Vitamin A Role and High Dose Supplementation

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DiscussiononVitaminA
Vitamin A: Introduction, Role in Public Health, and High Dose
Supplementation as an Intervention Strategy
I. Introduction to Vitamin A
Forms and Functions
Vitamin A is a fat soluble vitamin required for various metabolic activities such as proper
functioning of visual system, cell reproduction and differentiation, proper immune function,
proper functioning of epithelial tissues, and normal growth and development of the body (FAO,
2001 and Sherwin et. al., 2012) .Vitamin A is considered an essential micronutrient which is
required for the aforementioned metabolic activities in the body. Vitamin A is not a single
compound, rather it is a group of similar compounds which can be processed into the active
retinol form within the body. This includes compounds such as retinal, retinoic acid, and retinyl
esters. Likewise, carotenoids which act as precursors of retinol are also classified as vitamin A.
Carotenoids such as Beta-carotene, lycopene, and Beta-cryptoxanthin are a few compounds
which act as a precursor to retinol. The bioavailability of retinoid form is much higher than
carotenoids form.
Vitamin A has a crucial role in visual system in the body. The necessity of vitamin A for the
proper functioning of the visual system was recognized by researchers from earlier studies. In the
rod cells of the retina in the eye, vitamin A is required for the functioning of rhodopsin which
helps us to see in the dark. Thus, deficiency of vitamin A leads to night blindness, the first form
of Xeropthalmia. With further depletion of vitamin A in the body, Xeropthalmia chronologically
proceeds to more progressive forms like Bitot’s spot, corneal xerosis, reversible keratomalacia,
non-reversible keratomalacia, and corneal scar. (Sherwin et. al., 2012) Xeropthalmia is often

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associated with poor nutrition and diseases like diarrhea, measles, and respiratory infection.
(Sherwin et. al., 2012)
Another crucial role of vitamin A is in cellular differentiation and reproduction of the epithelial
tissues in the body. Various epithelial tissues in skin, gastrointestinal, respiratory and urogenital
tracts require vitamin A for differentiation and reproduction. Furthermore, vitamin A is thought
to be required in bone growth and reproductive processes. As a result, vitamin A is very
important for the growth and development of the body, especially among children. Finally, the
role of vitamin A in immune system function is also very important. Studies suggest the vitamin
A is involved in phagocytic activity, T-lymphocyte function, and antibody response to bacterial,
viral, and parasitic infections. (Ross A, 1992) Undoubtedly, these functions of vitamin A have
played major roles public health and nutrition policies as governments and stakeholders see
vitamin A interventions as a strategy to reduce blindness, infection, and mortality among
children under 5 years of age.
Food Sources of vitamin A
Normally vitamin A is obtained in the body through intake of foods which are either a source of
retinoid form or a carotenoid form of vitamin A. Retinoid form of vitamin A comes from animal
source food such as beef, liver, red meats, eggs, milk, butter, cheese, fish etc. (Sherwin et. al.,
2012) Similarly, carotenoid form comes from plant source food such as dark green leafy
vegetables ( e.g. spinach, kale) and deep orange/yellow/red foods ( e.g. mangoes, sweet potatoes,
squash, carrots, papayas, pumpkins). (Sherwin et. al., 2012)

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Absorption and Storage in the body
Regardless of form of intake, the digestion, absorption, and transport of vitamin A requires
adequate amount of fat in the diet. In the stomach and the intestine, the vitamin A compounds
bound to proteins are released with the help of enzymes. These vitamin A compounds combine
with fats into globular form which is absorbed and transported through the intestinal wall as
micelle. The vitamin A is then transported to other cells using chylomicron, a lipoprotein
structure that also carries fat in the body. The extra vitamin A obtained thorough diet is stored as
retinoid form in the stellate cells of the liver for future uses. This helps to keep the blood retinol
level in the fairly constant. The liver can store a lot of extra vitamin A for future use and toxicity
occurs only in very high doses when the liver cells are vitamin A replenished to its full capacity.
These characteristics of vitamin A are important as it forms the basis for the high dose
supplementation strategy, which is discussed in the following sections of this paper.
II. Vitamin A in Public Heath
Prevalence of Vitamin A deficiency (VAD)
Globally, VAD is a major nutrition and public health problem among vulnerable population
groups such as infants, children, and pregnant women because they have increased requirements
due to rapid growth and development in the body. Vitamin A is of significant public health
concern because VAD manifests into poor growth and symptoms of Xeropthalmia, and also due
to its role in preventing infection and mortality among children. Although adults and elders may
also suffer from VAD, children under 5, pregnant and lactating women are recognized as the
most at-risk population group for VAD. Lancet Series 2008 defines VAD as having symptoms of
Xeropthalmia or blood serum retinol of <0.7micromol/L. (Black et. al, 2008) Severe deficiency

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is defined as having <0.35 micromol/L blood serum retinol. Lancet 2008 shows that the
prevalence of VAD among children under 5 is high mainly in countries of Africa, South Asia,
and sub national population in Brazil and China. Among pregnant women, the global prevalence
of night blindness among is 7.8%, which accounts to 9.7 million pregnant women. Similarly,
15.3% of pregnant women (i.e. 19.1 million) are estimated to have low serum retinol levels. Data
for children (aged 6-59 months) states that about 2-3% i.e. about 157,000 child deaths are
attributable to VAD. Similarly, the prevalence of VAD among preschool children is estimated to
be around 33% or 90 million children globally. (Black et. al., 2013)The prevalence of night
blindness among preschool children is estimated to be about 0.9% or 5.17 million children
globally.
Given the prevalence and the risk among vulnerable population, the prevention and treatment of
VAD deficiency has been a public health priority for many countries especially in the last few
decades. The increased focus is also because optimal levels of vitamin A has been shown to
reduce mortality among children (especially via reduction in measles and diarrhea related
mortality). Likewise, studies have found that poor health and infection are increased among
children with depleted vitamin A stores. This public health significance is backed by many
clinical studies that have established the critical role of vitamin A in proper functioning of
mucosal surfaces and immune function. In addition, vitamin A metabolites interact with the
genome to control the sequence of expression in various genes. In summary, it can be said that
these findings has led to vitamin A status among infants, children, and pregnant and lactating
women being top national public health and nutritional priorities for many governments
throughout the world.

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Causes for Vitamin A deficiency
There are various dietary, socio-economic, environmental, and biological causes that leads to
vitamin A deficiency. Dietary causes include diets low in vitamin A rich foods such as meat,
liver, beef, eggs, dark leafy vegetables, and orange and red colored fruits. Similarly, poor diets of
pregnant and lactating women leads to depleted stores in women and consequently leads to
vitamin A deficiency in infants and neonates. Also, inadequate intake of fats may cause vitamin
A deficiency as it is a fat soluble vitamin. Other poor infant and young child feeding (IYCF)
practices such as sub-optimal breastfeeding and complementary feeding practices can also cause
vitamin A deficiency. Social causes like poverty, limited income, and marginalized groups are
also contributing cause for VAD as poor households. Lower socio-economic households have
limited access (financial and/or market access) to vitamin A rich foods like meat, liver, eggs,
green leafy vegetables, and orange or red fruits. Environmental factors such as repeated
infections due to unhygienic living environment may also lead to VAD by increasing
requirements, metabolism, and excretion. (Stephenson, 1994) Finally, there can be biological and
physiological causes for vitamin A deficiency such as decreased bioavailability due to liver or
pancreatic problems, fat malabsorption, and competition with vitamin D for absorption.
As a result of multi-faceted causes for vitamin A deficiency, various types of interventions can
be used for improving vitamin A status among vulnerable population. High dose vitamin A
supplementation, food fortification, improvement of IYCF practices, provision of
complementary foods, improvements of perinatal health services, and school feeding programs
are some examples of intervention for addressing VAD. Moreover, there are cross-sectoral
interventions which aim to tackle the underlying causes for poor nutrition and health.

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Improvement in quality and quantity of agricultural products, social safety net programs,
improvement of market access are some interventions that aim to address a broader set of
underlying causes for poor health and nutrition. This paper focuses on high dose vitamin A
supplementation as an intervention strategy.
III. DiscussiononHigh Dose Vitamin A Supplementation
Evidence for Supplementation
It was already established from clinical trials that vitamin A plays a major role in correcting the
symptoms of Xeropthalmia such as night blindness, corneal damage, and blindness. From a
public health point of view, the interest in vitamin A supplementation as a major intervention
strategy for reducing mortality started with a large study among more than 25000 children from
450 villages in Sumatra. (Sommer et al, 1986). The study found that child mortality in children
without the vitamin A supplementation (control villages) was 49% higher than mortality in
children with vitamin A supplementation. In summary, the study predicted that vitamin A
supplementation can reduce mortality by 34%. The results of this large research prompted a
series of studies that aimed to examine the effects of high dose vitamin A supplementation on
mortality. There were vitamin A supplementation studies conducted in various developing
countries with high burden of vitamin A deficiency. The results of 10 such experimental studies
was analyzed in a UN policy brief in 1992 and it concluded that vitamin A supplementation can
reduce mortality among children by about 23% ( Relative risk ratio= 0.77, 95% CI 0.68 - 0.88
random effects model). These studies were from high burden countries like India, Nepal, Sudan,
Ghana, and Indonesia. (United Nations, 1992) The results of the analysis is shown in Appendix
A. The same policy brief also examined the role of vitamin A on morbidity. It concluded that

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although effects of vitamin A supplementation on morbidity could not be teased out, there
seemed to be a clear benefit of good vitamin A status on fighting infection. Especially the
severity of morbidity and mortality due to measles and diarrhea was reduced by vitamin A.
Following these findings, the public health and nutrition policy realm started to recommend high
dose supplementation as an intervention strategy in treating vitamin A deficiency. This is evident
in the World Health Organization (WHO) report in 1996 which stated that the objective of
supplementation strategy is to achieve high coverage of vitamin A doses for children in high
VAD endemic areas by a system that is administratively feasible, culturally acceptable, and
economically practical. (WHO, 1996)
Supplementation as a Prominent Intervention Strategy
The results from these vitamin A supplementation studies on treating night blindness and
reducing mortality was picked up by many governments with high burden of vitamin A
deficiency among children in their country. Many governments pursued high dose vitamin A
supplementation as an intervention strategy starting the late 1990s. An advantage of the
supplementation strategy was that it was a straightforward intervention strategy that could be
carried out by governments with limited resources and capacities. Supplementation strategy
which commonly included giving one high dose vitamin A capsule (200 000) IU to children (6-
59) months twice a year was manageable by most governments.
The popularity in supplementation strategy is evident in UNICEF vitamin A supplementation
2007 report which points out that out of 60 high impact supplementation countries most have an
under 5 vitamin A supplementation program and many countries also pursue a post-partum
supplementation program. (UNICEF, 2007) In comparison, other intervention strategies such as
food fortification is only carried out in a smaller number of the countries.

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Usually, the dosage of vitamin A supplementation capsule is many times higher (about 400 times
higher) than the recommended daily requirement for children. However, the scientific rationale
behind this strategy is that since vitamin A is fat soluble and is stored in liver, the high dose
replenishes the vitamin A stores in children which can be later mobilized in the body during
deficits due to poor intake. (WHO, 2011) When the stores of vitamin A are replete in the body, it
usually takes months of deprivation of vitamin A rich diet to result in vitamin A deficiency in the
body. Hence, high dose vitamin A supplementation every 4-6 months helps to keep adequate
stores of vitamin A in the body. Despite the potential use of supplementation and the justification
by scientific knowledge, it is important to note that high dose vitamin A supplementation was
recommended as a temporary treatment and prevention measure for VAD in endemic areas and it
was not recommended as a long term solution or replacement of other food based vitamin A
interventions. (WHO, 1996)
Argument against Supplementation
In subsequent years, many researchers point out that despite of the limited evidence on the
effectiveness of high dose supplementation, many governments and stakeholders are using
supplementation as the major intervention strategy against VAD. One of the most influential
study for backing this argument is the DEVTA study in the Uttar Pradesh region of India. This 5
year study used a cluster-randomized study to measure the effects of vitamin A supplementation
and deworming in 1 million pre-school children in Uttar Pradesh. The final analyses by Awasthi
et. al. showed no statistically significant difference in the final mortality rate ratio of children (1-
6 years) between the vitamin A supplemented group and the control group. The mortality results
were not statistically significant even when disaggregated by gender, diseases, time period, and
presence or absence of deworming. For diarrheal mortality (responsible for 28% of all deaths)

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the risk ratio was 0·94 (95% CI 0·83–1·06) and for measles mortality (6% of all deaths). Overall,
the study concluded moderate effect of vitamin A supplementation which is significantly less
than previous estimation. (Awasthi et.al., 2013) The results of the DEVTA study is shown in
Appendix B.
The results from DEVTA and other studies were used by academics to show the flaws in vitamin
A supplementation strategy. For instance, Mason et.al. point out that many of the studies used for
the establishing the initial 23% reduction of mortality finding was based on trials in late 1980s
and early 1990s with varied results and inconclusive findings. (Mason et. al., 2014) Furthermore,
Mason points out that only one vitamin A study after 1994 has shown significant effect on
mortality. Mason states that newer meta-analyses adding nine newer studies (which includes
DEVTA) with the original studies have estimated the effect of vitamin A supplementation at 11
% rather than the initial 23%. He adds that the patterns of disease have changed over the years
and many developing countries have reduced the prevalence of diseases like measles and
diarrhea. This might be the reason for seeing newer studies showing significantly lesser effect (or
no effect) of vitamin A supplementation on mortality. When the results of the newer studies are
combined with the older studies, the estimated effect of vitamin A is reduced from 23% to 11%.
Mason criticizes the policymakers for using high dose vitamin A supplementation strategy as a
cheap fix for VAD rather than focusing on diet based approaches. He points out that the rate of
decrease of VAD prevalence from 1990-2005 is just 0.3 percentage points per year clearly
outlining the ineffectiveness of the current supplementation strategy and the need for pursuing
other strategies.

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IV. Recommendations
Needfor change
Over the years the criticism against high dose vitamin A supplementation has grown. The recent
studies have failed to show substantive benefits of vitamin A supplementation on mortality and
health. The evidence for recommending high dose vitamin A supplementation was based on
studies that were conducted about 25-30 years ago. Critics point out that the nature of diseases
have changed over the years and fewer children die from diseases like measles and diarrhea.
Hence, the policy and programming response for correcting VAD has to change. More
worryingly, critics point out that the extensive use of this strategy is diverting resource from
other long term interventions such as improved dietary diversity and fortification of foods.
The risk of toxicity and side effects from mega dosing is another argument against high dose
supplementation. This is the reason why WHO strongly recommends no supplementation for
pregnant women, postpartum women, neonates, and infants from 1-5 months. Supplementation is
only strongly recommended for children aged 6-59 months. (Sherwin et al., 2012)
Alternative Interventions
Currently, single intervention or a combination of interventions such as food fortification,
consumption of vitamin A rich foods via diverse diets, improved breastfeeding, better
complementary feeding practices, and improved WASH practices are proposed as the
alternatives to high dose supplementation. Many agree that the primary focus for treatment of
VAD should be improved production and consumption of vitamin A rich foods like dark green
leafy vegetables and red/yellow fruits.(Kapil, 2009) Furthermore, increased production and
consumption of animal source foods such as eggs, liver, meat, and milk should also be the focus

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for countering VAD. In his chapter “Vitamin A” Solomons provides evidence that consumption
of indigenous fish in Bangladesh and addition of milk or meat to school snacks in Kenya have
improved vitamin A intake. Similarly, in South Africa and Thailand home gardening
interventions promoting consumption of plant sources have also shown improvements in vitamin
A. (Solomons, 2012)
Fortification of commonly consumed food with low doses of vitamin A is another intervention
strategy that is widely used to treat VAD. Usually, large scale fortification involves selecting an
appropriate vehicle food that is consumed universally by the population group (regardless of
social status and income). (Solomons, 2012) Sugar and oil are the common vehicle for
fortification as they are widely consumed by all groups of people in most population. Bio
fortification is another type of fortification includes modifying the food source so that it has
more nutritional values. Golden rice and orange flesh sweet potatoes are some popular examples
of bio fortification. (Solomons, 2012)
Finally other cross cutting interventions aimed at improvement of health and nutrition are
recommended for reduction in VAD. Since pregnant and lactating women, neonates, infants and
children under 5 years are the most vulnerable group for vitamin A deficiency, cross cutting
interventions such as IYCF practices, better complementary foods, improvement in prenatal
health services, improved WASH practices, and behavior change are effective in improvement of
vitamin A status.

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Conclusion
The academic literature suggests that the evidence against high dose vitamin A supplementation
is mounting. However, policymakers and stakeholders are sticking to high dose supplementation
strategy in many countries. It is important to gradually phase out vitamin A supplementation
programs with more sustainable and long term interventions. All parties agree that improvement
of diet via production and consumption of vitamin A rich foods is the best option. The next best
option suggested by the academic literature is the adequate intake of vitamin A via low dose
fortification of most commonly used foods. Along with these two interventions, constant focus
and development of cross cutting sectors such as health, education, and agriculture also provide
dividends in future.
In defense of high dose supplementation, many countries still have areas with high burden of
vitamin A deficiency. Mainly people with low SES status, limited market access, and education
have high prevalence of VAD. Currently, high dose supplementation might be the only feasible
and economic way to help these groups. Then, there is the question of capacity and
implementation. Governments from many high burden countries have programmatic structures,
resources, and personnel to carry out high dose supplementation twice a year. Many countries
have claimed this intervention to be highly successful. It will be difficult to abruptly eliminate
these programs and push for other interventions. Hence, high dose supplementation must be
phased out gradually by working with the stakeholders.

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References
Awasthi, S., Peto, R., Read, S., Clark, S., Pande, V., Bundy, D., & DEVTA team, (2013).
Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north
India: DEVTA, a cluster-randomised trial. Lancet Series, 381, 1469-1477.
Black, R. E., Allen, L. H., Bhutta, Z. A., Laura E Caulfield, deOnis, M., Ezzati, M., . . . Rivera, J.
(2008). Maternal and child undernutrition: global and regional exposures and health
consequences. Lancet Series, 371, 243-260. doi:10.1016/S0140-6736(07)61690-0
Black, R. E., Victora, C. G., Walker, S. P., Bhutta, Z. A., Christian, P., deOnis, M. (2013).
Maternal and child undernutrition and overweight in low-income and middle-income
countries. Lancet Series, 382, 427-451.
FAO. Chapter 7. Vitamin A. Human Vitamin and Mineral requirements, 2001.
Kapil U. Invited commentary: Time to stop giving indiscriminate massive doses of
synthetic vitamin A to Indian children. Public Health Nutrition 2009;12:285-86.
Mason J, Greiner T, Shrimpton R, Sanders D, Yukich J. Vitamin A policies need rethinking.
International Journal of Epidemiology 2014:1-10.
Ross A. Vitamin A and protective immunity, Nutr Today. 1992;27: 18-26
Sherwin JC, Reacher MH, Dean WH, Ngondi J. Epidemiology of vitamin A deficiency and
xerophthalmia in at-riskpopulations. Royal Society for Tropical Medicine and Hygiene 2012;
106:205-14.
Solomons NW. Vitamin A. In: John W. Erdman Jr IAMaSHZ, editor. Present Knowledge in
Nutrition: International Life Sciences Institute; 2012.
Sommer, A., Tarwotjo, I, Djunaedi, E., West, Jr., K. P., Loeden, A. A., Tilden, R., Mele, L., and
the Aceh Study Group (1986). Impact of vitamin A supplementation on childhood mortality: a
randomised controlled community trial. Lancet 327: 1169−73.
Stephensen CB, Alvarez JO, Kohatsu J, Hardmeier R, Kennedy Jr JI, Gammon Jr RB. Vitamin A
is excreted in the urine during acute infection. Am J Clin Nutr 1994;60:388–92.
UNICEF. Vitamin A Supplementation: A Decade of Progress. 2007.
United Nations. Effectiveness of Vitamin A Supplementation in the Control of Young Child
Morbidity and Mortality in Developing Countries − Nutrition policy discussion paper No.
13 1992.
WHO. Guideline: Vitamin A supplementation in infants and children 6–59 months of age 2011.

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WHO. Indicators for Assessing Vitamin A Deficiency And their Application in Monitoring and
Evaluating Intervention Programmes. 1996.

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Appendix A
Source: United Nations. Effectiveness of Vitamin A Supplementation in the Control of Young Child
Morbidity and Mortality in Developing Countries− Nutrition policy discussion paper No. 13 1992.

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Appendix B
Source: Awasthi, S., Peto,R., Read, S., Clark, S., Pande,V., Bundy, D., & DEVTA team,(2013).
Vitamin A supplementation every 6 monthswith retinol in 1 million pre-school children in north India:
DEVTA, a cluster-randomised trial. Lancet Series,381, 1469-1477

Vitamin A Role and High Dose Supplementation

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