Excessive Vitamin A Supplementation Increased the Incidence of Acute Respiratory Tract Infections: A Systematic Review and Meta-Analysis.

(1) Background: vitamin A deficiency (VAD) is highly prevalent in children living in poor conditions. It has been suggested that vitamin A supplementation (VAS) may reduce the risk of acute respiratory tract infections (ARTI). Our study provides updates on the effects of oral VAS (alone) in children on ARTI and further explores the effect on interesting subgroups. (2) Methods: eight databases were systematically searched from their inception until 5 July 2021. The assessments of inclusion criteria, extraction of data, and data synthesis were carried out independently by two reviewers. (3) Results: a total of 26 randomized trials involving 50,944 participants fulfilled the inclusion criteria. There was no significant association of VAS with the incidence of ARTI compared with the placebo (RR 1.03, 95% CI 0.92 to 1.15). Subgroup analyses showed that VAS higher than WHO recommendations increased the incidence of ARTI by 13% (RR 1.13, 95% CI 1.07 to 1.20), and in the high-dose intervention group, the incidence rate among well-nourished children rose by 66% (RR 1.66, 95% CI 1.30 to 2.11). (4) Conclusions: no more beneficial effects were seen with VAS in children in the prevention or recovery of acute respiratory infections. Excessive VAS may increase the incidence of ARTI in children with normal nutritional status.

Red Palm Oil: A Review on Processing, Health Benefits and Its Application in Food.

This review is aimed to provide a comprehensive overview of the physicochemical properties and extraction processes of red palm oil, its nutritional properties and applications in food. Crude palm oil is firstly extracted from the fruit mesocarp and processed into red palm oil using pre-treatment of crude palm oil, with deacidification steps, and deodorization via short-path distillation. These processes help to retain ß-carotene and vitamin E in red palm oil. Palmitic, stearic and myristic acids are the saturated fatty acids in red palm oil, while the unsaturated fatty acids are oleic, linoleic and linolenic acids. It is reported to overcome vitamin A deficiency, promote heart health and have anti-cancer properties.

Effect of Fat-Soluble Vitamins A, D, E and K on Vitamin Status and Metabolic Profile in Patients with Fat Malabsorption with and without Urolithiasis.

Patients with intestinal fat malabsorption and urolithiasis are particularly at risk of acquiring fat-soluble vitamin deficiencies. The aim of the study was to evaluate the vitamin status and metabolic profile before and after the supplementation of fat-soluble vitamins A, D, E and K (ADEK) in 51 patients with fat malabsorption due to different intestinal diseases both with and without urolithiasis. Anthropometric, clinical, blood and 24-h urinary parameters and dietary intake were assessed at baseline and after ADEK supplementation for two weeks. At baseline, serum aspartate aminotransferase (AST) activity was higher in stone formers (SF; n = 10) than in non-stone formers (NSF; n = 41) but decreased significantly in SF patients after supplementation. Plasma vitamin D and E concentrations increased significantly and to a similar extent in both groups during intervention. While plasma vitamin D concentrations did not differ between the groups, vitamin E concentrations were significantly lower in the SF group than the NSF group before and after ADEK supplementation. Although vitamin D concentration increased significantly in both groups, urinary calcium excretion was not affected by ADEK supplementation. The decline in plasma AST activity in patients with urolithiasis might be attributed to the supplementation of ADEK. Patients with fat malabsorption may benefit from the supplementation of fat-soluble vitamins ADEK.

Night Blindness in Cystic Fibrosis: The Key Role of Vitamin A in the Digestive System.

Vitamin A is a fundamental micronutrient that regulates various cellular patterns. Vitamin A deficiency (VAT) is a worldwide problem and the primary cause of nocturnal blindness especially in low income countries. Cystic fibrosis (CF) is a known risk factor of VAD because of liposoluble vitamin malabsorption due to pancreatic insufficiency. We describe a case of a 9-year-old girl who experienced recurrent episodes of nocturnal blindness due to profound VAD. This little girl is paradigmatic for the explanation of the key role of the gut-liver axis in vitamin A metabolism. She presents with meconium ileus at birth, requiring intestinal resection that led to a transient intestinal failure with parenteral nutrition need. In addition, she suffered from cholestatic liver disease due to CF and intestinal failure-associated liver disease. The interaction of pancreatic function, intestinal absorption and liver storage is fundamental for the correct metabolism of vitamin A.

Fortification of staple foods with vitamin A for vitamin A deficiency.

BACKGROUND: Vitamin A deficiency is a significant public health problem in many low- and middle-income countries, especially affecting young children, women of reproductive age, and pregnant women. Fortification of staple foods with vitamin A has been used to increase vitamin A consumption among these groups. OBJECTIVES: To assess the effects of fortifying staple foods with vitamin A for reducing vitamin A deficiency and improving health-related outcomes in the general population older than two years of age. SEARCH METHODS: We searched the following international databases with no language or date restrictions: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) in the Cochrane Library; MEDLINE and MEDLINE In Process OVID; Embase OVID; CINAHL Ebsco; Web of Science (ISI) SCI, SSCI, CPCI-exp and CPCI-SSH; BIOSIS (ISI); POPLINE; Bibliomap; TRoPHI; ASSIA (Proquest); IBECS; SCIELO; Global Index Medicus - AFRO and EMRO; LILACS; PAHO; WHOLIS; WPRO; IMSEAR; IndMED; and Native Health Research Database. We also searched clinicaltrials.gov and the International Clinical Trials Registry Platform to identify ongoing and unpublished studies. The date of the last search was 19 July 2018. SELECTION CRITERIA: We included individually or cluster-randomised controlled trials (RCTs) in this review. The intervention included fortification of staple foods (sugar, edible oils, edible fats, maize flour or corn meal, wheat flour, milk and dairy products, and condiments and seasonings) with vitamin A alone or in combination with other vitamins and minerals. We included the general population older than two years of age (including pregnant and lactating women) from any country. DATA COLLECTION AND ANALYSIS: Two authors independently screened and assessed eligibility of studies for inclusion, extracted data from included studies and assessed their risk of bias. We used standard Cochrane methodology to carry out the review. MAIN RESULTS: We included 10 randomised controlled trials involving 4455 participants. All the studies were conducted in low- and upper-middle income countries where vitamin A deficiency was a public health issue. One of the included trials did not contribute data to the outcomes of interest.Three trials compared provision of staple foods fortified with vitamin A versus unfortified staple food, five trials compared provision of staple foods fortified with vitamin A plus other micronutrients versus unfortified staple foods, and two trials compared provision of staple foods fortified with vitamin A plus other micronutrients versus no intervention. No studies compared staple foods fortified with vitamin A alone versus no intervention.The duration of interventions ranged from three to nine months. We assessed six studies at high risk of bias overall. Government organisations, non-governmental organisations, the private sector, and academic institutions funded the included studies; funding source does not appear to have distorted the results.Staple food fortified with vitamin A versus unfortified staple food We are uncertain whether fortifying staple foods with vitamin A alone makes little or no difference for serum retinol concentration (mean difference (MD) 0.03 µmol/L, 95% CI -0.06 to 0.12; 3 studies, 1829 participants; I² = 90%, very low-certainty evidence). It is uncertain whether vitamin A alone reduces the risk of subclinical vitamin A deficiency (risk ratio (RR) 0.45, 95% CI 0.19 to 1.05; 2 studies; 993 participants; I² = 33%, very low-certainty evidence). The certainty of the evidence was mainly affected by risk of bias, imprecision and inconsistency.It is uncertain whether vitamin A fortification reduces clinical vitamin A deficiency, defined as night blindness (RR 0.11, 95% CI 0.01 to 1.98; 1 study, 581 participants, very low-certainty evidence). The certainty of the evidence was mainly affected by imprecision, inconsistency, and risk of bias.Staple foods fortified with vitamin A versus no intervention No studies provided data for this comparison.Staple foods fortified with vitamin A plus other micronutrients versus same unfortified staple foods Fortifying staple foods with vitamin A plus other micronutrients may not increase the serum retinol concentration (MD 0.08 µmol/L, 95% CI -0.06 to 0.22; 4 studies; 1009 participants; I² = 95%, low-certainty evidence). The certainty of the evidence was mainly affected by serious inconsistency and risk of bias.In comparison to unfortified staple foods, fortification with vitamin A plus other micronutrients probably reduces the risk of subclinical vitamin A deficiency (RR 0.27, 95% CI 0.16 to 0.49; 3 studies; 923 participants; I² = 0%; moderate-certainty evidence). The certainty of the evidence was mainly affected by serious risk of bias.Staple foods fortified with vitamin A plus other micronutrients versus no interventionFortification of staple foods with vitamin A plus other micronutrients may increase serum retinol concentration (MD 0.22 µmol/L, 95% CI 0.15 to 0.30; 2 studies; 318 participants; I² = 0%; low-certainty evidence). When compared to no intervention, it is uncertain whether the intervention reduces the risk of subclinical vitamin A deficiency (RR 0.71, 95% CI 0.52 to 0.98; 2 studies; 318 participants; I² = 0%; very low-certainty evidence) . The certainty of the evidence was affected mainly by serious imprecision and risk of bias.No trials reported on the outcomes of all-cause morbidity, all-cause mortality, adverse effects, food intake, congenital anomalies (for pregnant women), or breast milk concentration (for lactating women). AUTHORS' CONCLUSIONS: Fortifying staple foods with vitamin A alone may make little or no difference to serum retinol concentrations or the risk of subclinical vitamin A deficiency. In comparison with provision of unfortified foods, provision of staple foods fortified with vitamin A plus other micronutrients may not increase serum retinol concentration but probably reduces the risk of subclinical vitamin A deficiency.Compared to no intervention, staple foods fortified with vitamin A plus other micronutrients may increase serum retinol concentration, although it is uncertain whether the intervention reduces the risk of subclinical vitamin A deficiency as the certainty of the evidence has been assessed as very low.It was not possible to estimate the effect of staple food fortification on outcomes such as mortality, morbidity, adverse effects, congenital anomalies, or breast milk vitamin A, as no trials included these outcomes.The type of funding source for the studies did not appear to distort the results from the analysis.

Rethinking integrated nutrition-health strategies to address micronutrient deficiencies in children under five in Mozambique.

In Mozambique, about two thirds of children 6-59 months of age are affected by vitamin A deficiency and anaemia. The objective of this case study is to provide programme considerations for planning, implementing, monitoring, and evaluating vitamin A and iron deficiency interventions within the context of lessons learned to date for vitamin A supplementation, micronutrient powders (MNPs), and food-based strategies. For 15 years, the Mozambique Ministry of Health implemented twice-yearly vitamin A supplementation through both campaigns and routine health services. Yet coverage in 2017 (55%) was not much higher than in 2003 (44%). Reaching every district/reaching every child, a strategy adapted from the field of immunization, was used to achieve equitable coverage of vitamin A and for microplanning of outreach services in health facilities, with support from the Maternal and Child Survival Program. In Mozambique, a free or subsidized distribution model for MNPs has been rolled out, yet integration of MNPs into infant and young child feeding programming (i.e., cooking demonstrations) is needed to reinforce "the who, what, and why" of MNPs through culturally sensitive behaviour change communication. Food-based strategies to promote dietary diversity, such as through complementary feeding recipes, are also critical. To harmonize efforts, the Mozambique government should consider the development of a national strategy for the prevention and control of micronutrient malnutrition, with clear monitoring and evaluation targets. Ongoing monitoring of the prevalence of micronutrient deficiencies and coverage of implemented micronutrient interventions is needed to make evidence-based decisions to drive nutrition-health programming.

Early neonatal vitamin A supplementation and infant mortality: an individual participant data meta-analysis of randomised controlled trials.

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.

Modulation of Intestinal Immune and Barrier Functions by Vitamin A: Implications for Current Understanding of Malnutrition and Enteric Infections in Children.

The micronutrient vitamin A refers to a group of compounds with pleiotropic effects on human health. These molecules can modulate biological functions, including development, vision, and regulation of the intestinal barrier. The consequences of vitamin A deficiency and supplementation in children from developing countries have been explored for several years. These children live in an environment that is highly contaminated by enteropathogens, which can, in turn, influence vitamin A status. Vitamin A has been described to modulate gene expression, differentiation and function of diverse immune cells; however, the underlying mechanisms are not fully elucidated. This review aims to summarize the most updated advances on elucidating the vitamin A effects targeting intestinal immune and barrier functions, which may help in further understanding the burdens of malnutrition and enteric infections in children. Specifically, by covering both clinical and in vivo/in vitro data, we describe the effects of vitamin A related to gut immune tolerance/homeostasis, intestinal barrier integrity, and responses to enteropathogens in the context of the environmental enteric dysfunction. Some of the gaps in the literature that require further research are also highlighted.

SUSPECTED HYPOVITAMINOSIS A-ASSOCIATED SALT GLAND ADENITIS IN NORTHERN ROCKHOPPER PENGUINS ( EUDYPTES MOSELEYI).

Supraorbital salt-excreting glands are present in at least 10 avian orders and are largest in marine species, including penguins. Diseases of the avian salt gland have been described infrequently. From September 2015, five captive northern rockhopper penguins ( Eudyptes moseleyi) were presented over a 6-wk period for unilateral or bilateral supraorbital swellings. In September 2016, two cases recurred and two additional cases were identified. Histopathology demonstrated salt gland adenitis with extensive squamous metaplasia. Blood plasma testing demonstrated marked vitamin A and E deficiencies within the colony. Prolonged frozen storage of feed-fish was implicated as a cause of vitamin depletion; reducing storage times and addition of dietary supplementation prevented recurrence.

National control programme against nutritional blindness due to vitamin A deficiency: Current status & future strategy.

Vitamin A deficiency (VAD) among 1-5 yr old children is reported to be widely prevalent in Southeast Asia and some parts of Africa. It is the leading cause of preventable blindness in young children in the low-income countries in the world. Children even with milder signs of VAD have higher risk of morbidity and mortality. Inadequate dietary intakes of vitamin A with poor bioavailability associated with frequent infections are the primary contributory factors. Currently available approaches to control VAD are ensuring adequate intakes of vitamin A in daily diets, fortification of foods consumed regularly particularly among the low-income communities and periodic administration of massive dose of vitamin A supported by public health interventions and reinforced by behaviour change communication. Under the National Programme in India, six monthly administration of mega dose of vitamin A to 6-59 month old children has been implemented since 1970, to prevent particularly blindness due to VAD and control hypovitaminosis A. Despite inadequate coverage and poor implementation of the programme, blindness due to VAD in children has almost disappeared, though subclinical VAD is still widely prevalent. Based on the results of meta-analysis of eight trials, which indicated that vitamin A supplementation to children aged 6-59 months reduced child mortality rates by about 23 per cent, the World Health Organization made a strong recommendation that in areas with VAD as a public health problem, vitamin A supplementation should be given to infants and children of 6-59 months of age as a public health intervention to reduce child morbidity and improve child survival. At present, in India, there is a need for change in policy with respect to the national programme to opt for targeted instead of universal distribution. However, NITI (National Institution for Transforming India) Aayog, which formulates policies and provides technical support to the Government of India, recommends strengthening of the National Programme for control of VAD through six monthly vitamin A supplementation along with health interventions. Eventually, the goal is to implement food based and horticulture-based interventions harmonizing with public health measures, food fortification and capacity building of functionaries for elimination of VAD.

The Effect of Red Palm Oil on Vitamin A Deficiency: A Meta-Analysis of Randomized Controlled Trials.

Red palm oil (RPO) has been investigated for preventing or alleviating vitamin A deficiency (VAD). Previous data has offered inconclusive and inconsistent results about the effects of RPO in patients with VAD. Our objective was to undertake a meta-analysis to assess the effects of RPO in preventing VAD in the population. After conducting a comprehensive literature search, nine randomized controlled trials (RCTs) were included. Overall, when trial results were pooled, the results indicated that RPO reduced the risk of VAD (relative risk (RR) (95% confidence interval (CI)) = 0.55 (0.37, 0.82), p = 0.003), increasedserum retinol levels in both children (p < 0.00001) and adults (p = 0.002), and increased ß-carotene levels (p = 0.01). However, RPO supplementation did not have a significant overall effect on serum α-carotene levels (p = 0.06), body weight (p = 0.45), and haemoglobin levels (p = 0.72). The results also showed that low level of PRO intake (≤8 g RPO) could increase serum retinol concentrations whereas PRO intake above 8 g did not lead to further increase of serum retinol concentrations. This meta-analysis demonstrated that RPO might be effective for preventing or alleviating VAD.

Comparison of administrative and survey data for estimating vitamin A supplementation and deworming coverage of children under five years of age in Sub-Saharan Africa.

OBJECTIVE: To compare administrative coverage data with results from household coverage surveys for vitamin A supplementation (VAS) and deworming campaigns conducted during 2010-2015 in 12 African countries. METHODS: Paired t-tests examined differences between administrative and survey coverage for 52 VAS and 34 deworming dyads. Independent t-tests measured VAS and deworming coverage differences between data sources for door-to-door and fixed-site delivery strategies and VAS coverage differences between 6- to 11-month and 12- to 59-month age group. RESULTS: For VAS, administrative coverage was higher than survey estimates in 47 of 52 (90%) campaign rounds, with a mean difference of 16.1% (95% CI: 9.5-22.7; P < 0.001). For deworming, administrative coverage exceeded survey estimates in 31 of 34 (91%) comparisons, with a mean difference of 29.8% (95% CI: 16.9-42.6; P < 0.001). Mean ± SD differences in coverage between administrative and survey data were 12.2% ± 22.5% for the door-to-door delivery strategy and 25.9% ± 24.7% for the fixed-site model (P = 0.06). For deworming, mean ± SD differences in coverage between data sources were 28.1% ± 43.5% and 33.1% ± 17.9% for door-to-door and fixed-site distribution, respectively (P = 0.64). VAS administrative coverage was higher than survey estimates in 37 of 49 (76%) comparisons for the 6- to 11-month age group and 45 of 48 (94%) comparisons for the 12- to 59-month age group. CONCLUSION: Reliance on health facility data alone for calculating VAS and deworming coverage may mask low coverage and prevent measures to improve programmes. Countries should periodically validate administrative coverage estimates with population-based methods.

Vitamin A in pediatrics: An update from the Nutrition Committee of the French Society of Pediatrics.

Vitamin A (retinol) fulfills multiple functions in vision, cell growth and differentiation, embryogenesis, the maintenance of epithelial barriers and immunity. A large number of enzymes, binding proteins and receptors facilitate its intestinal absorption, hepatic storage, secretion, and distribution to target cells. In addition to the preformed retinol of animal origin, some fruits and vegetables are rich in carotenoids with provitamin A precursors such as ß-carotene: 6µg of ß-carotene corresponds to 1µg retinol equivalent (RE). Carotenoids never cause hypervitaminosis A. Determination of liver retinol concentration, the most reliable marker of vitamin A status, cannot be used in practice. Despite its lack of sensitivity and specificity, the concentration of retinol in blood is used to assess vitamin A status. A blood vitamin A concentration below 0.70µmol/L (200µg/L) indicates insufficient intake. Levels above 1.05µmol/L (300µg/L) indicate an adequate vitamin A status. The recommended dietary intake increases from 250µg RE/day between 7 and 36 months of age to 750µg RE/day between 15 and 17 years of age, which is usually adequate in industrialized countries. However, intakes often exceed the recommended intake, or even the upper limit (600µg/day), in some non-breastfed infants. The new European regulation on infant and follow-on formulas (2015) will likely limit this excessive intake. In some developing countries, vitamin A deficiency is one of the main causes of blindness and remains a major public health problem. The impact of vitamin A deficiency on mortality was not confirmed by the most recent studies. Periodic supplementation with high doses of vitamin A is currently questioned and food diversification, fortification or low-dose regular supplementation seem preferable.

The effect of daily consumption of the small fish Amblypharyngodon mola or added vitamin A on iron status: a randomised controlled trial among Bangladeshi children with marginal vitamin A status.

BACKGROUND AND OBJECTIVES: Mola (Amblypharyngodon mola) is a nutrient-rich, small fish found in ponds and rice fields in Bangladesh. The aim of the present intervention was to assess the effect of mola consumption on iron status in children with marginal vitamin A status. METHODS AND STUDY DESIGN: Bangladeshi children (n=196), aged 3-7 years, with marginal vitamin A status were randomly allocated to one of three intervention groups served different fish curries: mola curry (experimental group); rui (Labeo rohita) curry with added retinyl palmitate (positive control group); or rui curry (negative control group). The intervention meals were served 6 days/week for 9 weeks. The experimental and positive control meals were designed to contain similar amounts of retinol activity equivalents per portion. The mola curry contained four times more iron compared to the rui curries due to different iron content in the two fish species. Haemoglobin, ferritin, serum transferrin receptor and Creactive protein were measured at screening and endpoint. RESULTS: In the experimental group receiving mola, serum transferrin receptor concentration declined 0.73 mg/L (95% CI 0.17, 1.28, p=0.01) compared to the positive control group, while there were no differences between groups in ferritin or haemoglobin. CONCLUSIONS: Consumption of mola instead of rui has potentially an effect on iron status in children with marginal vitamin A status, seen as a decrease in serum transferrin receptor concentration.

ß-carotene-producing bacteria residing in the intestine provide vitamin A to mouse tissues in vivo.

Vitamin A deficiency (VAD) is an overwhelming public health problem that affects hundreds of millions of people worldwide. A definitive solution to VAD has yet to be identified. Because it is an essential nutrient, vitamin A or its carotenoid precursor ß-carotene can only be obtained from food or supplements. In this study, we wanted to establish whether ß-carotene produced in the mouse intestine by bacteria synthesizing the provitamin A carotenoid could be delivered to various tissues within the body. To achieve this, we took advantage of the Escherichia coli MG1655*, an intestine-adapted spontaneous mutant of E. coli MG1655, and the plasmid pAC-BETA, containing the genes coding for the 4 key enzymes of the ß-carotene biosynthetic pathway (geranylgeranyl pyrophosphate synthase, phytoene synthase, phytoene desaturase, and lycopene cyclase) from Erwinia herbicola. We engineered the E. coli MG1655* to produce ß-carotene during transformation with pAC-BETA (MG1655*-ßC) and gavaged wild-type and knockout mice for the enzyme ß-carotene 15,15'-oxygenase with this recombinant strain. Various regimens of bacteria administration were tested (single vs. multiple and low vs. high doses). ß-Carotene concentration was measured by HPLC in mouse serum, liver, intestine, and feces. Enumeration of MG1655*-ßC cells in the feces was performed to assess efficiency of intestinal colonization. We demonstrated in vivo that probiotic bacteria could be used to deliver vitamin A to the tissues of a mammalian host. These results have the potential to pave the road for future investigations aimed at identifying alternative, novel approaches to treat VAD.

Sustainability of market-based community distribution of Sprinkles in western Kenya.

To evaluate the sustainability of market-based community distribution of micronutrient powders (Sprinkles(®), Hexagon Nutrition, Mumbai, India.) among pre-school children in Kenya, we conducted in August 2010 a follow-up survey, 18 months after study-related marketing and household monitoring ended. We surveyed 849 children aged 6-35 months randomly selected from 60 study villages. Nutritional biomarkers were measured by fingerstick; demographic characteristics, Sprinkles purchases and use were assessed through household questionnaires. We compared Sprinkles use, marketing efforts and biomarker levels with the data from surveys conducted in March 2007, March 2008 and March 2009. We used logistic regression to evaluate associations between marketing activities and Sprinkles use in the 2010 survey. At the 2010 follow-up, 21.9% of children used Sprinkles in the previous 7 days, compared with 64.9% in 2008 (P < 0.001). Average intake was 3.2 sachets week(-1) in 2008, 1.6 sachets week(-1) in 2009 and 1.1 sachets week(-1) in 2010 (P < 0.001). Factors associated with recent Sprinkles use in 2010 included young age [6-23 months vs. 24-35 months, adjusted odds ratio (aOR) = 1.5, P = 0.02], lowest 2 quintiles of socio-economic status (aOR = 1.7, P = 0.004), household attendance at trainings or launches (aOR = 2.8, P < 0.001) and ever receiving promotional items including free Sprinkles, calendars, cups and t-shirts (aOR = 1.7, P = 0.04). In 2010, there was increased prevalence of anaemia and malaria (P < 0.001), but not iron deficiency (P = 0.44), compared with that in 2008. Sprinkles use in 2010 was associated with decreased iron deficiency (P = 0.03). Sprinkles coverage reduced after stopping household monitoring and reducing marketing activities. Continued promotion and monitoring of Sprinkles usage may be important components to sustain the programme.

Combining vitamin A and vaccines: convenience or conflict?

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.

Vitamin A supplementation for the prevention of morbidity and mortality in infants six months of age or less.

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.