review of literature on vitamin a deficiency

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Vitamin A Deficiency: Health, Survival, and Vision

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Many studies over the past decade and a half have indicated that vitamin A status is an important determinant of health. The World Bank now estimates that vitamin A intervention programs are some of the most cost-effective health strategies globally. This new book, written by leading investigators in the field, is the first to synthesize the many important studies to date. The authors identify and quantify the biological, clinical and public health impact of vitamin A deficiency on childhood growth, mortality and morbidity, including anemia and blindness. They deal with the epidemiologic and biological basis of these findings, and with the prevention and treatment of these disorders, particularly of measles, diarrhea and xeorophthalmia. Alternative approaches to identifying individuals and populations in need of intervention, alternative strategies for improving vitamin A and carotenoids, and the relationship between vitamin A and immunity are discussed. This comprehensive volume on a critically important and widespread nutritional deficiency will serve as a unique resource for nutritionists, physicians, public health workers and policy makers, and will be especially relevant to clinicians and researchers in international health.

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• Open access
• Published: 12 September 2013

Review of the safety and efficacy of vitamin A supplementation in the treatment of children with severe acute malnutrition

• Lora L Iannotti 1 ,
• Indi Trehan 1 , 2 , 3 &
• Mark J Manary 1 , 2 , 4 , 5  

Nutrition Journal volume  12 , Article number:  125 ( 2013 ) Cite this article

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World Health Organization (WHO) guidelines recommend for children with severe acute malnutrition (SAM), high-dose vitamin A (VA) supplements be given on day 1 of admission, and on days 2 and 14 in the case of clinical signs of vitamin A deficiency (VAD). Daily low-dose VA follows, delivered in a premix added to F-75 and F-100. This study aimed to systematically review the evidence for safety and effectiveness of high-dose VA supplementation (VAS) in treatment of children with SAM.

A comprehensive literature review was undertaken for all relevant randomized controlled trials (RCT) and observational studies from 1950 to 2012. Studies identified for full review were evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology using a set of pre-defined criteria: indirectness; inconsistency; imprecision; and study limitations. A quality rating of high, moderate, or low was then assigned to each study, and only those attaining moderate to high were considered in making recommendations.

Of the 2072 abstracts screened, 38 met criteria for full review, and 20 were rated moderate to high quality. Only one study replicated the WHO VA protocol in children with SAM. Indirectness was a critical limitation, as studies were not exclusive to children with SAM. There was inconsistency across trials for definitions of malnutrition, morbidities, and ages studied; and imprecision arising from sub-group analyses and small sample sizes. Evidence showed improved outcomes associated with low-dose compared to high-dose VAS, except in cases presenting with signs of VAD, measles, and severe diarrhea or shigellosis. Adverse outcomes related to respiratory infection, diarrhea, and growth were associated with high-dose VAS in children who were predominantly adequately nourished. No adverse effects of the high dose were found in children with SAM in the trial that replicated the WHO VA guideline.

This is the first systematic review of the safety and efficacy of high-dose VAS in treatment of SAM. We recommend a low-dose VAS regimen for children with SAM, except in cases presenting with measles, severe diarrhea (shigellosis), and any indication of VAD. Further research is needed in exclusively malnourished children and to explore alternate delivery strategies.

Peer Review reports

Globally, vitamin A deficiency (VAD) affects 100–140 million children, 4.4 million of whom have xerophthalmia [ 1 , 2 ]. Coverage rates for full vitamin A supplementation (VAS) of children 6–59 months delivered through primary care have risen significantly over the last decade, reaching 88% for the least developed countries [ 3 ]. In recent years, alternative strategies to improve micronutrient nutrition have been increasingly applied for high-risk populations already supplemented with vitamin A (VA): micronutrient powders; fortification of staple foods; ready-to-use supplemental and therapeutic foods (RUSF and RUTF); and other food-based approaches.

Among the populations particularly vulnerable to VAD are children with severe acute malnutrition (SAM) [ 4 ]. The World Health Organization (WHO) currently recommends that for inpatient care of children with SAM, VA supplements be given on day 1 of admission unless there is clear evidence that VA was received in the last month [ 5 ]. Dosing guidelines are the following: 200,000 international units (IU) for children over 12 months of age, 100,000 IU for children 6–12 months, and 50,000 IU for children below 6 months. If clinical signs of vitamin A deficiency are present, then another age-specific, large dose is administered on day 2 and again, on day 14 [ 4 , 5 ]. Low-dose VA is then given as part of a vitamin mix added to F-75 or F-100 therapeutic milk formulations, or alternatively, as a proprietary multivitamin supplement or combined mineral-vitamin mix (CMV). There is a need to revisit these guidelines in the context of improved VA availability, but also in view of evidence showing the potential for harmful effects of such VAS dosages [ 6 ].

This systematic review aimed to assess the safety and effectiveness of VAS in children with SAM, with regards to mortality, nutritional recovery, and signs of symptomatic VAD [ 7 ]. A literature review was undertaken to search for all randomized controlled trials (RCT) and observational studies published from 1950 to March 2012. Databases searched included MEDLINE, EMBASE, and Google Scholar. The clinical trial registries at clinicaltrials.gov, pactr.org, and apps.who.int/trialsearch were also searched. Initial key words for the searches included “malnutrition”, “severe malnutrition”, “kwashiorkor”, “marasmus”, “vitamin A”, and “retinol”. A number of outcome measures were sought, including mortality, weight gain, nutritional recovery, and VAD. Further terms were added iteratively to the search based on results obtained from the initial searches.

Searches were also conducted to identify relevant publications and study documents produced by international health organizations such as the WHO and UNICEF. The titles and abstracts were scanned to identify relevant studies. The full text of relevant studies was obtained and the list of articles for inclusion further optimized based on an evaluation of the full text. Reference lists in relevant articles were also scanned manually and electronically to identify other studies that may have been missed in the original searches. Relevant publications that cited those previously identified articles were similarly sought.

Studies were included for full review based on relevance to the population of interest, study interventions, study design, outcome measures, and an assessment of the study’s methodological rigor and quality. These studies were then assessed and entered into a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) table summarizing design, aim, outcomes, GRADE criteria assessment (indirectness, inconsistency, imprecision, and study limitations), and quality ranking (high, moderate, or low) [ 8 ].

Indirectness was judged based on study relevance to the review question in terms of the study population (children with SAM), intervention of interest (VAS), and outcome measures (mortality, recovery from SAM, signs of symptomatic VAD, and adverse outcomes due to supplementation) [ 9 ]. Consideration was given under this category to VA dosing relative the WHO protocol. Inconsistency was assessed by comparing point estimates and examining the heterogeneity of methods and statistical analyses [ 10 ]. Imprecision was based primarily on the 95% confidence interval with consideration of effect and sample sizes [ 11 ]. Potential biases (selection, recall, information/observation, misclassification) arising from failure to blind, losses in follow-up, inappropriate controls, and failure to adjust for confounding factors, among other problems, were considered under the study limitations (risk of bias) criteria [ 12 ].

Once these criteria were assessed, each study was assigned a quality ranking ranging from low to high. Only those studies with some degree of moderate or high ( i.e. , low-moderate, moderate, moderate-high, or high) quality ranking were included in this review for consideration in making recommendations on the use of VAS for the treatment of children with SAM.

Of the 2072 abstracts identified and screened, 38 were selected for full review (Figure  1 ). Twenty-two were of moderate- to high-quality, and were grouped into 3 categories and listed primary outcomes assessed: 1) previous reviews; 2) observational studies; and 3) randomized controlled trials (RCT).

Flow diagram for studies included in review. The figure presents a flow diagram detailing the number of records screened and excluded, full-text articles reviewed, and ultimately, the number of studies included in the systematic review. The included observational and RCT studies are enumerated according to the primary outcome examined.

Previous reviews

Two previous reviews of VAS trials were identified; both considered malnourished children together with those not malnourished [ 7 , 13 ]. Preventive VAS reduced all-cause mortality by 25% and diarrhea-specific mortality by 30%. VA showed greater protection against morbidity and mortality in Asia than in Africa or Latin America [ 13 ]. An earlier review found that the severity of measles and diarrheal infections were reduced by VAS, but the risk of lower respiratory tract infection was increased in some trials [ 7 ]. Because the reviews did not provide new evidence for VA and management of SAM and all studies from the reviews were screened for this review, they were not included in the GRADE assessment.

Observational studies

Five observational studies were identified and assigned a GRADE quality ranking of low to moderate [ 14 – 18 ] (Additional file 1 : Table S1). These studies found significant associations between serum or plasma retinol concentrations and SAM [ 14 – 16 ]. Others established a link between VAD, SAM, and diarrhea. In Bangladesh, reduced serum retinol concentrations were associated with shigellosis and low weight-for-age Z-score [ 18 ]. Another case–control study in Bangladesh showed that the duration of diarrhea and SAM were independently associated with xerophthalmia [ 17 ].

Randomized controlled trials

Fifteen RCTs of moderate to high quality based on GRADE criteria were included in the systematic review on the safety and efficacy of high-dose VAS in children with SAM (Table  1 ). Issues of indirectness were present in all trials. Only one trial included children with SAM exclusively [ 19 ]. The remaining 14 included non-malnourished and malnourished children [ 20 – 33 ]. VA dosing also varied; only five trials administered the recommended high-dose on day 1 [ 19 , 26 , 30 , 31 , 33 ], while the remaining administered VA doses in varying quantities and forms. Only one trial followed the WHO protocol [ 19 ]; two compared high dose with daily low dose [ 26 , 33 ], and the remaining 12 compared high dose VAS with placebo [ 20 – 25 , 27 – 32 ].

Inconsistency across trials was observed with regards to the ages of children studied, ranging from birth to 14 years. Definitions of morbidity and malnutrition varied, as well as use of differing growth references and standards. Small sample sizes and rare events were the most common problems related to imprecision . Despite randomization, several studies also showed significant differences in baseline characteristics that elevated the risk of bias . Notably, these included baseline age and nutritional status differences with higher likelihoods of confounding [ 28 , 32 , 33 ].

Some key findings were identified across trials. First, low-dose VAS conferred more or similar health and recovery advantages when compared to high-dose supplementation in the treatment of malnourished children [ 19 , 26 , 33 ]. Second, high-dose VAS showed mixed results relative to placebo for infectious disease outcomes in children with and without SAM, showing benefit in some trials for children with severe diarrhea or shigellosis [ 27 , 31 ], measles [ 21 , 22 ], other acute respiratory infections [ 30 ], and undifferentiated fever [ 24 ]. However, in other trials, there was no benefit for children with acute respiratory infections or diarrhea [ 24 – 26 , 29 , 32 ]. There was also some evidence of improved growth outcomes associated with high-dose VAS among VA deficient children [ 20 ] and children with measles [ 22 ].

Finally, adverse effects were found to be associated with high-dose VAS in some trials, including an increased rate of respiratory illnesses [ 23 , 28 ] and diarrhea [ 26 , 31 ]. These findings appear primarily in samples or sub-samples of adequately nourished children. As noted previously, we identified only one RCT that included only severely malnourished children [ 19 ]. Some explicitly excluded children with marasmus, kwashiorkor, or all children with SAM [ 25 , 27 , 30 , 32 ], while the remaining included both malnourished and adequately nourished children. Among the five studies finding adverse events in association with VAS, two of these studies carried out sub-group analyses showing an increased risk of diarrhea among normally nourished children [ 31 ] and among children without edema [ 26 ]. One trial included only adequately nourished children [ 28 ], another found increased risk of ALRI in mainly adequately nourished children [ 23 ], and one included both malnourished and adequately nourished children, excluding children with SAM [ 32 ]. No adverse effects of the high-dose VAS were found in children with SAM in the trial that replicated the WHO VA guidelines [ 19 ].

Our systematic review of the literature using the GRADE methodology revealed only limited evidence that directly addresses the safety and effectiveness of high-dose VAS for children with SAM. Fourteen of the 15 RCTs identified for this review included both malnourished and non-malnourished children, thereby complicating the extrapolation of findings directly to efficacy and safety of VAS for SAM. There is sufficient evidence to recommend the use of high-dose VAS for children with SAM when presenting with measles, severe diarrhea (shigellosis), or evidence of VAD. The low-dose VAS regimen should be considered as the preferred protocol in other cases of malnourished children, given the potential for adverse events and similar recovery outcomes when compared to high-dose VAS. Higher quality prospective studies are still needed to directly examine VAD in children with SAM, applying more contemporary definitions of morbidity and malnutrition, and powered sufficiently to detect the critical outcomes of interest.

Observational studies demonstrated an association between SAM and VAD, but metabolic disruptions in SAM might preclude accurate measures of true VA status. Blood biomarkers of retinol concentrations were primarily used to indicate VA status [ 14 – 16 , 18 ]. Protein-energy malnutrition has been associated with reduced hepatic synthesis of retinol binding protein (RBP) and transthyretin used to transport VA in the body [ 34 , 35 ]. Thus, VA stores in the liver may not be mobilized appropriately in malnourished children and therefore not be reflected in blood biomarkers. Mitra showed that VA status improved from baseline to hospital discharge, even without VAS [ 18 ]. That study also showed that while urinary losses of retinol were associated with low retinol concentrations in children with dysentery, other inflammatory markers such as body temperature and serum α-1-acid glycoprotein and C reactive protein concentrations were more highly and negatively correlated with vitamin A status.

There is some evidence that diarrhea could be mediating this relationship, as revealed by independent associations between diarrhea, low WAZ, and VA levels [ 17 ]. Shigellosis , in particular, increases the risk of VAD [ 18 ]. A study in Brazil showed a possible interaction between SAM and low serum retinol concentrations for higher diarrheal morbidities [ 15 ]. Evidence from RCTs also finds that high-dose VAS may be beneficial for treating severely malnourished children in cases of severe diarrhea [ 27 , 31 ]. Again, the mechanism by which VA may be operating to mitigate severe diarrhea in SAM has not been elucidated, but it may be either through the repair of the gut epithelium or immune pathways that restore balance between T-cell subsets [ 36 ].

Two studies showed unequivocally the benefit of lose-dose (5000 IU daily until discharge) compared to a single high-dose (200,000 IU for children over 12 months or 100,000 IU for children under 12 months on day 1 of hospitalization) VAS regimen [ 26 , 33 ]. The low-dose regimen was more strongly correlated with lower incidence and shorter duration of respiratory disease [ 33 ] and a lower incidence of severe diarrhea [ 26 ]. A third study in Bangladesh also examined the administration of a lose-dose protocol in relation to a high-dose on day 1 followed by daily low doses until hospital discharge. [ 19 ]. That study did not find any differences in the two groups on a range of morbidity and nutrition recovery outcomes and adverse events. All children at baseline had diarrhea and while clinical signs of VAD were not apparent, baseline measures of VA status did indicate VAD in the sample. With regards to other morbidities, high-dose VAS was effective in reducing measles-specific respiratory illness [ 21 , 22 ], but showed mixed results with regards to non-measles pneumonia and other acute lower respiratory tract infections in children with SAM [ 23 – 25 , 28 – 30 , 32 , 37 , 38 ].

Only one trial identified in this review specifically included children who were HIV + [ 31 ]. Sub-group analyses stratified by HIV status showed a trend towards a protective effect of high-dose VAS on cough and rapid respiratory rate for HIV-infected children [RR 0.54 (0.24-1.20), p = 0.07], while children without HIV infection were at increased risk for these conditions [RR 1.47 (1.16-1.86), p = 0.001]. Because children infected with HIV are highly vulnerable to SAM and VAD, more research is needed to understand the optimal protocols for this population [ 39 ].

The evidence for growth outcomes in the follow-up period from hospital discharge was limited and somewhat dated [ 20 , 22 ]. One study showed that only among children who were VA deficient at baseline were there greater improvements in weight and MUAC in those who received high-dose VAS; this was not evident in the non-VA deficient children and high-dose VAS even reduced height gain among non-VA deficient girls [ 20 ]. Standard therapeutic foods designed for growth recovery in SAM may be a safer source of VA in certain cases. The foods contain VA as retinyl acetate, similar to VA supplements, in the following concentrations (per 100 g): F-75, 900 μg; F-100, 800 μg; and RUTF, 800–1100 μg. Thus, for a child weighing 5 kg, this would translate into 1,119 μg/d VA for F-75, or 1,544 μg/d VA for F-100, and 1,680 μg/d VA for RUTF. These quantities are comparable to the low-dose regimen of 5000 IU or 1500 μg retinol and are well below the high-dose recommendation of 100,000 IU or 30,000 μg/d VA that would be given to children under 12 mo. While these foods have not specifically been assessed as alternatives to VAS, the safety and efficacy of these products in the treatment of SAM is well-accepted [ 40 – 42 ]. Particularly in cases when a child’s VA status is unknown or adequate, therapeutic foods could thus serve as the delivery mechanism for low-dose VAS, though more research is needed.

Adverse effects found to be associated with high-dose VAS warrant more research. The most frequent negative outcome was an increased risk of acute respiratory infections [ 23 , 28 , 31 , 33 ]. There was also evidence of an increased risk of acute, non-severe diarrhea, mediated in part by nutritional status [ 26 , 31 , 32 ]. It should be noted that the adverse effects arising from high-dose VAS were found in samples or sub-samples that included primarily adequately nourished children. Heterogeneity in baseline characteristics and study design complicates comparisons across the various studies, but these safety issues should not be ignored. Excessive intake of preformed VA, notably in the absence of dietary fatty acids, may overwhelm the esterification process and introduce more harmful forms of VA into the child’s circulation [ 6 ]. Further along the metabolic pathway, VA presented to cell membranes in forms other than the RBP complex (as may be the case in SAM) can also lead to significant cellular damage [ 43 ]. Carotenoid forms of VA or lipid-based nutrient supplements such as RUTF, should be explored to minimize oxidative stress while still addressing VAD [ 44 ].

Conclusions

In the treatment of children with SAM, a high-dose VAS protocol can be safely recommended in cases presenting with measles, severe diarrhea (shigellosis), or symptoms of VAD. More research is needed to study this specific question in populations exclusively malnourished and to understand and prevent adverse outcomes related to high-dose VAS. We recommend exploration of alternative low-dose protocols and strategies beyond VAS, such as use of carotenoids or RUTF interventions, to address VA deficiency and associated health outcomes in the treatment of children with SAM.

Abbreviations

Acute lower respiratory infection

Grading of recommendations assessment development and evaluation

Mid-upper arm circumference

Randomized controlled trial

Ready-to-use therapeutic food

• Severe acute malnutrition

Vitamin A deficiency

• Vitamin A supplementation

Weight-for-age Z score

Weight-for-height Z score.

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LLI, IT, and MJM contributed to the conception and design of the study. IT and MJM supervised the literature search and initial screening of studies. LLI carried out the full text review and initial GRADE assessment, followed by additional assessment from IT and MJM. All authors contributed to the analysis and interpretation of the compiled evidence. LLI drafted the manuscript with significant inputs received by IT and MJM. All authors have granted approval to this version of the manuscript.

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Iannotti, L.L., Trehan, I. & Manary, M.J. Review of the safety and efficacy of vitamin A supplementation in the treatment of children with severe acute malnutrition. Nutr J 12 , 125 (2013). https://doi.org/10.1186/1475-2891-12-125

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• Published: 28 March 2022

Vitamin A supplementation policy: A shift from universal to geographical targeted approach in India considered detrimental to health and nutritional status of under 5 years children

• Nimmathota Arlappa   ORCID: orcid.org/0000-0001-5405-1872 1  

European Journal of Clinical Nutrition volume  77 ,  pages 1–6 ( 2023 ) Cite this article

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Evolvement of Vitamin A supplementation (VAS) programme in India: Universal coverage of children 6–59 months

Vitamin A is an essential fat-soluble micronutrient required for normal growth and development, maintenance of healthy mucosal membranes, reproductive health, immunity, and vision, especially for dark adaptation. Vitamin A deficiency (VAD) continues to be a major nutritional problem of public health concern in India, despite the implementation of a programme for vitamin A supplementation for over four decades. Although the incidence of clinical VAD in India has declined significantly over the period of time, the highest proportion of the world’s VAD children still lives in India [ 1 , 2 ]. The proportion of rural preschool children in India with Bitot’s spots, an objective clinical sign of VAD is reported to be over 0.5%, making VAD a public health problem [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. A similar pattern of prevalence of sub-clinical VAD (serum retinol ≤ 0.70 µmol/L or ≤ 20 µg/dL) is also observed and confirms VAD to be a severe public health problem (≥ 20%) in India [ 4 , 5 , 6 , 7 , 8 , 9 , 11 , 14 ] Table 1 .

Taking into consideration the grave public health problem of VAD and nutritional blindness in India, the National Institute of Nutrition (NIN) carried out a series of clinical, biochemical, and field intervention studies in the 1960s [ 15 ]. Following this, a countrywide high dose (200000 IU) six-monthly Vitamin A Supplementation (VAS) program was recommended [ 16 , 17 ]. In 1970, the Government of India launched the “National program for prophylaxis against blindness in children due to vitamin A deficiency” targeting children 1–5 years [ 18 ]. Subsequently, the VAS programme was revisited in 1991 by the Indian experts in the context of emerging evidence of the impact of VAS on child mortality [ 19 ] and an India study on seroconversion of measles vaccine by the NIN [ 20 ]. The revised VAS programme included infants 6–11 months and was renamed as “Management of Vitamin A deficiency Programme”. In the early period of implementation, taking into consideration the supply of vitamin A solution and cost, the policy accorded a higher priority to administer VAS to the most vulnerable children aged 9–36 months. However, in 2006, with increased prevalence of VAD in 36–59 months children and no constraint on the supply of vitamin A solution, the Government of India expanded the target age group to meet the 1991 policy guidelines to 6–59 months [ 21 ]. The VAS is in operation in India as well as in more than 70 countries around the world and is recognised to be one of the most effective public health interventions ever undertaken [ 22 , 23 ]. Taking into consideration, the need for improving the coverage of six monthly administration of VAS In India, a biannual VAS strategy was piloted and scaled up in India [ 21 ].

Proposed policy shift from universal VAS coverage to targeting to the selected states: Questioning the rationale

Some studies carried out in India during the last two decades have reported a considerable decrease in the prevalence of Bitot’s Spots [ 24 , 25 , 26 ] and these findings have led to a constant opposition to the continuation of the universal VAS programme in India. The recommendation to discontinue the VAS programme by a selected group of experts has been persistent for over a decade despite the lack of state or nationally representative database that confirms substantial improvement in clinical, sub-clinical VAD or dietary vitamin A consumption among children under 5 years. In fact, after the NNMB-2003-05 rural survey in 8 states in India, no large-scale study has been carried out to measure sub-clinical vitamin A status in children [ 27 ]. Moreover, the dietary survey findings of the National Nutrition Monitoring Bureau (NNMB) surveys that were available also do not support discontinuation of VAS since the diets of children under 5 were reported to be extremely poor in vitamin A [ 25 , 26 ].

The argument by a select group of experts to discontinue universal Vitamin A Supplementation (VAS) for children 6–59 months under the national programme gained momentum following the release of the Comprehensive National Nutrition Survey (CNNS) report 2019 on micronutrients, including vitamin A status of young children and adolescents [ 28 ]. The Expert Group constituted by the Ministry of Health, Government of India recommended modification in the existing national programme and shifting the focus of VAS from universal coverage of children to a geographical targeted approach. This recommendation was primarily based on the CNNS findings of a low prevalence of sub-clinical VAD of 17.6% among children aged 1–4 years as assessed by the measure of serum retinol levels below 20 µg/dl and VAD as a severe public health problem (prevalence of ≥ 20%) only in 10 of the 30 states/union territories that were surveyed. An examination of the CNNS methodology, however, raises a number of questions on the prevalence of sub-clinical VAD among children reported by the CNNS, since there is a substantial gap in the design and the actual execution. Similarly, a substantial difference is noted in the CNNS methodology that prescribed the representative sample of children to be covered in various states and at the national level for estimation of various micronutrients including vitamin A and the actual number of children that were covered for estimation of serum retinol [ 28 ]. The CNN survey covered only 6694 children aged 1–4 years as against the 20,350 children proposed in the study methodology. Likewise, none of the 30 states/union territories surveyed met the target sample of children that was prescribed in the survey design. In about half of the states, the coverage was only around one-third of the proposed sample size, while the coverage was more than 75% of the proposed sample in only two of the 30 states- Odisha (80.5%) and Sikkim (76%) (Table 2 ). In such a situation of coverage of grossly inadequate sample size, valid estimation and inference on the prevalence of VAD are scientifically not correct. Such an inadequate sample could result in unduly large standard errors; inadequate power with the resulting inferences drawn being misleading. Moreover, the report on VAD situation does not represent the entire country and is limited to 28 states and two union territories (UTs). Similarly, the CNNS report has excluded serum retinol data of two states i.e. Rajasthan and Nagaland and the survey did not cover the six union territories. Therefore, the findings of the CNNS were derived from the grossly inadequate and non-representative sample for the country. Despite such apparent limitations in the CNNS survey, the Expert Committee recommends to discontinue the VAS programme in all the states and union territories except for 3 states with a high prevalence of VAD [ 24 ]. The rationale for zeroing on 3 states from the 10 states reported having VAD as a severe public health problem remains an enigma. On that account, the evidence is not sufficient to indicate a low prevalence of sub-clinical VAD to argue for modification of the existing VAS policy in India.

Assumption of vitamin A inadequacy is not convincing

In addition to the CNNS findings on VAD, the Expert Committee also substantiated their recommendation for change in vitamin A policy on the basis of dietary intake of vitamin A and fortification of oil and milk with vitamin A. These inferences on dietary vitamin A consumption were based on secondary data collected at two different time periods, a decade ago by the NNMB [ 25 ] and the National Sample Survey Office (NSSO) [ 29 ]. Likewise, it was also projected by the Expert Committee that the dietary inadequacy (≤ 70% of Recommended Dietary Allowances) of vitamin A will reduce substantially with the ongoing efforts by the country to fortify oil and milk with vitamin A [ 24 ]. There was no scientific data presented to support this assumption. Moreover, consumption of oil and milk used as food vehicles for fortification is rather low and the consumption of these food items differ widely in the various socio- economic groups. In fact, even if the fortification is 100%, the deficit intake will continue to be high as most rural, tribal, and peri-urban households in India purchase milk and oil from local vendors. As per the NNMB surveys, the intakes of oil and milk among the rural, tribal, and urban children in India are extremely poor [ 25 , 26 , 30 ] with the inadequacy (≤70% of Recommended Dietary Intakes) of intakes ranging from a low of 86.2 to a high of 100%. Likewise, the dietary inadequacy (≤ 70% of RDA) of vitamin A is also very high ranging from a low of 86.3% in rural children 4–6 years age to a high of 93.4% in urban children 1–3 years [ 25 , 26 , 30 ] Table 3 . The total available vitamin A gets further reduced due to the fact that the dietary source of vitamin A in the Indian diet is primarily from vegetarian source and the availability of vitamin A is rather low as compared with animal source of vitamin A. Provitamin A carotenoids from plant sources have lower relative absorption efficiency ranging from only 5% to 26% [ 31 ] and the ratio of conversion of provitamin A carotenoids to retinol in humans varies from 2:1 to 24:1 on a µg:µg basis [ 32 , 33 ]. While in contrast, pre-formed vitamin A (retinol) found only in animal-sourced foods is an active form of vitamin A with 70–90% bio-availability [ 34 , 35 ].

Therefore, it is scientifically inappropriate to argue for the modification of the existing vitamin A policy based on dietary data collected more than a decade ago. Moreover, the Expert Committee conveniently ignored the latest dietary data collected by the CNN survey (2016–18) that indicated extremely poor intake of dietary source of vitamin A, where only 5% of Indian children of 2–4 years reportedly consumed vitamin A-rich fruits and vegetables and the negligible proportion of them consumed animal source foods rich in vitamin A [ 24 , 28 ].

Presumption of Vitamin A hypervitaminosis has no basis

Besides the arguments stressing vitamin A deficiency is not a public health problem in the country and the dietary inadequacy of vitamin A is low, the Expert Committee has presented an additional viewpoint for the discontinuation of VAS programme. This argument pertains to the speculation and concerns that introduction of fortification of oils and milk with vitamin A combined with continuation of VAS would lead to hypervitaminosis among young children. No evidence is presented to support this rationale. Reports of acute toxicity have been reported only in case when erroneously an extremely high dose of VAS has been administered in a short period of time [ 36 ]. On the other hand, chronic toxicity has been reported only on long-term ingestion of vitamin A when the intake is higher than 10 times the recommended daily allowance [ 34 ]. Except for few reports of toxic effects in infants below six months, side effects of VAS are usually rare in children aged six months or older [ 37 , 38 , 39 ]. Penniston & Tanumihardjo substantiate that hypervitaminosis is not at all relevant to the age beyond 9 months with the recommended massive dose VAS for public health programmes or combination of interventions i.e., diet, fortified foods, and supplements [ 40 ]. In India, as indicated earlier, dietary intake of vitamin A, as well as the consumption of food vehicle selected for vitamin A fortification, is rather low and the issue of vitamin A toxicity remains totally hypothetical. Having a scientific basis is imperative for drawing such a conclusion and would require the use of an appropriate method such as application of sensitive biomarkers to assess the adverse impact of vitamin A supplement when combined with food fortification, the condition of hypervitaminosis cannot be detected by the mere measure of serum retinol concentrations [ 41 ].

Reflecting on Impact of VAS programmes in India: Imperative to ensure each and every child is protected from vitamin A deficiency

In public health programmes, the provision of micronutrient supplements such as vitamin A, iodine, and iron are viewed as a short-term strategy to reinforce dietary approaches to mitigate micronutrient deficiencies [ 42 ]. Administration of VAS is also recommended to be progressively phased out as soon as micronutrient-rich food-based interventions enable adequate consumption [ 43 , 44 ], and therefore, administration of VAS is not viewed to be a long-term strategy for prevention of VAD [ 45 ]. Several studies have supported a dietary modification (food-based) approach as a sustainable model for the prevention and control of multiple micronutrient deficiencies, particularly the VAD [ 46 , 47 , 48 , 49 ]. However, Sommer and Davidson have proposed that, based on dietary data and kinetic modelling, it is virtually impossible to correct widespread VAD by diet alone in developing countries, where populations remain dependent on conventional plant-based foods [ 50 ]. In Western societies, preformed vitamin A provides > 70% of daily vitamin A requirement [ 51 ] while people in developing countries meet 80–85% of their daily requirement of vitamin A from plant sources of foods [ 52 ]. Paradoxically VAD is common even in Indian children of affluent households when the source of vitamin A is predominantly from vegetarian diets [ 30 , 53 ]. If we consider this scientific evidence, it is impractical to assume children in India consume such amounts of fruits and vegetables, considering not only the access and cost but, the bioavailability and the rate of conversion of carotenoids to retinol.

Since the 1970s, food-based approaches have been an integral part of vitamin A deficiency control programme in India; but despite this, the dietary intakes of vitamin A have remained persistently low and have not changed much at all in the past four decades [ 49 ]. Thus, improving dietary intake of vitamin A through dietary diversification remains a challenge in India. Chronic poverty and ignorance, deep-rooted cultural and religious factors, as well as seasonal accessibility to micronutrient-rich foods, have longstanding impact on dietary intakes of vitamin A by Indian population. The unique requirements of caste and religion in India have further contributed to extreme variations in the diet; even among individuals living in geographic proximity [ 15 ].

In India, the introduction of the biannual fixed months VAS programme since mid 2000 has positively impacted VAS with coverage of children under 5 years for massive dose VAS reported to have increased from 25% in 2003–05 [ 27 ] to 60.2% in 2015–16 [ 54 ]. Recent NFHS-5 (2019–21) data also indicates a significant improvement in the percentage of children 9–36 months who received VAS in the preceding six months to be 71.2 % [ 55 ]. Such an improvement in coverage of children 6–59 months with VAS administration is possibly the reason for the low prevalence of sub-clinical VAD (17.6%) [ 34 ] and Bitot’s spots (0.3%) [ 25 ] in contrast to a high prevalence of Bitot’s spots (1.4%) [ 25 ] and sub-clinical VAD (21.5%) [ 28 ] in children aged 5–10years. Hence, the lower prevalence of VAD in children under 5 years as compared to that of 5–10 years old could definitely be attributed to the coverage under VAS. On the other hand, discontinuation of VAS when not replaced with adequate intake of vitamin A rich foods would possibly worsen the vitamin A status. Therefore, suspending the VAS programme prior to an improvement in dietary vitamin A intakes solely on the basis of nationally non-representative CNNS findings may reverse the progress in vitamin A status and lead to the re-emergence of blinding xerophthalmia [ 56 ]. This is also evident from an Indian study that reported corneal xerosis (0.3%) and corneal scars (0.5%) among children of Uttar Pradesh in 2011 [ 5 ]. Global Alliance for Vitamin A (GAVA) advocated that before scaling-back the existing VAS policy, countries should ascertain that the dietary intakes of vitamin A are adequate, the sub-clinical vitamin A status of children is optimal, and the prevalence of sub-clinical VAD among children 6–59 months is less than 10% [ 57 ]. Therefore, considering these recommendations of the GAVA, it is pertinent to judge the ground realities of vitamin A status in the country. From the available recent data, it is obvious that the diets of children are extremely poor in vitamin A and the prevalence of sub-clinical VAD among children is 17.6%, which cannot be considered low enough to revise the existing VAS policy in India [ 58 , 59 , 60 ].

Change of VAS Policy in India in the current situation is not conducive

It is imperative that prior to taking any decision on revision of India’s existing vitamin supplementation A policy, the Ministry of Health and Family Welfare (MoHFW) should appraise the ground realities of vitamin A status among children under 5 years in rural, tribal, urban and urban slums within the various states in India by undertaking a well-designed study with adequate state and nationally representative sample size using various parameters comprising serum retinol, Bitot’s spots and dietary vitamin A intake. Additionally, study with more sensitive biomarkers like relative dose response tests [ 58 ] is required to be undertaken in a sub-sample of children. In absence of such valid information, discontinuation of VAS programme in India implies denying children’s right to receive VAS until their vitamin A intake has improved optimally. Deprivation of vitamin A during formative years is detrimental to the growth and development of a child, resulting in morbidity and mortality [ 61 ]. In the Pandemic situation of Covid-19, we need to provide support in building immunity of children who are yet to receive vaccination against Covid-19 infection and may have lower intake of dietary vitamin A due to possible interruptions in the world’s largest ongoing supplementary feeding programme under the Integrated Child Development Services (ICDS) for children or poor food purchasing power. In such a grave situation, the significance of continuing the VAS policy of six monthly administration of vitamin A supplement to young children cannot be ignored.Universal coverage of all children 6–59 months with VAS in the current Covid-19 Pandemic situation needs high priority. The implications of the recommendation of Expert Committee to shift the existing universal coverage of VAS approach to a targeted geographical approach, with coverage limited to less than one tenth of the country could be devastating to the health of children, particularly those from poor and marginalised households. There is a need for substantial supportive scientific evidence. In absence of convincing rationale, the recommendation by selected experts to make changes in the existing VAS policy in India appears to be very similar to the well documented initial resistance by few scientists and experts who had strong opinions but not sufficient scientific basis to their claims for opposing the public health intervention of introduction of Bacille Calmette-Guerin (BCG) and many other novel vaccines across the globe [ 22 ].

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I am extremely thankful to Dr. G.Sarika, Scientist-B, for her help in the review of literature.

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Arlappa, N. Vitamin A supplementation policy: A shift from universal to geographical targeted approach in India considered detrimental to health and nutritional status of under 5 years children. Eur J Clin Nutr 77 , 1–6 (2023). https://doi.org/10.1038/s41430-022-01122-5

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Signs and Symptoms of Vitamin D Deficiency

Many parts of your body rely on vitamin D for sustenance—including your bones, muscles, brain, and immune system . Most people have the vitamin D that their body needs, but as many as one in four adults in the U.S. are deficient and can experience symptoms such as muscle weakness, hair loss, and fatigue.

This is partly because vitamin D isn’t quite as easy to get naturally as some other nutrients. While your body makes some vitamin D when you are in the sun, this nutrient isn't easily found or abundant in Western diets. 

Vitamin D deficiency can be hard to diagnose because it either produces no symptoms or its symptoms overlap with many other types of health conditions. The good news: a vitamin D deficiency is relatively easy to treat with supplements once your healthcare provider identifies that you're deficient. 

Frequent Illness

Vitamin D bolsters the immune system, so if you’re constantly getting sick—or becoming seriously ill with even minor infections—a deficiency could be to blame. In fact, some research has found a link between higher disease severity in people in the ICU and low levels of vitamin D. This was examined again after the onset of COVID-19 , with studies showing that people with deficiencies may have had a higher risk of getting COVID and getting sicker from the virus. 

Hair Loss        

Vitamin D plays an important part in regulating the hair cycle, including the regeneration of new hair . That said, it’s possible that a deficiency could slow your hair growth process down. In fact, people with alopecia (an autoimmune disorder that causes hair loss ) have lower levels of vitamin D, and topical vitamin D treatments have been used to improve symptoms. 

Bone Fractures

Because it’s a key nutrient in strengthening your bones , a vitamin D deficiency can cause osteomalacia in adults, or a condition that leads to the softening of the bones. This deficiency can also increase your risk of developing osteoporosis —a condition that causes a decrease in bone mass and density, making your bones more prone to breakage.

Muscle Pain and Weakness

Vitamin D promotes muscle function, so low levels of the vitamin may boost your likelihood of experiencing symptoms such as loss of muscle tone, atrophy, weakness, and pain . Due to the loss of muscle mass and strength, it's also possible to be more prone to experiencing falls.  

The loss of muscle strength—and subsequent stress on the back and neck muscles—can lead to back pain. Lower back pain, in particular, is a common complaint among people with vitamin D deficiencies. Some experts suggest screening people with lower back pain for vitamin D deficiencies may be helpful, as treatment such as vitamin D supplements, can ease pain-related symptoms. 

Fatigue 

It’s unclear exactly why low vitamin D levels might lead to fatigue , but multiple studies have shown that people who take vitamin D supplements report an improvement in fatigue and an increase in overall energy levels.

The research is mixed on whether taking vitamin D supplements can improve existing symptoms of depression , but multiple studies have shown that people with a vitamin D deficiency may be at an increased risk of experiencing depressive episodes.  

Symptoms in Children 

A severe lack of vitamin D in children can lead to rickets, a condition that causes softening in developing bones. Many children get their vitamin D from the sun and from dairy products, but very young babies are typically not exposed to much sun and don’t consume dairy until they begin solid foods .

Rickets is especially common in breastfed babies. The condition may be even more common in babies if their breastfeeding parent also has a vitamin D deficiency . That's why healthcare providers recommend giving a vitamin D supplement to all babies, regardless of whether they're breastfed or fed by formulas. However, your baby may not need a vitamin D supplement if they are drinking at least 32 ounces of formula daily. 

If your baby does develop rickets, they may experience the following symptoms:

• Bowed legs 
• Changes in shape to the spinal curve, ribs, or breastbones
• Dental problems
• Stunted growth
• Loss of muscle tone

Although rickets is most common in young babies, older kids are also prone to having a vitamin D deficiency. About 15% of kids between the ages of one and 11 have a vitamin D deficiency, while 17% of adolescents don’t get enough vitamin D. 

When to See a Healthcare Provider 

If you or your child has symptoms of bone or hair loss, muscle pain, or fatigue, or are frequently becoming ill or experiencing bone fractures with no clear cause, make an appointment with a healthcare provider.

They can better assess your symptoms and order diagnostic measures (such as blood tests) to check your vitamin D levels, among other results from your bloodwork. If your results show that you have a vitamin D deficiency , your provider can recommend the right amount of vitamin D supplementation you will need to bring your levels back to normal.

Keep in mind: you should not self-treat a vitamin D deficiency, since too much vitamin D from supplements can have adverse side effects. 

A Quick Review 

Vitamin D is a vital nutrient for your bones, muscles, nerves, and immune system. Too little vitamin D can lead to fatigue, frequent illness or bone fractures, hair loss, and muscle and bone pain. In children, severe deficiency can cause rickets—a condition that leads to the softening of their bones.

A blood test can confirm if you have a vitamin D deficiency, so it's a good idea to see your healthcare provider for proper testing and diagnosis. If you have a deficiency, your healthcare provider can guide you in safely increasing your levels with vitamin D supplementation. 

Frequently Asked Questions

What causes vitamin D to drop?

Vitamin D levels can become deficient if you don’t get enough exposure to sunlight, don’t consume enough of the vitamin in the foods you eat, or if you have a health condition that limits your ability to process or absorb vitamin D. 

Does low vitamin D cause weight gain?

There is some evidence that people with vitamin D deficiency are more likely to become obese, possibly because excess fat prohibits the processing of the vitamins in the body. But there hasn’t been a direct correlation made between low vitamin D and weight gain and more research is still needed.

Does vitamin D affect sleep?

Vitamin D levels are often lower in people with sleep disorders, but researchers haven’t been able to demonstrate that vitamin D supplementation improves symptoms of sleep disorders or reduces their occurrence. 

What happens when your vitamin D is very low?

Often, nothing noticeable happens. Most people with vitamin D deficiency are asymptomatic, but that doesn’t mean there aren't changes occurring within the body. Vitamin D is considered a “building block” for many body systems, so low levels can interfere with your body’s ability to produce strong and healthy bones, maintain proper muscle tone, fight infections, and regulate mood, energy, and sleep.

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Review of the safety and efficacy of vitamin A supplementation in the treatment of children with severe acute malnutrition

Lora l iannotti.

1 Institute for Public Health/George Warren Brown School of Social Work, Washington University in St. Louis, Campus Box 1196, St. Louis, MO 63130, USA

Indi Trehan

2 Department of Pediatrics, Washington University in St. Louis, 1 Childrens Pl, St Louis, MO 63110, USA

3 Department of Paediatrics and Child Health, University of Malawi, Blantyre, Malawi

Mark J Manary

4 Department of Community Health, University of Malawi, Blantyre, Malawi

5 Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA

Associated Data

World Health Organization (WHO) guidelines recommend for children with severe acute malnutrition (SAM), high-dose vitamin A (VA) supplements be given on day 1 of admission, and on days 2 and 14 in the case of clinical signs of vitamin A deficiency (VAD). Daily low-dose VA follows, delivered in a premix added to F-75 and F-100. This study aimed to systematically review the evidence for safety and effectiveness of high-dose VA supplementation (VAS) in treatment of children with SAM.

A comprehensive literature review was undertaken for all relevant randomized controlled trials (RCT) and observational studies from 1950 to 2012. Studies identified for full review were evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology using a set of pre-defined criteria: indirectness; inconsistency; imprecision; and study limitations. A quality rating of high, moderate, or low was then assigned to each study, and only those attaining moderate to high were considered in making recommendations.

Of the 2072 abstracts screened, 38 met criteria for full review, and 20 were rated moderate to high quality. Only one study replicated the WHO VA protocol in children with SAM. Indirectness was a critical limitation, as studies were not exclusive to children with SAM. There was inconsistency across trials for definitions of malnutrition, morbidities, and ages studied; and imprecision arising from sub-group analyses and small sample sizes. Evidence showed improved outcomes associated with low-dose compared to high-dose VAS, except in cases presenting with signs of VAD, measles, and severe diarrhea or shigellosis. Adverse outcomes related to respiratory infection, diarrhea, and growth were associated with high-dose VAS in children who were predominantly adequately nourished. No adverse effects of the high dose were found in children with SAM in the trial that replicated the WHO VA guideline.

This is the first systematic review of the safety and efficacy of high-dose VAS in treatment of SAM. We recommend a low-dose VAS regimen for children with SAM, except in cases presenting with measles, severe diarrhea (shigellosis), and any indication of VAD. Further research is needed in exclusively malnourished children and to explore alternate delivery strategies.

Globally, vitamin A deficiency (VAD) affects 100–140 million children, 4.4 million of whom have xerophthalmia [ 1 , 2 ]. Coverage rates for full vitamin A supplementation (VAS) of children 6–59 months delivered through primary care have risen significantly over the last decade, reaching 88% for the least developed countries [ 3 ]. In recent years, alternative strategies to improve micronutrient nutrition have been increasingly applied for high-risk populations already supplemented with vitamin A (VA): micronutrient powders; fortification of staple foods; ready-to-use supplemental and therapeutic foods (RUSF and RUTF); and other food-based approaches.

Among the populations particularly vulnerable to VAD are children with severe acute malnutrition (SAM) [ 4 ]. The World Health Organization (WHO) currently recommends that for inpatient care of children with SAM, VA supplements be given on day 1 of admission unless there is clear evidence that VA was received in the last month [ 5 ]. Dosing guidelines are the following: 200,000 international units (IU) for children over 12 months of age, 100,000 IU for children 6–12 months, and 50,000 IU for children below 6 months. If clinical signs of vitamin A deficiency are present, then another age-specific, large dose is administered on day 2 and again, on day 14 [ 4 , 5 ]. Low-dose VA is then given as part of a vitamin mix added to F-75 or F-100 therapeutic milk formulations, or alternatively, as a proprietary multivitamin supplement or combined mineral-vitamin mix (CMV). There is a need to revisit these guidelines in the context of improved VA availability, but also in view of evidence showing the potential for harmful effects of such VAS dosages [ 6 ].

This systematic review aimed to assess the safety and effectiveness of VAS in children with SAM, with regards to mortality, nutritional recovery, and signs of symptomatic VAD [ 7 ]. A literature review was undertaken to search for all randomized controlled trials (RCT) and observational studies published from 1950 to March 2012. Databases searched included MEDLINE, EMBASE, and Google Scholar. The clinical trial registries at clinicaltrials.gov, pactr.org, and apps.who.int/trialsearch were also searched. Initial key words for the searches included “malnutrition”, “severe malnutrition”, “kwashiorkor”, “marasmus”, “vitamin A”, and “retinol”. A number of outcome measures were sought, including mortality, weight gain, nutritional recovery, and VAD. Further terms were added iteratively to the search based on results obtained from the initial searches.

Searches were also conducted to identify relevant publications and study documents produced by international health organizations such as the WHO and UNICEF. The titles and abstracts were scanned to identify relevant studies. The full text of relevant studies was obtained and the list of articles for inclusion further optimized based on an evaluation of the full text. Reference lists in relevant articles were also scanned manually and electronically to identify other studies that may have been missed in the original searches. Relevant publications that cited those previously identified articles were similarly sought.

Studies were included for full review based on relevance to the population of interest, study interventions, study design, outcome measures, and an assessment of the study’s methodological rigor and quality. These studies were then assessed and entered into a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) table summarizing design, aim, outcomes, GRADE criteria assessment (indirectness, inconsistency, imprecision, and study limitations), and quality ranking (high, moderate, or low) [ 8 ].

Indirectness was judged based on study relevance to the review question in terms of the study population (children with SAM), intervention of interest (VAS), and outcome measures (mortality, recovery from SAM, signs of symptomatic VAD, and adverse outcomes due to supplementation) [ 9 ]. Consideration was given under this category to VA dosing relative the WHO protocol. Inconsistency was assessed by comparing point estimates and examining the heterogeneity of methods and statistical analyses [ 10 ]. Imprecision was based primarily on the 95% confidence interval with consideration of effect and sample sizes [ 11 ]. Potential biases (selection, recall, information/observation, misclassification) arising from failure to blind, losses in follow-up, inappropriate controls, and failure to adjust for confounding factors, among other problems, were considered under the study limitations (risk of bias) criteria [ 12 ].

Once these criteria were assessed, each study was assigned a quality ranking ranging from low to high. Only those studies with some degree of moderate or high ( i.e. , low-moderate, moderate, moderate-high, or high) quality ranking were included in this review for consideration in making recommendations on the use of VAS for the treatment of children with SAM.

Of the 2072 abstracts identified and screened, 38 were selected for full review (Figure  1 ). Twenty-two were of moderate- to high-quality, and were grouped into 3 categories and listed primary outcomes assessed: 1) previous reviews; 2) observational studies; and 3) randomized controlled trials (RCT).

Flow diagram for studies included in review. The figure presents a flow diagram detailing the number of records screened and excluded, full-text articles reviewed, and ultimately, the number of studies included in the systematic review. The included observational and RCT studies are enumerated according to the primary outcome examined.

Previous reviews

Two previous reviews of VAS trials were identified; both considered malnourished children together with those not malnourished [ 7 , 13 ]. Preventive VAS reduced all-cause mortality by 25% and diarrhea-specific mortality by 30%. VA showed greater protection against morbidity and mortality in Asia than in Africa or Latin America [ 13 ]. An earlier review found that the severity of measles and diarrheal infections were reduced by VAS, but the risk of lower respiratory tract infection was increased in some trials [ 7 ]. Because the reviews did not provide new evidence for VA and management of SAM and all studies from the reviews were screened for this review, they were not included in the GRADE assessment.

Observational studies

Five observational studies were identified and assigned a GRADE quality ranking of low to moderate [ 14 - 18 ] (Additional file 1 : Table S1). These studies found significant associations between serum or plasma retinol concentrations and SAM [ 14 - 16 ]. Others established a link between VAD, SAM, and diarrhea. In Bangladesh, reduced serum retinol concentrations were associated with shigellosis and low weight-for-age Z-score [ 18 ]. Another case–control study in Bangladesh showed that the duration of diarrhea and SAM were independently associated with xerophthalmia [ 17 ].

Randomized controlled trials

Fifteen RCTs of moderate to high quality based on GRADE criteria were included in the systematic review on the safety and efficacy of high-dose VAS in children with SAM (Table  1 ). Issues of indirectness were present in all trials. Only one trial included children with SAM exclusively [ 19 ]. The remaining 14 included non-malnourished and malnourished children [ 20 - 33 ]. VA dosing also varied; only five trials administered the recommended high-dose on day 1 [ 19 , 26 , 30 , 31 , 33 ], while the remaining administered VA doses in varying quantities and forms. Only one trial followed the WHO protocol [ 19 ]; two compared high dose with daily low dose [ 26 , 33 ], and the remaining 12 compared high dose VAS with placebo [ 20 - 25 , 27 - 32 ].

Randomized controlled trials included in the systematic review

The table presents the included RCT studies in the review by date of publication, from most recent to oldest. For each study, the design, aim, quality assessment by GRADE criteria, findings, and GRADE rating are provided.

Inconsistency across trials was observed with regards to the ages of children studied, ranging from birth to 14 years. Definitions of morbidity and malnutrition varied, as well as use of differing growth references and standards. Small sample sizes and rare events were the most common problems related to imprecision . Despite randomization, several studies also showed significant differences in baseline characteristics that elevated the risk of bias . Notably, these included baseline age and nutritional status differences with higher likelihoods of confounding [ 28 , 32 , 33 ].

Some key findings were identified across trials. First, low-dose VAS conferred more or similar health and recovery advantages when compared to high-dose supplementation in the treatment of malnourished children [ 19 , 26 , 33 ]. Second, high-dose VAS showed mixed results relative to placebo for infectious disease outcomes in children with and without SAM, showing benefit in some trials for children with severe diarrhea or shigellosis [ 27 , 31 ], measles [ 21 , 22 ], other acute respiratory infections [ 30 ], and undifferentiated fever [ 24 ]. However, in other trials, there was no benefit for children with acute respiratory infections or diarrhea [ 24 - 26 , 29 , 32 ]. There was also some evidence of improved growth outcomes associated with high-dose VAS among VA deficient children [ 20 ] and children with measles [ 22 ].

Finally, adverse effects were found to be associated with high-dose VAS in some trials, including an increased rate of respiratory illnesses [ 23 , 28 ] and diarrhea [ 26 , 31 ]. These findings appear primarily in samples or sub-samples of adequately nourished children. As noted previously, we identified only one RCT that included only severely malnourished children [ 19 ]. Some explicitly excluded children with marasmus, kwashiorkor, or all children with SAM [ 25 , 27 , 30 , 32 ], while the remaining included both malnourished and adequately nourished children. Among the five studies finding adverse events in association with VAS, two of these studies carried out sub-group analyses showing an increased risk of diarrhea among normally nourished children [ 31 ] and among children without edema [ 26 ]. One trial included only adequately nourished children [ 28 ], another found increased risk of ALRI in mainly adequately nourished children [ 23 ], and one included both malnourished and adequately nourished children, excluding children with SAM [ 32 ]. No adverse effects of the high-dose VAS were found in children with SAM in the trial that replicated the WHO VA guidelines [ 19 ].

Our systematic review of the literature using the GRADE methodology revealed only limited evidence that directly addresses the safety and effectiveness of high-dose VAS for children with SAM. Fourteen of the 15 RCTs identified for this review included both malnourished and non-malnourished children, thereby complicating the extrapolation of findings directly to efficacy and safety of VAS for SAM. There is sufficient evidence to recommend the use of high-dose VAS for children with SAM when presenting with measles, severe diarrhea (shigellosis), or evidence of VAD. The low-dose VAS regimen should be considered as the preferred protocol in other cases of malnourished children, given the potential for adverse events and similar recovery outcomes when compared to high-dose VAS. Higher quality prospective studies are still needed to directly examine VAD in children with SAM, applying more contemporary definitions of morbidity and malnutrition, and powered sufficiently to detect the critical outcomes of interest.

Observational studies demonstrated an association between SAM and VAD, but metabolic disruptions in SAM might preclude accurate measures of true VA status. Blood biomarkers of retinol concentrations were primarily used to indicate VA status [ 14 - 16 , 18 ]. Protein-energy malnutrition has been associated with reduced hepatic synthesis of retinol binding protein (RBP) and transthyretin used to transport VA in the body [ 34 , 35 ]. Thus, VA stores in the liver may not be mobilized appropriately in malnourished children and therefore not be reflected in blood biomarkers. Mitra showed that VA status improved from baseline to hospital discharge, even without VAS [ 18 ]. That study also showed that while urinary losses of retinol were associated with low retinol concentrations in children with dysentery, other inflammatory markers such as body temperature and serum α-1-acid glycoprotein and C reactive protein concentrations were more highly and negatively correlated with vitamin A status.

There is some evidence that diarrhea could be mediating this relationship, as revealed by independent associations between diarrhea, low WAZ, and VA levels [ 17 ]. Shigellosis , in particular, increases the risk of VAD [ 18 ]. A study in Brazil showed a possible interaction between SAM and low serum retinol concentrations for higher diarrheal morbidities [ 15 ]. Evidence from RCTs also finds that high-dose VAS may be beneficial for treating severely malnourished children in cases of severe diarrhea [ 27 , 31 ]. Again, the mechanism by which VA may be operating to mitigate severe diarrhea in SAM has not been elucidated, but it may be either through the repair of the gut epithelium or immune pathways that restore balance between T-cell subsets [ 36 ].

Two studies showed unequivocally the benefit of lose-dose (5000 IU daily until discharge) compared to a single high-dose (200,000 IU for children over 12 months or 100,000 IU for children under 12 months on day 1 of hospitalization) VAS regimen [ 26 , 33 ]. The low-dose regimen was more strongly correlated with lower incidence and shorter duration of respiratory disease [ 33 ] and a lower incidence of severe diarrhea [ 26 ]. A third study in Bangladesh also examined the administration of a lose-dose protocol in relation to a high-dose on day 1 followed by daily low doses until hospital discharge. [ 19 ]. That study did not find any differences in the two groups on a range of morbidity and nutrition recovery outcomes and adverse events. All children at baseline had diarrhea and while clinical signs of VAD were not apparent, baseline measures of VA status did indicate VAD in the sample. With regards to other morbidities, high-dose VAS was effective in reducing measles-specific respiratory illness [ 21 , 22 ], but showed mixed results with regards to non-measles pneumonia and other acute lower respiratory tract infections in children with SAM [ 23 - 25 , 28 - 30 , 32 , 37 , 38 ].

Only one trial identified in this review specifically included children who were HIV + [ 31 ]. Sub-group analyses stratified by HIV status showed a trend towards a protective effect of high-dose VAS on cough and rapid respiratory rate for HIV-infected children [RR 0.54 (0.24-1.20), p = 0.07], while children without HIV infection were at increased risk for these conditions [RR 1.47 (1.16-1.86), p = 0.001]. Because children infected with HIV are highly vulnerable to SAM and VAD, more research is needed to understand the optimal protocols for this population [ 39 ].

The evidence for growth outcomes in the follow-up period from hospital discharge was limited and somewhat dated [ 20 , 22 ]. One study showed that only among children who were VA deficient at baseline were there greater improvements in weight and MUAC in those who received high-dose VAS; this was not evident in the non-VA deficient children and high-dose VAS even reduced height gain among non-VA deficient girls [ 20 ]. Standard therapeutic foods designed for growth recovery in SAM may be a safer source of VA in certain cases. The foods contain VA as retinyl acetate, similar to VA supplements, in the following concentrations (per 100 g): F-75, 900 μg; F-100, 800 μg; and RUTF, 800–1100 μg. Thus, for a child weighing 5 kg, this would translate into 1,119 μg/d VA for F-75, or 1,544 μg/d VA for F-100, and 1,680 μg/d VA for RUTF. These quantities are comparable to the low-dose regimen of 5000 IU or 1500 μg retinol and are well below the high-dose recommendation of 100,000 IU or 30,000 μg/d VA that would be given to children under 12 mo. While these foods have not specifically been assessed as alternatives to VAS, the safety and efficacy of these products in the treatment of SAM is well-accepted [ 40 - 42 ]. Particularly in cases when a child’s VA status is unknown or adequate, therapeutic foods could thus serve as the delivery mechanism for low-dose VAS, though more research is needed.

Adverse effects found to be associated with high-dose VAS warrant more research. The most frequent negative outcome was an increased risk of acute respiratory infections [ 23 , 28 , 31 , 33 ]. There was also evidence of an increased risk of acute, non-severe diarrhea, mediated in part by nutritional status [ 26 , 31 , 32 ]. It should be noted that the adverse effects arising from high-dose VAS were found in samples or sub-samples that included primarily adequately nourished children. Heterogeneity in baseline characteristics and study design complicates comparisons across the various studies, but these safety issues should not be ignored. Excessive intake of preformed VA, notably in the absence of dietary fatty acids, may overwhelm the esterification process and introduce more harmful forms of VA into the child’s circulation [ 6 ]. Further along the metabolic pathway, VA presented to cell membranes in forms other than the RBP complex (as may be the case in SAM) can also lead to significant cellular damage [ 43 ]. Carotenoid forms of VA or lipid-based nutrient supplements such as RUTF, should be explored to minimize oxidative stress while still addressing VAD [ 44 ].

Conclusions

In the treatment of children with SAM, a high-dose VAS protocol can be safely recommended in cases presenting with measles, severe diarrhea (shigellosis), or symptoms of VAD. More research is needed to study this specific question in populations exclusively malnourished and to understand and prevent adverse outcomes related to high-dose VAS. We recommend exploration of alternative low-dose protocols and strategies beyond VAS, such as use of carotenoids or RUTF interventions, to address VA deficiency and associated health outcomes in the treatment of children with SAM.

Abbreviations

ALRI: Acute lower respiratory infection; GRADE: Grading of recommendations assessment development and evaluation; MUAC: Mid-upper arm circumference; RCT: Randomized controlled trial; RUTF: Ready-to-use therapeutic food; SAM: Severe acute malnutrition; VA: Vitamin A; VAD: Vitamin A deficiency; VAS: Vitamin A supplementation; WAZ: Weight-for-age Z score; WHZ: Weight-for-height Z score.

Competing interests

There were no competing interests in this research.

Authors’ contributions

LLI, IT, and MJM contributed to the conception and design of the study. IT and MJM supervised the literature search and initial screening of studies. LLI carried out the full text review and initial GRADE assessment, followed by additional assessment from IT and MJM. All authors contributed to the analysis and interpretation of the compiled evidence. LLI drafted the manuscript with significant inputs received by IT and MJM. All authors have granted approval to this version of the manuscript.

Supplementary Material

Observational studies included in systematic review [ 45 ].

Acknowledgements

Funding was provided by the World Health Organization (WHO) to support the work of M. Manary and L. Iannotti.

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Vitamin B12 deficiency-induced megaloblastic anemia in a pediatric patient with autism spectrum disorder with a chronically unbalanced diet

• Case Report
• Published: 25 March 2024

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• Yuri Sawada 1 ,
• Kenichi Sakamoto   ORCID: orcid.org/0000-0003-1499-538X 1 ,
• Atsushi Tsukamura 1 &
• Chihiro Sawai 1  

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a lack of behavioral flexibility and stereotyped language. Food selectivity is common among children with ASD because of their persnickety nature. A prolonged unbalanced diet results in an increased risk of several diseases, such as iron deficiency anemia, scurvy, rickets, dry eye, and Wernicke encephalopathy. However, no cases of megaloblastic anemia have been reported to date. We report the case of an 11-year-old boy with ASD who developed megaloblastic anemia due to vitamin B12 deficiency. He had a prolonged history of selective eating for more than 10 years. His nutritional status on admission was poor, and he had low weight and short stature. His food selectivity was so strong that intervention to expand diet variety was unsuccessful. A developmental-behavioral pediatrician found that the patient had visual dominance and could take some medications when suffering from a minor illness. Nutritional supplements were selected after consultation with a nutritionist. Although compulsory treatment was necessary during the acute phase, the therapy was continued at home. With multidisciplinary intervention tailored to the patient and his parents’ characteristics, his nutritional status improved in a few months.

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Acknowledgements

Consent for publication of the case was obtained from the patient’s parents.

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Department of Pediatrics, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan

Yuri Sawada, Kenichi Sakamoto, Atsushi Tsukamura & Chihiro Sawai

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Y.S. and K.S. designed the study. Y. S. drafted the manuscript. A.T. and C.S. reviewed the manuscript. All the authors have read and approved the final version of the manuscript.

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Correspondence to Kenichi Sakamoto .

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Sawada, Y., Sakamoto, K., Tsukamura, A. et al. Vitamin B12 deficiency-induced megaloblastic anemia in a pediatric patient with autism spectrum disorder with a chronically unbalanced diet. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03759-3

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Received : 04 December 2023

Revised : 11 March 2024

Accepted : 14 March 2024

Published : 25 March 2024

DOI : https://doi.org/10.1007/s12185-024-03759-3

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Autoimmune Thyroiditis and Vitamin D

Affiliations.

• 1 Department of Pediatrics, School of Medicine, University of Navarra, 431008 Pamplona, Spain.
• 2 Navarrabiomed (Biomedical Research Center), 31008 Pamplona, Spain.
• 3 Department of Pediatrics, Navarra Hospital Complex, 31008 Pamplona, Spain.
• PMID: 38542128
• PMCID: PMC10969999
• DOI: 10.3390/ijms25063154

Hashimoto's thyroiditis (HT) is marked by self-tissue destruction as a consequence of an alteration in the adaptive immune response that entails the evasion of immune regulation. Vitamin D carries out an immunomodulatory role that appears to promote immune tolerance. The aim of this study is to elaborate a narrative review of the relationship between vitamin D status and HT and the role of vitamin D supplementation in reducing HT risk by modulating the immune system. There is extensive literature confirming that vitamin D levels are significantly lower in HT patients compared to healthy people. On the other hand, after the supplementation with cholecalciferol in patients with HT and vitamin D deficiency, thyroid autoantibody titers decreased significantly. Further knowledge of the beneficial effects of vitamin D in the prevention and treatment of autoimmune thyroid diseases requires the execution of additional randomized, double-blind, placebo-controlled trials and longer follow-up periods.

Keywords: Hashimoto thyroiditis; anti-thyroglobulin antibodies; anti-thyroid peroxidase; autoimmune thyroiditis; autoimmunity; immune cells; vitamin D; vitamin D deficiency; vitamin D supplementation.

Publication types

• Hashimoto Disease* / drug therapy
• Randomized Controlled Trials as Topic
• Vitamin D / therapeutic use
• Vitamin D Deficiency* / complications
• Vitamin D Deficiency* / drug therapy
• Vitamins / therapeutic use

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