor. For instance, the predicted prevalence of vitamin A deficiency for 36 sub-Saharan African countries is 19.1%., Methods: Different strategies, including vitamin A supplementation, food fortification and dietary diversification, have been used to combat this problem. However, these strategies are not sustainable due to their high costs., Results: Orange-fleshed sweet potato (Ipomoea batatas L. Lam) is a low priced crop, which is part of staple foods in most of sub-Saharan Africa that can be a year-round source of vitamin A. Most of the orange-fleshed sweet potato varieties contain 3000-16000 μg 100 g(-1) of β-carotene and this contributes to 250 to 1300 μg 100 g(-1) Retinol Activity Equivalents (RAE). Therefore, by using orange-fleshed sweet potato, it is possible to improve vitamin A status, increase the bio-availability of different micro-nutrients such as Fe, Zn, Ca and Mg, reduce vitamin A deficiency and hence reduce child mortality rates by 23 to 30%., Conclusion: The article highlights the significance of vitamin A for human nutrition, the effect of vitamin A deficiency, the different prevention methods and the potential of orange- fleshed sweet potato as a food crop to prevent vitamin A deficiency.

Background: In north India, vitamin A deficiency (retinol <0·70 μmol/L) is common in pre-school children and 2-3% die at ages 1·0-6·0 years. We aimed to assess whether periodic vitamin A supplementation could reduce this mortality., Methods: Participants in this cluster-randomised trial were pre-school children in the defined catchment areas of 8338 state-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks (clusters) were cluster-randomly allocated in Oxford, UK, between 6-monthly vitamin A (retinol capsule of 200,000 IU retinyl acetate in oil, to be cut and dripped into the child's mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of retinol effects are by block (36 vs 36 clusters). The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6-72 months. Annually, one centre per block was randomly selected and visited by a study team 1-5 months after any trial vitamin A to sample blood (for retinol assay, technically reliable only after mid-study), examine eyes, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100,000 visits, 25,000 deaths at ages 1·0-6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547., Findings: Estimated compliance with 6-monthly retinol supplements was 86%. Among 2581 versus 2584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0·72 [SE 0·01] vs 0·62 [0·01] μmol/L, increase 0·10 [SE 0·01] μmol/L) and the prevalence of severe deficiency was halved (retinol <0·35 μmol/L 6%vs 13%, decrease 7% [SE 1%]), as was that of Bitot's spots (1·4%vs 3·5%, decrease 2·1% [SE 0·7%]). Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0-6·0 years during the 5-year study were 3·01 retinol versus 3·15 control (absolute reduction 0·14 [SE 0·11], mortality ratio 0·96, 95% CI 0·89-1·03, p=0·22), suggesting absolute risks of death between ages 1·0 and 6·0 years of approximately 2·5% retinol versus 2·6% control. No specific cause of death was significantly affected., Interpretation: DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20-30%, but cannot rule out some more modest effect. Meta-analysis of DEVTA plus eight previous randomised trials of supplementation (in various different populations) yielded a weighted average mortality reduction of 11% (95% CI 5-16, p=0·00015), reliably contradicting the hypothesis of no effect., Funding: UK Medical Research Council, USAID, World Bank (vitamin A donated by Roche)., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The present thesis is based on 11 papers from 1995-2010. The studies have mainly taken place at the Bandim Health Project in Guinea-Bissau, West Africa, but a reanalysis of a randomised trial from Ghana is also included. My research has explored the consequences of combining high-dose vitamin A supplementation and childhood vaccines. Vitamin A deficiency is associated with increased mortality. To protect against the consequences of vitamin A deficiency the World Health Organization recommends that high-dose vitamin A supplements be given together with routine vaccines to children between 6 months and 5 years of age in more than 100 low-income countries. The recommendation is based on logistical considerations. The consequences of combining vitamin A and vaccines were not investigated in randomised trials prior to the implementation of this policy - it was assumed that the interventions were independent. My first project aimed to study the effect on the immune response to measles of providing vitamin A together with measles vaccine. We found that the two interventions were not independent. Vitamin A enhanced the antibody response to measles vaccine given at 9 months of age significantly, especially in boys. The effects were sustained over time; the children who had received vitamin A with their measles vaccine were more protected against measles at 6-8 years of age. Though vitamin A supplementation had a beneficial effect on the immune response to measles vaccine, it intrigued me that the effect of vitamin A supplementation on overall mortality was not always beneficial. While vitamin A was beneficial when given after 6 months of age, and two studies had shown a beneficial effect when given at birth, all studies testing the effect between 1-5 months of age had found no effect. These time windows are dominated by three different childhood vaccines: BCG vaccine given at birth, diphtheria-tetanus-pertussis (DTP) vaccine given between 1-5 months of age, and measles vaccine given at 9 months of age. These vaccines have been shown to have strong effects on mortality from infectious diseases in general, so-called non-specific effects. The live BCG and measles vaccine protects against more mortality than can be ascribed to the prevention of tuberculosis and measles, respectively. The inactivated DTP vaccine worryingly has been associated with increased mortality from other infectious diseases. Both positive and negative effects are strongest for girls. I proposed the hypothesis that vitamin A amplifies not only the specific vaccine effects, as we saw for measles vaccine, but also the non-specific effects of vaccines on mortality from other infectious diseases. According to my hypothesis, vitamin A would enhance the non-specific beneficial effects on mortality of BCG and measles vaccine, but also the negative effects of DTP vaccine. Hence, the hypothesis offered an explanation for the mortality-age pattern after vitamin A supplementation. Since it was formulated, I have aimed to test this hypothesis. Since it is associated with ethical problems to randomise children above 6 months of age to vitamin A supplementation, and to randomise children in general to recommended vaccines, we have had to be pragmatic when designing the trials. Hence, our studies have taken many different forms. We conducted an observational study during a vitamin A campaign in which missing vaccines were also provided, and a randomised trial testing the effect of two different doses of vitamin A during another campaign; we tested the effect of providing vitamin A with BCG at birth in two randomised trials, and we reanalysed data from one of the original randomised trials of vitamin A supplementation from the perspective of vaccination status. In all studies the main outcome was mortality. The results document that vitamin A supplements do more than protect against vitamin A deficiency. They support the hypothesis that vitamin A supplements interact with vaccines with important consequences for mortality. First, a smaller dose of vitamin A was more beneficial than a larger dose for girls. Second, the effect of vitamin A given with DTP vaccine was significantly different from the effect of vitamin A given with measles vaccine, and children, who received vitamin A with DTP vaccine, had higher mortality than children, who had received vitamin A alone, or who did not receive anything. Third, vitamin A given with BCG at birth interacted negatively with subsequent DTP vaccines in girls. Fourth, the effect of vitamin A to older children in Ghana depended on vaccination status, being beneficial in boys, but harmful in girls who received DTP vaccine during follow-up. The results also show that boys and girls respond differently to vitamin A and vaccines. It is a common assumption within public health in low-income countries that interventions can be combined without producing unexpected consequences. The work presented in this thesis confronts this assumption; the results show that vitamin A and vaccines should be seen not only as specific interventions with specific and independent effects, but as immuno-modulators, which can interact with important consequences for overall mortality. Combining interventions can be convenient and lead to synergistic health benefits, but we documented several examples, where it also leads to unexpectedly increased mortality. Thus, to optimise the child health intervention policy in low-income countries a shift in paradigm is needed. Health interventions should no longer be seen as merely specific and independent, and the policy should probably not be the same for boys and girls. Though more complex, it is necessary to evaluate all health interventions in terms of their effect on overall mortality - and their potential interactions with other health interventions and potential sex-differential effects should always be investigated. Only in this way can we assure that the children in the poorest countries get the best possible treatment and avoid using large amounts of money and resources on interventions which may, in worst case, kill them.

Deficiencies of multiple micronutrients are prevalent among women of reproductive age and young children, and represent a risk factor for increased morbidity and mortality in these women and children. The role of multiple micronutrient supplementation during pregnancy and early childhood has been evaluated in randomized trials. Multiple micronutrient supplementation during pregnancy has a positive effect on birthweight and reduces prevalence of low birthweight and small for gestational age babies. It had comparable effects on prevalence of anemia regarding iron-folate supplementation. Multiple micronutrient supplementations in children have been shown to improve linear growth, weight, hemoglobin, serum zinc, serum retinol levels and motor development. Some of the most commonly used strategies to deliver multiple micronutrients include powders (e.g. Sprinkles(®)), crushable tablets (e.g. Foodlets), etc. Multiple micronutrient supplementation during pregnancy and early childhood seems to be an effective way of prevention of micronutrient deficiencies and has a significant protective effect against adverse outcomes related to their deficiencies. Their use on a larger scale should be considered to improve the survival and decrease morbidity and mortality in children and women., (Copyright © 2012 S. Karger AG, Basel.)

Maternal mortality, low birthweight infants and childhood stunting continue to be major global public health problems, part of a recurring cycle of disadvantage. Maternal undernutrition in particular is one of the most neglected aspects of nutrition in public health. One possible low-cost public health intervention that might help address these problems is the antenatal provision of multiple micronutrient supplements. If the evidence base could be established, cost-effectiveness found to be acceptable and safety ensured, supplementation could ameliorate the impact of poor nutrition and diets, high disease burdens and the sociocultural factors contributing to these problems. There have been good studies in over a dozen countries addressing some of these issues but with conflicting results. Consequently, at least three meta-analyses have been undertaken to establish significant findings that could help guide policies and programs. They concluded that multimicronutrient supplementation improves birthweight and likely reduces the number of infants born low birthweight. Supplementation with iron-folic acid or multimicronutrients also appears to have positive longer-term impacts on the health and development of the offspring. There remain concerns about possible increased infant mortality in some populations. Given the results of the meta-analyses, cautious scaling-up of country effectiveness trials appears justified with careful monitoring and evaluation., (Copyright © 2012 S. Karger AG, Basel.)

Background: Vitamin A deficiency is a significant public health problem in low and middle income countries. Vitamin A supplementation (VAS) provided to lactating postpartum mothers or to infants less than six months of age are two possible strategies to improve the nutrition of infants at high risk of vitamin A deficiency and thus potentially reduce their mortality and morbidity., Objectives: To evaluate the effect of:1. VAS in postpartum breast feeding mothers in low and middle income countries, irrespective of antenatal VAS status, on mortality, morbidity and adverse effects in their infants up until the age of one year.2. VAS initiated in the first half of infancy (< 6 months of age) in low and middle income countries, irrespective of maternal antenatal or postnatal VAS status, on mortality, morbidity and adverse effects up until the age of one year., Search Strategy: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), EMBASE, MEDLINE, clinical trials websites, conference proceedings, donor agencies, 'experts' and researchers (up to October 15, 2010)., Selection Criteria: Randomized or quasi-randomised, individually or cluster randomised, placebo controlled trials involving synthetic VAS provided to the postpartum mothers or their infants up to the age of six months were eligible., Data Collection and Analysis: Two review authors assessed the studies for their risk of bias and collected data on outcomes., Main Results: Of the 18 included studies, eight provided information on maternal VAS and 15 on infant VAS.For maternal VAS, there was no evidence of a reduced risk of mortality of their babies during infancy (96,203 participants, seven studies, high quality evidence; random-effects model RR 1.00, 95% CI 0.94 to 1.06, P = 0.9; test of heterogeneity I(2) = 0%, P = 0.9) or in the neonatal period (moderate quality evidence); nor of morbidities (very low quality evidence).  For infant VAS, there was no evidence of a reduced risk of mortality during infancy (59,402 participants, nine studies, moderate quality evidence; random-effects model RR 0.97, 0.83 to 1.12, P = 0.65; test of heterogeneity I(2) = 49%, P = 0.05) or in the neonatal period, nor morbidities (low quality evidence), but an increased risk of bulging fontanelle (32,978 participants, 10 studies, low quality evidence; random-effects model RR 1.55, 1.05 to 2.28, P = 0.03; test of heterogeneity I(2) = 68%, P = 0.0009)., Authors' Conclusions: There is no convincing evidence that either maternal postpartum or infant vitamin A supplementation results in a reduction in infant mortality or morbidity in low and middle income countries.

Background: Vitamin A deficiency (VAD) is a major public health problem in low and middle income countries affecting 190 million children under 5. VAD can lead to many adverse health consequences, including death., Objectives: To evaluate the effect of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged 6 months to 5 years., Search Strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2010 Issue 2),  MEDLINE (1950 to April Week 2 2010), EMBASE (1980 to 2010 Week 16), Global Health (1973 to March 2010), Latin American and Caribbean Health Sciences (LILACS), metaRegister of Controlled Trials and African Index Medicus (27 April 2010)., Selection Criteria: Randomised controlled trials (RCTs) and cluster RCTs evaluating the effect of synthetic VAS in children aged 6 months to 5 years living in the community. We excluded studies concerned with children in hospital and children with disease or infection. We excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods or beta-carotene supplementation., Data Collection and Analysis: Two review authors independently assessed studies for inclusion. Data were double abstracted and discrepancies were resolved by discussion. Meta-analyses were performed for outcomes including all-cause and cause-specific mortality, disease, vision, and side-effects., Main Results: 43 trials involving 215,633 children were included. A meta-analysis for all-cause mortality included 17 trials comprising 194,795 children with 3536 deaths in both groups. At follow-up, there was a 24% observed reduction in the risk of all-cause mortality for Vitamin A compared with Control (Relative risk (RR) = 0.76 [95% confidence interval (CI) 0.69, 0.83]). Seven trials reported diarrhoea mortality and a 28% overall reduction for VAS (RR = 0.72 [0.57, 0.91]). There was no significant effect of VAS on cause specific mortality of measles, respiratory disease and meningitis. VAS reduced incidence of diarrhoea (RR = 0.85 [0.82, 0.87]) and measles morbidity (RR = 0.50 [0.37, 0.67]); however, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR = 2.75 [1.81, 4.19])., Authors' Conclusions: VAS is effective in reducing all-cause mortality by about 24% compared to no treatment. In our opinion, given the evidence that VAS causes considerable reduction in child mortality, further placebo-controlled trials of VAS in children between 6 months and 5 years of age are not required. There is a need for further studies comparing different doses and delivery mechanisms (for example, fortification).

Background: Twenty-eight percent of Ugandan preschool children suffer from vitamin A deficiency. With vitamin A supplementation covering only a third of children under 5 years of age, fortification is essential to reduce their vitamin A deficiency-related disease burden. At present, the only widely consumed food in Uganda that is fortified with vitamin A is vegetable oil., Objective: To compare the feasibility, coverage, costs, and cost-effectiveness of fortifying vegetable oil and sugar with vitamin A in order to assess, from a public health policy perspective, whether sugar should also be fortified., Methods: The 2005/6 Uganda Household Budget Survey was used to analyze households' apparent consumption levels of sugar and vegetable oil and to model the additional intake of vitamin A, assuming the sugar and oil fortification levels are those set by the Uganda Bureau of Standards., Results: The annual incremental private sector cost of vitamin fortification is US $555,668 for oil and US $2,644,765 for sugar. Assuming that oil and sugar fortification are both effective in reducing vitamin A deficiency by 30% among those who consume these foods, the estimated cost per disability-adjusted life year (DALY) averted is US $82 for sugar and US $18 for oil. Vitamin Afortification of vegetable oil is 4.6 times more cost-effective than vitamin A fortification of sugar. If sugar were to be fortified, the 17% of Ugandans who purchase sugar but do not purchase oil would become new beneficiaries of vitamin A fortification. This would increase the coverage of vitamin A-fortified foods by 31% and reduce the percentage of Ugandans without any coverage to 25%. Those most at risk for vitamin A deficiency-members of rural, poor households-would benefit disproportionately from the introduction of sugar fortification., Conclusions: Although the lack of information on the vitamin A deficiency status of consumers of oil and sugar precludes making definitive conclusions, the increased coverage and cost per DALY averted due to sugar fortification suggests-based on World Health Organization guidelines-that the Government of Uganda should pursue sugar fortification.

Objective: To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates., Design: Randomised, placebo controlled, two by two factorial trial., Setting: Bissau, Guinea-Bissau., Participants: 1717 low birthweight neonates born at the national hospital., Intervention: Neonates who weighed less than 2.5 kg were randomly assigned to 25 000 IU vitamin A or placebo, as well as to early BCG vaccine or the usual late BCG vaccine, and were followed until age 12 months., Main Outcome Measure: Mortality, calculated as mortality rate ratios (MRRs), after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo., Results: No interaction was observed between vitamin A supplementation and BCG vaccine allocation (P=0.73). Vitamin A supplementation at birth was not significantly associated with mortality: the MRR of vitamin A supplementation compared with placebo, controlled for randomisation to "early BCG" versus "no early BCG" was 1.08 (95% CI 0.79 to 1.47). Stratification by sex revealed a significant interaction between vitamin A supplementation and sex (P=0.046), the MRR of vitamin A supplementation being 0.74 (95% CI 0.45 to 1.22) in boys and 1.42 (95% CI 0.94 to 2.15) in girls. When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau, the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 (95% CI 0.87 to 1.33); 0.80 (95% CI 0.58 to 1.10) in boys and 1.41 (95% CI 1.04 to 1.90) in girls (P=0.01 for interaction between neonatal vitamin A and sex)., Conclusions: The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that, overall, it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau. Worryingly, the trials show that vitamin A supplementation at birth can be harmful in girls. Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects. Trial registration ClinicalTrials.gov NCT00168610.

Objective: To determine the cause of exceptionally high mortality (41.4%) in perinatal calves on a beef cattle property 50 km south-west of Julia Creek in north-western Queensland., Design: Investigations were based on clinical assessment of affected calves and laboratory analysis of pre- and postmortem specimens taken from 12 calves aged from 6 to 36 h of age., Methods: Associations between gross and histopathological findings and biochemical analyses conducted on serum and tissue samples were examined in relation to clinical observations., Results: Clinical signs varied, but commonly included mild to severe ataxia, difficulty finding a teat and sucking, blindness (partial or complete, as judged by avoidance of obstacles) and depression with prominent drooping of the head. Gross and histopathological findings included herniation of the cerebellar vermis through the foramen magnum, squamous metaplasia of interlobular ducts in the parotid salivary glands and Wallerian degeneration of the optic nerves. Biochemical analysis of serum and liver samples available from four of the calves revealed low or undetectable levels of both vitamin A and vitamin E., Conclusion: Although vitamin E is known to have a sparing effect on vitamin A, the role (if any) played by deficiency of this vitamin was uncertain. The combination of clinical signs, postmortem findings, histopathological features and biochemical findings indicate that gestational vitamin A deficiency was highly likely to have been an important contributor to perinatal calf mortalities in this herd.

Background: In vitamin A-deficient populations, children hospitalized with infections and/or malnutrition are at particular risk of developing severe vitamin A (VA) deficiency. High-dose VA supplements are recommended as part of the treatment but results on its effect on recovery from morbidity and on prevention from nosocomial morbidity are conflicting., Objective: We aimed to assess the effect of a single high dose and daily low dose of VA on hospitalized malnourished children's morbidity., Design: We carried out a double-blind, randomized trial in 604 and 610 Senegalese hospitalized children. The first mentioned batch received a high-dose VA supplement (200,000 IU) on admission, the second a daily low-dose VA supplement (5000 IU per day) during hospitalization. Children were followed up until discharged. Data on all-cause morbidity were collected daily., Results: Survival analysis showed that the incidence of respiratory disease was significantly lower in the low-dose group than in the high-dose group, hazard ratios (HR): 0.26, 95% CI: 0.07-0.92. The duration of respiratory infection was also significantly lower in the low-dose group than in the high-dose group (HR of cure: 1.41, 95% CI: 1.05-1.89). Duration and incidence of diarrhoea were not significantly different between treatment groups. In children with oedema on admission, mortality was significantly lower in the low-dose group (Adjusted odds ratio: 0.21; 95% CI: 0.05-0.99)., Conclusions: Daily low dose of VA compared with single high dose significantly reduced duration and incidence of respiratory infection but not of diarrhoea in hospitalized children.

We consider the problem of estimating covariate effects in the marginal Cox proportional hazard model and multilevel associations for child mortality data collected from a vitamin A supplementation trial in Nepal, where the data are clustered within households and villages. For this purpose, a class of multivariate survival models that can be represented by a functional of marginal survival functions and accounts for hierarchical structure of clustering is exploited. Based on this class of models, an estimation strategy involving a within-cluster resampling procedure is proposed, and a model assessment approach is presented. The asymptotic theory for the proposed estimators and lack-of-fit test is established. The simulation study shows that the estimates are approximately unbiased, and the proposed test statistic is conservative under extremely heavy censoring but approaches the size otherwise. The analysis of the Nepal study data shows that the association of mortality is much greater within households than within villages.

Background: Vitamin A supplementation reduces morbidity and mortality in children living in areas endemic for vitamin A deficiency. Routine vitamin A supplementation usually starts only at age 9 mo, but high rates of illness and mortality are seen in the first months of life., Objective: The objective of the study was to evaluate the safety and efficacy of vitamin A supplementation at the same time as routine vaccination in infants aged 1-3 mo., Design: We recruited 780 newborn infants and their mothers to a randomized double-blind controlled trial in Ifakara in southern Tanzania. In one group, mothers received 60,000 microg vitamin A palmitate shortly after delivery, and their infants received 7500 microg at the same time as vaccinations given at approximately 1, 2, and 3 mo of age. In the other group, mothers received a second 60,000-microg dose when their infant was aged 1 mo, and their infants received 15,000 microg at the same time as the routine vaccinations. VAD was defined as a modified relative dose-response test result of >or=0.060., Results: High-dose vitamin A supplementation was well tolerated. The relative risk of VAD at 6 mo in the high-dose group compared with the lower dose group was 0.91 (95% CI: 0.76, 1.09; P=0.32). Serum retinol and incidence of illness did not differ significantly between the 2 groups. Some vitamin A capsules degraded toward the end of the study., Conclusions: Doubling the doses of vitamin A to mothers and their young infants is safe but unlikely to reduce short-term morbidity or to substantially enhance the biochemical vitamin A status of infants at age 6 mo. The stability of vitamin A capsules merits further investigation.

Six pairs of alipochromatic ('recessive-white') canaries (Serinus canaria) and six pairs of coloured canaries were kept through a complete breeding cycle while being fed a diet providing 12,000 iu vitamin A/kg. The eggs of three pairs (one recessive-white and two coloured) were all unfertilised and there were only 23 hatchlings (14 recessive-white and nine coloured), of which 14 (10 recessive-white and four coloured) were alive after the first moult. However, there was no clinical, biochemical or pathological evidence that the recessive-white canaries were suffering from vitamin A deficiency or that the coloured canaries were suffering from vitamin A toxicity, suggesting that the diet met the vitamin A requirements of both groups.

Background: Low maternal serum retinol level is a risk factor for mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). Multiple-large-dose vitamin A supplementation of HIV-positive children reduces mortality. The World Health Organization recommends single-large-dose vitamin A supplementation for postpartum women in areas of prevalent vitamin A deficiency; neonatal dosing is under consideration. We investigated the effect that single-large-dose maternal/neonatal vitamin A supplementation has on MTCT, HIV-free survival, and mortality in HIV-exposed infants., Methods: A total of 14,110 mother-infant pairs were enrolled < or =96 h after delivery, and both mother and infant, mother only, infant only, or neither received vitamin A supplementation in a randomized, placebo-controlled trial with a 2 x 2 factorial design. All but 4 mothers initiated breast-feeding. A total of 4495 infants born to HIV-positive women were included in the present analysis., Results: Neither maternal nor neonatal vitamin A supplementation significantly affected postnatal MTCT or overall mortality between baseline and 24 months. However, the timing of infant HIV infection modified the effect that supplementation had on mortality. Vitamin A supplementation had no effect in infants who were polymerase chain reaction (PCR) positive [corrected] for HIV at baseline. In infants who were PCR negative at baseline and PCR positive at 6 weeks, neonatal supplementation reduced mortality by 28% (P=.01), but maternal supplementation had no effect. In infants who were PCR negative at 6 weeks, all 3 vitamin A regimens were associated with ~2-fold higher mortality (P< or =.05)., Conclusions: Targeted vitamin A supplementation of HIV-positive children prolongs their survival. However, postpartum maternal and neonatal vitamin A supplementation may hasten progression to death in breast-fed children who are PCR negative at 6 weeks. These findings raise concern about universal maternal or neonatal vitamin A supplementation in HIV-endemic areas.

Background: Children with vitamin A deficiency have higher risk of morbidity and mortality than vitamin A-sufficient children. Estimates on the potential child survival benefits of vitamin A deficiency control are needed for policy and program advocacy., Objective: To determine the current prevalence of children at risk for vitamin A deficiency in sub-Saharan Africa in order to estimate the potential child-survival benefits of effective and sustained policies and programs for the control of vitamin A deficiency in this region., Methods: Estimates of the prevalence of vitamin A deficiency generated in 1998, data from 11 nationally representative vitamin A deficiency surveys conducted in sub-Saharan Africa between 1997 and 2003, and the measured effects of vitamin A deficiency on child mortality were combined to estimate the prevalence of children at risk for vitamin A deficiency in sub-Saharan Africa and the potential child-survival benefits of effective and sustained policies and programs for the control of vitamin A deficiency in this region., Results: Our analysis shows that in the absence of effective and sustained policies and programs for the control of vitamin A deficiency, an estimated 42.4% of children 0 to 59 months of age in sub-Saharan Africa (43.2 million children) are at risk for vitamin A deficiency. Such effective and sustained policy and program action for the control of vitamin A deficiency can bring about a potential 25% reduction in mortality in children 0 to 59 months with respect to 1995 mortality levels (i.e., before the onset of large-scale vitamin A supplementation programs in sub-Saharan Africa)., Conclusions: Effective and sustained control of vitamin A deficiency has the potential to be among the most cost-effective and high-impact child-survival interventions in sub-Saharan Africa. A stronger political commitment and a more appropriate level of investment in the effective control of vitamin A deficiency could make a large contribution toward the attainment of the Millennium Development Goal for the reduction of child mortality rates by two-thirds between 1990 and 2015. Among the many challenges that Africa will need to face in the coming years, vitamin A deficiency is one that can be overcome. The need is urgent, and the solutions are known, effective, and affordable.

Background: Measles is a major cause of childhood morbidity and mortality. Vitamin A deficiency is a recognized risk factor for severe measles infections. The World Health Organization (WHO) recommends administration of an oral dose of vitamin A (200,000 international units (IU), or 100,000 IU in infants) each day for two days to children with measles when they live in areas where vitamin A deficiency may be present., Objectives: To determine whether vitamin A therapy, commenced after measles has been diagnosed, is beneficial in preventing mortality, pneumonia and other secondary complications in children., Search Strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to March 2005), EMBASE (1980 to December 2004) and looked for unpublished studies., Selection Criteria: Only randomized controlled trials in which children with measles were given vitamin A or placebo along with standard treatment were considered., Data Collection and Analysis: Studies were assessed independently by two authors. The analysis of dichotomous outcomes was done using the StatXact software and results expressed as relative risk (RR) with 95% confidence interval (CI). Subgroup analyses were carried out for dose, formulation, age, hospitalization and pneumonia-specific mortality. Weighted mean differences (WMD) with 95% CI were calculated for continuous outcomes., Main Results: There was no significant reduction in the risk of mortality in the vitamin A group when all the studies were pooled using the random-effects model (RR 0.70; 95% CI 0.42 to 1.15). Using two doses of vitamin A (200,000 IU) on consecutive days was associated with a reduction in the risk of mortality in children under the age of two years (RR 0.18; 95% CI 0.03 to 0.61) and a reduction in the risk of pneumonia-specific mortality (RR 0.33; 95% CI 0.08 to 0.92). There was no evidence that vitamin A in a single dose was associated with a reduced risk of mortality among children with measles. There was a reduction in the incidence of croup (RR 0.53; 95% CI 0.29 to 0.89) but no significant reduction in the incidence of pneumonia (RR 0.92; 95% CI 0.69 to 1.22) or diarrhoea (RR 0.80; 95% CI 0.27 to 2.34) with two doses., Authors' Conclusions: Although we found no overall significant reduction in mortality with vitamin A therapy for children with measles there was evidence that two doses were associated with a reduced risk of mortality and pneumonia-specific mortality in children under the age of two years. There were no trials that directly compared a single dose with two doses.

Clustered failure time data are commonly encountered in biomedical research where the study subjects from the same cluster (e.g., family) share the common genetic and/or environmental factors such that the failure times within the same cluster are correlated. Two approaches that are commonly used to account for the intra-cluster association are frailty models and marginal models. In this paper, we study the marginal proportional hazards model, where the structure of dependence between individuals within a cluster is unspecified. An estimation procedure is developed based on a pseudo-likelihood approach, and a risk set sampling method is proposed for the formulation of the pseudo-likelihood. The asymptotic properties of the proposed estimators are studied, and the related issues regarding the statistical efficiencies are discussed. The performances of the proposed estimator are demonstrated by the simulation studies. A data example from a child vitamin A supplementation trial in Nepal (Nepal Nutrition Intervention Project-Sarlahi, or NNIPS) is used to illustrate this methodology.

In 1997, the reduction of child mortality became a policy priority for the Government of Niger because Niger's child mortality rate was the highest in the world. The Ministry of Public Health, Helen Keller International (HKI), and UNICEF spearheaded a coalition-building process linking vitamin A deficiency (VAD) control to national child survival goals. An evidence-based advocacy strategy was developed around the child survival benefits of adequate and sustained VAD control with one unambiguous message: "VAD control can avert over 25,000 child deaths per year." As a result, in 1997 Niger became one of the first countries in Africa to effectively integrate vitamin A supplementation into National Immunization Days (NIDs) for polio eradication. The challenge was then to provide children with a second annual dose of vitamin A. This led in 1999 to the first ever National Micronutrient Days (NMDs) in Africa. NMDs are mobilization campaigns in which caregivers are actively encouraged to take their children for the delivery of vitamin A supplements. Since 1999, the combination of NIDs and NMDs has ensured that over 80% of children 6 to 59 months of age receive two vitamin A doses annually. The success of NIDs/NMDs has relied on five pillars: leadership and ownership by the Ministry of Public Health; district-level planning and implementation; effective training and flexible delivery mechanisms; effective social information, communication, and mobilization; and responsiveness and flexibility of Ministry of Public Health and development partners. This successful approach has been widely disseminated, notably through the West African Nutrition Focal Points Network.

Background: In areas where vitamin A deficiency (VAD) is prevalent, vitamin A repletion reduces child mortality by 23% on average., Objectives: To estimate the potential child survival benefits of policies and programmes aimed at controlling VAD in Mozambique, and to make policy and programme recommendations., Methods: The potential contribution of VAD to child mortality in Mozambique was estimated by combining the observed VAD prevalence in the under-5s (71.2%), the measured child mortality effects of VAD (risk of death in children with VAD=1.75 times higher than in children without VAD) and the observed under-5 mortality rate in the country (210 per 1000 live births)., Results: In Mozambique, an estimated 2.3 million children below the age of 5 years are vitamin-A-deficient. In the absence of appropriate policy and programme action, VAD will be the attributable cause of over 30,000 deaths annually in the under-5s. This represents 34.8% of all-cause mortality in this age group., Discussion: Vitamin A supplementation (VAS) has been adopted as a short- to medium-term strategy to control VAD in children, and is integrated into routine child health services. However, the last VAS coverage survey showed that only 46% of children received a vitamin A supplement in the 6 months preceding the survey. If VAS coverage is to increase significantly in the foreseeable future, four areas appear to be of paramount importance: (1) reduce missed opportunities for VAS such as visits of sick children to child health services and community outreach activities; (2) take advantage of all potential opportunities for accelerating VAS coverage, such as additional vaccination campaigns and emergency response activities; (3) strengthen health workers' training, supervision and monitoring skills; and (4) increase community demand for VAS of children. Biannual VAS, as the primary component of an integrated strategy for VAD control in children, has the promise to be among the most cost-effective/high-impact child survival interventions in Mozambique.

Background: Young infants are at risk of vitamin A deficiency. Supplementation of breastfeeding mothers improves the vitamin A status of their infants, but there are no data regarding its effect on infant mortality, and data on the effect of directly supplementing infants during the first few weeks of life are conflicting., Objective: The objective was to measure the effect on infant mortality of supplementing neonates and their HIV-negative mothers with single, large doses of vitamin A during the immediate postpartum period., Design: A randomized, placebo-controlled, 2-by-2 factorial design trial was conducted in 14,110 mothers and their infants; 9208 of the mothers were HIV-negative at delivery, remained such during the postpartum year, and were retained in the current analysis. The infants were randomly assigned within 96 h of delivery to 1 of 4 treatment groups: mothers and infants received vitamin A (Aa), mothers received vitamin A and infants received placebo (Ap), mothers received placebo and infants received vitamin A (Pa), and both mothers and infants received placebo (Pp). The vitamin A dose in the mothers was 400,000 IU and in the infants was 50,000 IU. The mother-infant pairs were followed to 12 mo., Results: Hazard ratios (95% CI) for 12 mo mortality among infants in the maternal-supplemented and infant-supplemented groups were 1.17 (0.87, 1.58) and 1.08 (0.80, 1.46), respectively. Hazard ratios (95% CI) for the Aa, Ap, and Pa groups compared with the Pp group were 1.28 (0.83, 1.98), 1.27 (0.82, 1.97), and 1.18 (0.76, 1.83), respectively. These data indicate no overall effect. Serum retinol concentrations among a subsample of women were similar to reference norms., Conclusion: Postpartum maternal or neonatal vitamin A supplementation may not reduce infant mortality in infants of HIV-negative women with an apparently adequate vitamin A status.

Vitamin A deficiency is an endemic nutrition problem throughout much of the developing world, especially affecting the health and survival of infants, young children, and pregnant and lactating women. These age and life-stage groups represent periods when both nutrition stress is high and diet likely to be chronically deficient in vitamin A. Approximately 127 million preschool-aged children and 7 million pregnant women are vitamin A deficient. Health consequences of vitamin A deficiency include mild to severe systemic effects on innate and acquired mechanisms of host resistance to infection and growth, increased burden of infectious morbidity, mild to severe (blinding) stages of xerophthalmia, and increased risk of mortality. These consequences are defined as vitamin A deficiency disorders (VADD). Globally, 4.4 million preschool children have xerophthalmia and 6 million mothers suffer night blindness during pregnancy. Both conditions are associated with increased risk of morbidity and mortality. While reductions of child mortality of 19-54% following vitamin A treatment have been widely reported, more recent work suggests that dosing newborns with vitamin A may, in some settings, lower infant mortality. Among women, one large trial has so far reported a > or = 40% reduction in mortality related to pregnancy with weekly, low-dose vitamin A supplementation. Epidemiologic data on vitamin A deficiency disorders can be useful in planning, designing, and targeting interventions.

Most areas of health research will have accepted data and a dominating interpretation. If the interpretation is not correct, contradictions will accumulate, and it will eventually become clear that the current interpretation is untenable. In this situation, the best hypothesis is the one that accounts for all of the known data as well as the apparent contradictions. The area of vitamin A supplementation and childhood mortality in developing countries is afflicted with many contradictions and there is a need for a new hypothesis. We propose that the effect of vitamin A supplementation may depend on the amplification of non-specific effects of vaccines on childhood mortality.

Objective: To assess the impact of supplementing newborn infants with vitamin A on mortality at age 6 months., Design: Community based, randomised, double blind, placebo controlled trial., Setting: Two rural districts of Tamil Nadu, southern India., Participants: 11 619 newborn infants allocated 24 000 IU oral vitamin A or placebo on days 1 and 2 after delivery., Main Outcome Measure: Primary outcome measure was mortality at age 6 months., Results: Infants in the vitamin A group had a 22% reduction in total mortality (95% confidence interval 4% to 37%) compared with those in the placebo group. Vitamin A had an impact on mortality between two weeks and three months after treatment, with no additional impact after three months., Conclusion: Supplementing newborn infants with vitamin A can significantly reduce early infant mortality.

Micronutrients may have a role in enhancing reproductive health of women living in the developing world. Two illustrative micronutrients, zinc and vitamin A, have received some attention in this regard. Numerous animal experiments and observational studies suggest the potential role of zinc deficiency in labor and delivery-related complications such as premature rupture of membrane, placental abruption, preterm labor and inefficient uterine contraction. These associations have not been confirmed in supplementation studies. Zinc does not appear to be a limiting factor in intrauterine growth in the developing world, contrary to some evidence of its suggested benefit among women residing in industrialized countries. One study in Nepal found that maternal vitamin A or beta-carotene supplementation reduces pregnancy-related mortality but not infant mortality. These findings are corroborated by observations of the significantly higher risk of mortality among night-blind women compared to non-night-blind women long after the termination of pregnancy and the resolution of night blindness. Maternal multiple micronutrient supplementation needs more careful evaluation before its use in large-scale programs. Two recent trials indicated that a prenatal multiple micronutrient supplement provides no added advantage over iron and folate in reducing outcomes such as low birth weight and probably no survival benefit. Data are also suggestive that adding zinc may negate the beneficial effect of iron and folic acid on birth weight. Research is needed to further our understanding of nutrient-nutrient interactions.

Aim: To assess the effect of vitamin supplementation on the risk of sudden infant death syndrome (SIDS)., Methods: The analyses are based on data from the Nordic Epidemiological SIDS Study, a case-control study in which parents of SIDS victims in the Scandinavian countries were invited to participate together with parents of four matched controls between 1 September 1992 and 31 August 1995. The odds ratios presented are computed by conditional logistic regression analysis., Results: The crude odds ratio in Scandinavia for not giving vitamin substitution was 2.8 (95% CI (1.9, 4.3)). This effect was statistically significant in Norway and Sweden, which use A and D vitamin supplementation, but not in Denmark, where only vitamin D supplementation is given. The odds ratios remained significant in Sweden when an adjustment was made for confounding factors (OR 28.4, 95% CI (4.7, 171.3))., Conclusion: We found an association between increased risk of sudden infant death syndrome and infants not being given vitamin supplementation during their first year of life. This was highly significant in Sweden, and the effect is possibly connected with vitamin A deficiency. This effect persisted when an adjustment was made for potential confounders, includingsocioeconomic factors.

In all populations where vitamin A deficiency is an important public health problem, prophylactic vitamin A supplements should be given to all infants and young children (0-59 mo), pregnant women and postpartum women within 6 wk after delivery. The efficacy of vitamin A supplementation of young children is one of the best-proven, safest and most cost-effective interventions in international public health. The International Vitamin A Consultative Group (IVACG) also recommends that three 50,000-international unit (IU) doses of vitamin A should be given at the same time as infant vaccines during the first 6 mo of life. Recent kinetic studies have indicated that this regimen will be safe and is necessary to maintain the infant's vitamin A stores, even when the mother is also given 400,000 IU within the first 6 wk after delivery. IVACG will make a decision on whether to recommend prophylactic supplementation of all women of childbearing age when the results of two large trials in Ghana and Bangladesh are available. Active corneal xerophthalmia is always a medical emergency that should be treated with immediate high-dose vitamin A. High-dose vitamin A treatment is also recommended for infants and young children with xerophthalmia, severe malnutrition or measles. Low-dose vitamin A treatment is recommended for women with night blindness and/or Bitot's spots. Given the evidence of the cost-effectiveness of vitamin A supplementation, it is essential that effective vitamin A supplementation programs are made universally available to all populations where vitamin A deficiency is an important public health problem.