Description of the condition
Vitamin A deficiency (VAD) is a major nutritional public health problem in the developing world. According to the latest report of the World Health Organization (WHO), globally about 190 million preschool-aged children and 19.1 million pregnant women are vitamin A deficient (i.e. serum retinol < 0.70 µmol/l) (WHO 2009). This corresponds to 33.3% of preschool-aged children and 15.3% of pregnant women in populations at risk of VAD. According to current estimates, 122 countries are classified as having a moderate to severe public health problem based on biochemical VAD in preschool-aged children, and 88 countries based on biochemical VAD in pregnant women (WHO 2009).
VAD impairs numerous body functions and can lead to many adverse health consequences including xerophthalmia (dry eyes), infectious morbidity, mortality, sub-optimal physical growth and anaemia (Sommer 1996; Rice 2004). Xerophthalmia is the primary preventable cause of blindness; of the world’s children with xerophthalmia, nearly half reside in South or South-East Asia, of whom more than 85% live in India (West 2002a). About 5.2 million preschool-aged children and 9.8 million pregnant women suffer from night blindness, which represents 0.9% and 7.8% of the population at risk of VAD, respectively. The estimates show that Africa and South-East Asia contain the highest proportions of preschool-aged children and pregnant females with biochemical VAD and night blindness (WHO 2009).
The etiology of VAD is interconnected with a deprived ecological, social and economic environment, in which a chronically deficient dietary intake of vitamin A coexists with severe infections, such as measles, diarrhoea and respiratory diseases (Sommer 2002; Rice 2004). Intake of vitamin A is further lowered through depressed appetite and poor absorption, and body stores of vitamin A are depleted through excessive metabolism and excretion (Alvarez 1995; Mitra 1998). This combination of poor diet and increased frequency of infections in Vitamin A deficient populations leads to a vicious cycle of VAD and infection in vulnerable groups, notably young children and pregnant or lactating mothers (Sommer 2002; West KP 2003). These are the most compelling consequences of VAD, and underlie its significance as a public health problem around the world (West 2002a; WHO 2009).
Description of the intervention
Vitamin A is a term used for a subclass of a family of lipid-soluble compounds referred to as retinoic acids (Bates 1995). The molecule of retinoic acid consists of four isoprenoid units joined in a head to tail fashion. Vitamin A is found in two main forms: provitamin A carotenoids (beta-carotene and others), and preformed vitamin A. Provitamin A carotenoids, mainly found in plants, have many forms, but beta-carotene is the only one that is metabolised by mammals into vitamin A. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl esters), on the other hand, is the most active form of vitamin A and is found mainly in animal sources of food. It is also the form supplied in most supplements (Bates 1995; Shenai 1993). In humans, vitamin A is considered an essential nutrient which means that it cannot be synthesised by the body and therefore must be provided through diet (Bates 1995). Vitamin A is required for normal functioning of the visual system, and maintenance of cell function for growth, epithelial integrity, red blood cell production, immunity and reproduction (Sommer 1996).
In poor societies, especially in lower income countries, VAD among children is a major nutritional concern. In these areas, deficiency of dietary vitamin A can begin early in life, with colostrum being discarded or breastfeeding being inadequate, thereby denying infants their first, critical source of vitamin A (Haskell 1999). Later, in early childhood and adulthood, VAD continues to develop as a result of a diet deficient in vitamin A. It is a particular concern where consumption of animal source or fortified foods is minimal and diet relies heavily on vegetables and fruits (Ramakrishnan 2002). Modest amounts of vegetables and fruits as the sole source of vitamin A may not deliver adequate amounts, based on an intestinal carotenoid-to-retinol conversion ratio of 12:1, even though they are nutritious in many other ways (US Institute of Medicine, Food and Nutrition Board). This conversion efficiency reflects that VAD may even coexist in cultures that heavily depend on vegetables and fruits as their sole or main dietary source of vitamin A (West 2002). Due to the factors described above and the documented effect of synthetic vitamin A supplementation (VAS) in reducing infectious morbidity and mortality, the WHO recommends supplementation with vitamin A for preschool-aged children and pregnant mothers. It is recommended at a dose of 50,000 IU for infants under six months of age, 100,000 IU for infants six to 12 months of age and 200,000 IU for children over 12 months of age, every four to six months. Mothers should also be supplemented with 200,000 IU of vitamin A within eight weeks of giving birth (WHO 1997).
How the intervention might work
Vitamin A has been termed as an anti-infectious vitamin because of its role in regulating human immune function (Green 1928). Early studies in animals and humans revealed an association between VAD and increased susceptibility to infections (Semba 1999). Vitamin A also plays a major role in phototransduction in the eye. Vitamin A is required to produce rhodopsin, a photopigment in the retina that is responsible for sensing low light conditions. VAD causes degradation, beginning with night blindness and leading to xerophthalmia (Sommer 1996).
In addition to the documented preventive and therapeutic effect of VAS against xerophthalmia (Sommer 1996), prophylactic VAS in apparently healthy children (over six months of age) residing in developing countries has been shown to reduce childhood mortality by between 23% and 30% (Beaton 1993; Fawzi 1993; Glasziou 1993). Most of this reduction is due to the effect on diarrhoea and measles mortality. National and regional programmes of VAS are in place in over 70 countries worldwide and these programmes are not only highly effective in reducing mortality and morbidity, but also appear to be among the most cost-effective public health interventions available (Fawzi 2006). Side effects of VAS are rare in children aged six months or older with standard supplementation; however, vitamin A toxicity can develop if large amounts of vitamin A are used over a prolonged period of time. The symptoms of toxicity include liver damage, headaches, vomiting, skin desquamation, bone abnormalities, joint pain and alopecia (Smith 1976). A very high single dose can also cause transient acute toxic symptoms that may include a bulging fontanelle in infants; headaches in older children and adults; and vomiting, diarrhoea, loss of appetite, and irritability in all age groups. Toxicity from ingestion of food sources of preformed vitamin A is rare (Hathcock 1997). In addition to looking for specific effects, this review will examine all-cause mortality and morbidity to ensure that effects are not overestimated (for example, by discounting the possibility that the intervention reduces some causes of mortality whilst increasing others).
Why it is important to do this review
It is important to do this review given the huge burden of mortality and morbidity (infections) associated with VAD and to explore the role preventive VAS can play in reducing all-cause, cause-specific mortality and morbidities in children six months to five years of age. The role of prophylactic and therapeutic VAS has been the subject of several systematic and narrative reviews before; however, most of these are now out of date and the most recent includes fortification and maternal supplementation, which work differently for social (for example, delivery) and biological reasons.
The therapeutic role of vitamin A has been evaluated for measles and non-measles pneumonia in two separate Cochrane reviews (Ni 2005; Yang 2009). The prophylactic role of vitamin A has also been or is being evaluated in different Cochrane reviews in different subpopulations of children and mothers (Bello 2009; Chen 2008; Darlow 2007; Gogia 2008; Haider 2008; Oliveira 2006; van den Broek 2002; Wiysonge 2005). However, no Cochrane review has addressed VAS in children six months to five years of age. Four meta-analyses have been published that evaluate the role of VAS in reducing infant and childhood mortality in children under five years of age (Beaton 1993; Fawzi 1993; Glasziou 1993; Gogia 2008a). All reported a statistically significant reduction in all-cause child mortality in a range of 23% to 30%. However, these reviews had different inclusion and exclusion criteria and inadequate methodological evaluation of the included studies. For example, Gogia included studies of maternal VAS with childhood supplementation in the meta-analysis (Gogia 2008a). This makes it difficult to infer the impact of direct supplementation on the child with vitamin A alone compared to vitamin A reaching the child through breast milk with maternal VAS, or through both direct and breast milk pathways. In a review by Beaton, unpublished data were included whose methodological quality was not thoroughly evaluated (Beaton 1993).This review will include an up-to-date assessment of the best available evidence, including relevant subgroup analyses (described below), as a basis for recommendations to the WHO. VAS can be a very cost-effective intervention that can be easily administered to children and if evidence of benefit is found, then consideration could be given for its supplementation on a large-scale to save lives and avert morbidities like infections and blindness, especially among children in developing countries where routine VAS is not part of the national programme.