Contents - Previous - Next

This is the old United Nations University website. Visit the new site at http://unu.edu

Dietary vitamin-a deficiency: effects on growth, infection, and mortality

Keith P. West Jr.

Abstract

Vitamin A (VA) has been experimentally linked in animals to growth in weight, host resistance to infection, and survival for nearly eight decades. These consistent findings appear to have their human correlate. VA-deficient children are more likely to have comorbidity and to be stunted in growth, and they have a higher risk of mortality. In several large field trials VA supplementation has reduced mortality by >= 30%. Presumably a similar or greater public health impact can be achieved by improving dietary VA intake. The relation between dietary imbalance and VA deficiency starts at a young age. Early cessation of breast-feeding, poor quality of the weaning diet, and infrequent consumption of VA-rich foods appear to underlie mild xerophthalmia. These dietary imbalances often coexist with food access. We must know how to alter detrimental food habits before dietary interventions can be formulated. Improving dietary quality to enhance VA nutriture will likely carry numerous other nutritional benefits to children.

Introduction

Vitamin-A (VA) deficiency is a serious disease that primarily affects children living in developing countries. The magnitude and associated risks of VA deficiency have for years been evaluated in terms of potentially blinding xerophthalmia. Each year an estimated 8 to 10 million children develop xerophthalmia [1] as classified by the World Health Organization: night blindness (XN), conjunctival xerosis (X1A), Bitot's spots (X1B), corneal xerosis and ulceration (X2), or blinding keratomalacia (X3) [2]. Conservatively, more than a quarter of a million children go blind from xerophthalmia each year [3]. However, where VA deficiency is endemic, 1%-15% of preschool-aged children may have the condition [38]. However, on the basis of circulating VA levels [8-11], early VA-deficiency-induced cytologic abnormalities [12; 13], and depleted hepatic retinol stores [14], 30%-60% of the preschool-aged children in these areas may be VAdeficient.

Several epidemiological studies suggest that the risks of VA deficiency far exceed its ocular consequences, as long suggested by animal data and early clinical studies [15; 16]. The effects of the condition and repletion on growth, infection, and survival as well as basic dietary patterns that underlie VA deficiency are examined in this paper.

Vitamin A and growth

Vitamin A clearly influences growth, although the cellular mechanisms are only beginning to be revealed. For example, retinoic acid, an active metabolite of VA that is transported intracellularly by its own binding protein [17], activates gene transcription by way of a nuclear receptor [18], similar to those existing for steroids [19]. This retinoic acid receptor shares a common gene sequence with the thyroid hormone nuclear receptor [20]. As a result, retinoic acid may act with thyroid hormone to regulate growth hormone [21]. A metabolic link between growth-hormoneinduced growth and VA has been suggested [22], although the interactive role(s) of VA in growth in vivo remain unclear [23].

Less understood is the growth response of children to VA and, where such a response is seen, the degree to which it represents a direct or an indirect effect. Animal data provide most of the evidence on VA and growth, although the validity of models that often involve progressive depletion or repletion in explaining the VA growth function in children (who wax and wane in their VA status and growth rate throughout childhood) may be open to question.

Animals

Weight growth

Most references to VA and growth relate to the effect of the vitamin on experimental weight gain. The linkage between VA and growth in weight was established in 1913 [24]. Deceleration of weight gain is the most reliable early indicator of acute VA depletion in a young animal [25-27], being first detectable in the presence of measurable hepatic (e.g., > 25 mg of total stores in rats) and marginal circulating (<25 mg/dl) levels of retinol [28; 29]. As growth begins to slow, losses in efficiency of food utilization become apparent [26; 30]. Changes that appear with early deceleration of weight gain include reduced appetite [26], slower hepatic release [31] and enhanced enterohepatic recovery [32] of retinol, abnormal bone cartilage metabolism [33; 34], decreased urinary calcium excretion [35], loss of intestinal goblet cells [36], metaplasia of the respiratory tract [37], and mild alterations in immunocompetence [38; 39].

As VA depletion progresses, serum retinol levels initially remain normal despite a reduction in hepatic VA [28; 40]. Weight gain, although decelerating, continues as long as liver stores exist, ceasing altogether when hepatic and circulating retinol levels are nearly exhausted [28; 33; 41]. Other lesions that appear at this weight plateau stage include an elevation in cerebrospinal-fluid (CSF) pressure [25; 42; 43], reduced visceral growth [27], goblet-cell loss in the gut mucosa [26; 44; 45], and metaplasia with focal keratinization in the respiratory [26; 41; 46-48] and genitourinary tracts [46]. Thus, complete cessation of weight growth appears to herald frank experimental VA deficiency, signalling the collapse of normal adaptation. With continued VA deficiency, subsequent weight loss occurs with dramatic losses of body fat [49-51], deranged protein metabolism [49; 50; 52], and clear impairment in the immune response with a further increased risk of infection [53-55]. If experimental animals survive, xerophthalmia also develops [56].

Readministering a small fraction of the daily VA requirement to depleted animals has little effect on liver storage, raises serum retinol only marginally, and does not resolve clinical or histopathological signs of deficiency [57; 58], but promptly restores weight gain [32; 57-63] and reverses mortality [62; 64]. With a larger daily dosage, the rate of weight gain increases slightly and stabilizes as circulating levels of VA [60; 62] and CSF pressure [63] normalize, and survival improves [60; 62]. Larger (physiological) doses of VA stimulate significant liver storage [32; 58; 60; 61]. A similar sequence of tissue repletion, restoration of weight growth, reduced mortality, and build-up of liver reserves follows single, graded oral doses of VA [59].

VA requirements are reduced when other dietary deficiencies limit growth. For example, low protein intake reduces tissue growth and hepatic mobilization of VA, because, in part [65], of a decreased synthesis of the carrier (retinolbinding) protein in the liver [66]. VA supplementation will not reverse faltering weight growth in the presence of insufficient dietary protein [67-69], although it may spare protein to some extent and retard the rate of weight loss [70]. In a marginal VA state, a low protein intake will depress growth and delay the appearance of signs of VA deficiency [71]. Adding high-quality protein (e.g. case in) without VA will initially accelerate weight gain, rapidly deplete liver VA stores [65], and exacerbate clinical signs of deficiency [71]. Growth failure rapidly ensues [71].

Skelatal growth

Cartilaginous (endochondral) growth occurs within the epiphyseal growth plates of long bones, and compact bone remodelling is achieved through apposition by osteoblasts and resorption by osteoclasts on bone surfaces. These processes determine the length and shape of bone respectively and appear to be affected by VA. VA-deficient rats exhibited "inactive osteogenesis" (i.e. reduced cell proliferation, dense calcification, and irregular trabecular tunnelling) in the epiphyses of individual long bones [72], most evident in advanced deficiency [46]. Studies 40 to 50 years ago [73-75] reported retarded cartilaginous growth and bone shortening prior to the weight plateau. Later studies also reported depressed endochondral activity and shorter bones [37; 76], whereas others noted little initial effect on either epiphyseal growth [77; 78] or the length of individual long bones [79; 80] in VA-deficient animals. The balance of animal data, to date, suggests that endochondral growth is affected after VA deficiency is established and is probably, in part, secondary to inanition [37; 78; 79].

Bone remodelling may proceed at a normal pace during VA deficiency until disturbed by general malnutrition [73]. However, most studies observed distortion in bone remodelling occurring early rather than late [78; 81; 82]. In this regard, VA metabolites have been shown in vitro to act directly on bone resorption by osteoclasts [83].

Animal studies of changes in total body length that occur by altering VA intake are sparse. Early workers reported that chronically VA-deficient rats continued to grow in tail and body length despite weight loss [79], a condition that would lead to a decrease in weight relative to length. More recently, calves [77; 78] and ponies [84] given marginal VA intakes exhibited slightly lower rates of gain in both weight and height than animals eating similar amounts of food but with severalfold higher intakes of VA. Research on the effects of experimental VA deficiency and repletion on bone metabolism and growth should minimize the confounding effects of malnutrition and infection.

Children

Growth failure represents the most prevalent expression of childhood undernutrition in the developing world. Because of the complex interactions of factors that affect children's growth, such as individual components of the diet and metabolic responses to infection, it is often difficult to identify the independent effect of VA. Nevertheless, evidence suggests that under certain conditions, VA deficiency may limit the growth of children. The aspects of the growth response and the specific mechanisms responsible for the VA effect remain poorly understood. It is possible, for example, that the vitamin exerts a direct metabolic effect on bone growth, or that a secondary reduction in infectious morbidity with improved VA status may enhance growth. Studies of VA related to child growth may be descriptive or experimental. The former provide strictly associative evidence, whereas clinical trials attempt to establish cause and effect.

Attained growth

VA deficiency is consistently identified with stunted growth in cross-sectional studies. Children with corneal xerophthalmia (X2 or X3) are nearly always severely wasted and stunted [85-87] and usually have had antecedent severe infection [87]. Those with severe hyporetinaemia (serum retinol < 10 mg/dl) are twice as likely to be severely malnourished as children with higher serum VA levels [88; 89]. With such severe co-morbidity, however, it is impossible to relegate a specific growth-depressing role to VA deficiency in these children.

Mild xerophthalmia (XN or X1B), representing moderate VA deficiency, is occasionally related to mild wasting in preschoolers [6; 90]. Where specified, the association is weak and appears to be confined to those under two years of age. At older ages, mildly xerophthalmic children are similar in weight for height to their non-xerophthalmic peers [87; 91], suggesting that dietary energy and protein intakes are, at least quantitatively, similar between the groups.

Uncomplicated mild xerophthalmia appears to be due to a diet that is chronically insufficient in VA [91; 92]. It may then not be surprising that mild xerophthalmia is frequently associated with stunted height [87; 89; 91; 93; 94], itself a marker of chronic deprivation [95]. This relationship was clearly seen in Indonesia, where, at each age, preschool children with Bitot's spots were approximately 2 cm shorter than nonxerophthalmic children (fig. I ). A dose-response relationship was recently observed between "subclinical" VA deficiency (abnormal by impression cytology) and stunted height in a non-wasted population [96].

FIG. 1. Attained height of children 1-5 years old in Indonesia, by age and xerophthalmia status (Source: ref. 87; reproduced by permission)

An association between VA deficiency and stunting may be veiled by other nutritional imbalances. In Bangladesh, where chronic protein-energy undernutrition plagues child growth [97; 98], xerophthalmia was more prevalent only among children who were both stunted and wasted [99]. In Malawi, neither stunting nor wasting was associated with mild xerophthalmia [7; 100], suggesting that other nutrients or infections were the first limiting factors for growth.

Growth volocity

Data on VA status and growth velocity in children are limited. Early studies in Denmark [101; 102] noted coincidental poor growth, infection, and xerophthalmia among children lacking milk in their oatmeal diet during the spring, when European children usually grew at maximal rates. Bloch quickly observed a parallel between dystrophia alipogenetica (poor growth due to lack of a dietary fat-soluble substance) in these children and the deficiency syndrome in rats deficient in fat-soluble VA reported by McCollum and Davis [24].

New findings from an 18-month longitudinal study of about 4,000 Indonesian children conducted a decade ago [87] suggest that the dynamic effects of VA nutriture on child growth are complex. Children with mild xerophthalmia at the outset grew no differently over 18 months of follow-up than those who remained free of the disorder. However, children who were normal at the baseline but developed xerophthalmia by the end of the study (i.e. gradually became more VA-depleted) gained less weight and less height than those who remained clinically healthy (1. Tarwotjo, unpublished data).

Two large community trials in Indonesia examined the growth response to VA, employing different interventions. In one (the Aceh study), semi-annual distribution of VA (200,000 IU) improved weight gain and increased arm-muscle and fat areas in males two to five years old (i.e. past breast-feeding years), but had no consistent effect on female weight growth or on linear growth in either sex [ 103]. There was also no apparent effect among children less than 80% of the NCHS median weight for height [ 104] at baseline (K. P. West, unpublished data), suggesting that a minimum protein-energy reserve is necessary to mount a growth response to VA. Although the reasons for an age and sex difference in growth are unclear, the effect was internally consistent with reductions in xerophthalmia [5] and mortality [105; 106], and consistent externally with a generally higher risk of mild xerophthalmia in males and older preschool-age children [107].

A second field trial employed VA-fortified monosodium glutamate (MSG-A), distributed through normal marketing channels and consumed by over 90% of Indonesian families each week [10]. Daily average intake of VA from MSG-A by children was approximately 700 IU. The supplement lowered rates of xerophthalmia and raised serum and breastmilk levels of retinol [10]. Children who received MSG-A grew approximately 1 cm more per year in height between the ages of one and five years than controls [108]. There was no difference in weight gain, and sex differences were not evident.

The dissociated growth response to VA seen in these two trials may have been due, in part, to mode of delivery: a single' large bolus of VA given every six months may enhance weight gain (because of increased nitrogen retention or food efficiency) but have little effect on long-bone growth, at least over a 12-month period, whereas a small, daily increase in dietary VA through fortification may stimulate linear growth. The lack of weight gain in the MSG-A trial suggests that appetite may not have been improved in these marginally deficient children (in contrast to animal findings) or, alternatively, that usual household constraints on food availability continued to restrict the children's intake, requiring existing energy and protein reserves to support in part the incremental linear growth. Thus, changes in VA nutriture appear to affect growth where VA is the first limiting nutrient. A growth response to supplementation may not occur where other deficiencies are more severe.

Vitamin A and child morbidity and mortality

Over 20 years ago, Scrimshaw and colleagues posited a synergism between VA deficiency and infection based on decades of experimental evidence up to that time [15]. Since then the role of VA in immunity and host resistance to infection has been the subject of several extensive reviews [53-55; 109-111], to which the reader is referred.

VA deficiency has long been associated with an increased risk of infection in children. Cross-sectional and retrospective data point to a dose-response gradient in risk of acute lower-respiratory [87] and urinary-tract [112] infection among children with xerophthalmia. Severe corneal disease (X2, X3) is usually accompanied by a history of recent measles [87; 113], diarrhoea [87], and chronic plus acute malnutrition [85; 87;114].

Mild xerophthalmia (XN, X1B) [6; 7; 89; 100], hyporetinaemia (<20 mg/dl) [115], and an abnormal conjunctival cytology [96] have been associated with respiratory infection. An association with pre-existing diarrhoea generally is not observed when the duration of diarrhoea has not been specified [7;100;115;116]. However, each of several studies in Bangladesh found a consistent association between mild xerophthalmia and protracted diarrhoea (usually >= 14 days) [90; 117; 118], with one [90] reporting elevated risks due to Shigella and Entamoeba histolytica infection.

Prospective studies have helped to establish a temporal relation between VA deficiency and infection. In west Java, mildly xerophthalmic children were two to three times more likely to develop respiratory infection and diarrhoea [119] (table 1) and four times more likely to die [120] than non-xerophthalmic children. In India [121] and Thailand [115], VA-deficient children were at a higher risk of developing respiratory infection but not diarrhoea. perhaps due to imprecise specification of duration. These observations support animal data showing marked alterations in epithelial integrity and immune function and an increased risk of infection and mortality in the VA-depleted state [reviewed in 55].

However, observational studies do not establish cause and effect. Clinical trials have not yet produced clear findings about the role of VA in preventing childhood infections. Results may depend largely on the severity of pre-existing VA deficiency and the choice and measurement of morbidity outcome. To date, one small field trial has found a difference in morbidity [122] in the presence of marked reductions in mortality [8]. Several field studies are currently under way that may clarify this relationship. At present, the apparent paradox suggests that VA supplementation may not alter the incidence or duration of frequent childhood infections (at least as measured in field studies by parental history) but does influence the risk of dying from severe infection [123], with mortality representing the end stage of severe infection. The effect of VA on mortality from measles, as seen in three hospital-based clinical trials that have each reported reductions of 50% or more in case fatality following VA supplementation on admission (table 2) [124-126], demonstrates this point.

TABLE 1. Relative risks of infectious morbidity with mild xerophthalmia from comparable prospective field studies

a. Three-month intervals in Indonesia; six-month intervals in India.
*p= 06
**p<=.001.

Enhanced resistance to potentially fatal infection appears to underlie the marked reductions ( >= 30%) in preschool child mortality that have been observed in several community trials where VA supplements were given (in different dosages) twice [105] or three times [127] a year, weekly [8], or near-daily (through fortification) [108] (table 3). Verbal autopsy data, where available, suggest that fewer VA-supplemented children die from infections such as measles and severe diarrhoea or dysentery [8; 127]. One community trial has found a nonsignificant (about 6%) reduction in child mortality following semiannual supplementation [128] (table 3), the reasons for which may relate to regional variation in other risk factors for mortality.

Where VA has reduced preschool child mortality, infant mortality - largely between 6 and 11 months of age - has also been lowered by approximately 10% [108], 20% [105; 127], and over 70% [8] (table 3). These findings suggest that increasing the VA intake of older infants beyond what they consume in breast milk and weaning foods may measurably reduce their risk of dying. Whether enhancing VA nutriture (by improving maternal nutriture) can improve neonatal and early post-neonatal survival in endemically deficient populations is not known at present. Together, these studies provide rather convincing evidence that it is reasonable to expect a reduction in child mortality following VA supplementation of previously deficient populations [129; 130].

Vitamin A and early childhood feeding

The apparent impact on child survival of improving VA nutriture at a population level has invigorated the scientific, health, industrial, and political communities to focus unprecedented attention on the prevention of VA deficiency. Large-dose VA delivery in the community offers a practical, effective approach to short-term control [131], but its sustainability has been questioned. Fortification of sugar [88], monosodium glutamate [10; 108], or other centrally processed foods that are consumed by target groups represents another, potentially affordable option for increasing VA intake in some countries. However, for many countries, the long-term solution rests on improving dietary quality.

TABLE 2. Estimates of reduction in case fatality rates in hospitalized children with measles after treatment with vitamin A

a. Per 100 children.
b. Relative risk of mortality associated with not receiving vitamin-A therapy.
c. p<.02 for children under two years of age

TABLE 3. Protective effect of vitamin A against risk of infant and preschool-child mortality

a. Number of deaths per year/number of children enrolled at baseline or number of child-years of observation [129].
b. Per 1,000 children enrolled at baseline.
c. Mortality rate of children receiving vitamin A divided by that of controls-i.e. the risk of death among children receiving VA compared to controls.
d. Data refer primarily to infants 6-11 months old.
e. Mortality rates and relative risks recomputed from published data; confidence limits were not available.
f. Routine consumption of VA-fortified monosodium glutamate.

VA deficiency can result from consuming a diet that is chronically deficient in preformed VA (eggs, cheese, other dairy products) or provitamin-A carotenoids (dark green leafy vegetables, yellow fruits and vegetables, palm oil) in relation to requirements. However, epidemiological and anthropological studies of the causes of dietary VA deficiency are few. Most have reported negative correlations between the VA status and dietary intake of children and their households on the basis of cross-sectional or retrospective data. Dietary determinants of paediatric VA deficiency may be grouped into those related directly to the child's intake at different ages (breast-feeding and the weaning/early-childhood diet) and, less directly, those related to the usual dietary practices in a household.

Breast-feeding

During World War 1 Bloch noted that "xerophthalmia was never observed in children suckled by a mother capable of yielding sufficient milk" [102].

Several reports address the association of breast-feeding and weaning patterns with risk of mild xerophthalmia. The histograms in figure 2, showing breast-feeding as a dichotomous variable, are based on data from four studies. In three of these studies [92; 99; 100], the xerophthalmic children stopped breast-feeding earlier than the controls. Sommer estimated that 68% of all cases of Bitot's spots occurring in the second year of life in Indonesia may be attributable to lack of breast milk in the child's diet [87]. Although breast-feeding was discontinued at an earlier age for xerophthalmic children, the reasons given by the mothers for stopping were nearly identical to those for nonxerophthalmic children: the child no longer needed breast milk (~53%), the mother became pregnant (~ 36%), the mother gave birth (~4%), "no milk" (~2%), and miscellaneous (5%) [87]. Thus, the timing of maternal events and the mother's perceptions and decisions about weaning appear to influence a child's risk of becoming VA-deficient later in life.

A strong, adjusted, protective effect of breast-feeding against mild xerophthalmia (odds ratio= 0.10; 95% CL: 0, 0.7) has been reported from Bangladesh [117]. The lack of an apparent effect in Aceh was attributed in part to a marked tendency in that population for mothers to wean their children at a much earlier age than observed elsewhere in Indonesia [91].

FIG. 2. Percentages of children by age without (white bars) and with (black bars) xerophthalmia, in four studies using various assessment techniques: Bangladesh [99], west Java, Indonesia [87; 92], lower Shire valley, Malawi [100], and Aceh, Indonesia [91]. There were no xerophthalmic children under 12 months of age in the west Java study.

The importance of breast-feeding in VA nutrition is also apparent in Africa: Ethiopian children with mild xerophthalmia were weaned from the breast six months earlier on average than non-xerophthalmic children [6]. In Malawi xerophthalmic children reportedly began weaning (i.e. began routinely eating local porridge) one month earlier and, once begun, were also weaned more rapidly than non-xerophthalmic peers [100].

The usual dietary intake of VA by a mother is likely to influence the concentration of VA in breast milk and thereby affect the amount available to an infant [reviewed in 132]. VA levels in the breast milk of poor, undernourished women may be lower than that of mothers of higher socio-economic standing [133]. Still, where female adult diets traditionally include gruels and sauces made in part from green leaves, intakes [134] and breast-milk levels [135; 136] of VA remain normal.

Thus, a critical amount of VA [137], presumably in quantities sufficient to enhance hepatic stores for the weaned child, appears to be among the many nutritional benefits conferred by breast milk during the first two to three years of life [138], even in poorly nourished populations where the levels of VA in breast milk may be low [10; 133].

Early childhood diet

The mix of foods regularly offered to a child during weaning appears to influence VA status. Young xerophthalmic children tend to eat VA-rich foods less frequently than those who are clinically normal [6; 87; 91; 92]. Furthermore, an age-specific pattern in differences in consumption of individual foods emerges that corresponds to normal weaning habits (superimposed on the breast-feeding deficit): xerophthalmic children consume sweet, yellow fruits (papaya, mango) less often in the second and third years, green leaves less often from the third year on, and eggs less often throughout the preschool years than nonxerophthalmic children [87; 91; 92]. Variation in apparent risk associated with mango and papaya consumption may relate as much to the stage of ripeness of the fruits when consumed [134] as to their seasonal availability in the household when the diet is examined. Regular consumption of VA-rich foods during weaning may also protect children from xerophthalmia once breast-feeding has ceased. Indonesian children were three times more likely to have mild xerophthalmia if their reported diet during weaning had not routinely included eggs, dark green leaves, or yellow fruits and vegetables, after adjustment for differences in household socio-economic and child protein-energy status [91]. Whereas such a lagged protection could be due to a build-up of hepatic reserves, it may also reflect the establishment of proper dietary habits early in life that continue long after the child has been weaned. From early childhood through the early school years, xerophthalmic children are consistently reported to consume VA-rich foods less frequently than non-xerophthalmic children living in the same communities [6; 87; 91; 92; 117]. These findings indicate that, within the seasonal and annual flux of food availability, preventing VA deficiency in childhood (and perhaps beyond) is strongly linked to achieving nutritional balance in the diet.

Household dietary practices

The household encompasses the proximate environment through which a balanced diet must reach very young children. We can assume that, if VA-rich foods are not eaten in rural households, they are not eaten by their preschoolers. Even if such foods are in the household, however, they still may not be eaten by the children [92]. In Indonesia about 80% of interviewed households, both with and without xerophthalmic children, reported that family members consumed dark green leaves daily. Nearly all reported weekly consumption of dark green leaves [92]. However, if VA-rich foods are consumed, species differences in VA content [139], ripeness [134], methods of preservation and preparation, usual portions eaten, or absence of other enhancing dietary nutrients (e.g. fat) may limit the VA nutritional value of the diet.

When seasonality affects the availability of garden produce, preservation may extend consumption far into the dry season. However, the method of preservation could modify risk of deficiency. Whereas sun drying (for 2-3 days) may destroy 60% or so of the provitamin-A carotenoid content of green leaves, shade drying (for 7-8 days) can reduce the loss by a third [140].

Food-preparation methods can affect VA retention. Finely chopping and boiling vegetables with frequent stirring, with [141] or without [142] frying, as frequently practiced in South Asia, can reduce carotene content by as much as 35%. Methods involving less boiling and stirring can reduce these losses by more than half, to 11%-16% [141]. Steaming vegetables on top of rice as it cooks in a closed-lid boiler with no stirring (a little-used method) reduces net carotene content by only 2%-11% [141]. There is much to learn about how to improve existing food-preparation practices to maximize nutrient retention in ways that are practical and acceptable to mothers and children.

At times, the choice of which VA-rich vegetables and fruits are routinely consumed may not differentially affect a child's risk of VA deficiency but can influence the design, and chances of success, of dietary interventions to increase VA intake. For example, in Aceh, Indonesia, mothers reported frequencies with which they fed their children specified VA-rich foods during the previous month [91]. Table 4 lists the frequencies with which two types of green leafy vegetables, kangkong (Ipomoea aquatica) and drumstick leaves (Moringa oleifera), were fed to children with xerophthalmia and to controls. The odds ratio for xerophthalmia associated with consuming either food less than once a month was 1.7. The proportions of cases of xerophthalmia in the population associated with not consuming kangkong and drumstick leaves (the attributable risks) were 15% and 37% respectively, suggesting that a greater public impact could be expected if consumption of the latter were increased. However, eight times as many xerophthalmic children periodically consumed kangkong as drumstick leaves. The ratio for controls was around 10. The most common reason given for children not eating kangkong was "child dislikes," whereas for drumstick leaves it was "not eaten in the home. "

TABLE 4. Intake frequencies of dark green leafy vegetables - kangkong (Ipomoea aquatica) and drumstick leaves (Moringa oleifera) - by xerophthalmic children and controls, Aceh, Indonesia

a. Odds ratio for unmatched data.
b. Proportion of excess risk of xerophthalmia associated with non-consumption [143].
c. Percentage of children consuming kangkong once or more per month divided by percentage consuming drumstick leaves once or more per month, and vice versa.
d. Total n = 362 xerophthalmic children and 362 controls.
e. Total n = 361 xerophthalmic children and 362 controls.

These findings lead to questions about what factors (e.g. the way the food is prepared, family taboos, etc.) influence some children to reject a vegetable that is widely available, acceptable, and eaten by other children. Interventions that aim to modify food purchasing patterns, cooking methods, intake frequency, and portion sizes of items that are already acceptable to families (e.g. kangkong) may be more effective than attempts to increase consumption of less preferred foods (e.g. drumstick leaves).

Conclusion

Vitamin-A deficiency is associated with a wide range of consequences, from blinding xerophthalmia to apparent compromises in growth, resistance to infection, and survival. It is evident that VA deficiency is rooted in dietary imbalance and, therefore, in most developing countries will require a dietary solution for control. Given that food sources of VA are generally excellent sources of other micronutrients, successful dietary control of VA deficiency will also help to meet broader qualitative nutritional requirements of those at high risk.

Acknowledgements

This paper was prepared under cooperative agreement no. DAN-0045-A-5094 among the International Center for Epidemiologic and Preventive Ophthalmology, Johns Hopkins University, and the Office of Nutrition, Bureau for Science and Technology, United States Agency for International Development. Support from Task Force Sight and Life (Roche) and NIH grant no. S10-RR04060 are gratefully acknowledged.

References

1. Control of vitamin A deficiency and xerophthalmia: report of a joint WHO/UNICEFlUSAID/Helen Keller International/lVACG meeting. WHO Technical Report Series, no. 672. Geneva: World Health Organization, 1982.

2. Sommer A. Field guide to the detection and control of xerophthalmia. 2nd ed. Geneva: World Health Organization, 1982.

3. Sommer A, Tarwatjo 1, Hussaini G, Susanto D, Soogiharto T. Incidence, prevalence and scale of blinding malnutrition. Lancet 1981; 1: 1407-08.

4. Vijayaraghavan K, Naidu AN, Rao NP, Srikantia SG. A simple method to evaluate the massive dose vitamin A prophylaxis program in preschool children. Am J Clin Nutr 1975;28:1189-93.

5. Djunaedi E, Sommer A, Pandji A, Kusdiono, Taylor HR. Impact of vitamin A supplementation on xerophthalmia: a randomized controlled community trial. Arch Ophthalmol 1988;106:218-22.

6. de Sole G, Belay Y, Zegeye B. Vitamin A deficiency in southern Ethiopia. Am J Clin Nutr 1987;45:780-84.

7. Tielsch JM, West KP Jr, Katz J et al. Prevalence and seventy of xerophthalmia in southern Malawi. Am J Epidemiol 1986;124:561-68.

8. Rahmathullah L, Underwood BA, Thulasiraj RD et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990;323:929-35

9. Sommer A, Hussaini G, Muhilal, Tarwotjo 1. Susanto D, Saroso JS. History of nigh/blindness: a simple tool for xerophthalmia screening. Am J Clin Nutr 1980; 33:887-91.

10. Muhilal, Murdiana A, Azis 1, Saidin S, Jahari AB, Karyadi D. Vitamin A-fortified monosodium glutamate and vitamin A status: a controlled field trial. Am J Clin Nutr 1988;48:1265-70.

11. Solon F, Popkin BM, Fernandez TL, Latham MC. Vitamin A deficiency in the Philippines: a study of xerophthalmia in Cebu. Am J Clin Nutr 1978;31:36068.

12. Wittpenn JR, Tseng SCG, Sommer A. Detection of early xerophthalmia by impression cytology. Arch Ophthalmol 1986;104:237-39.

13. Natadisastra G, Wittpenn JR, Muhilal, West KP. Mele L, Sommer A. Impression cytology: a practical index of vitamin A status. Am J Clin Nutr 1988;48:695-701.

14. Campos FACS, Flores H, Underwood BA. Effects of an infection on vitamin A status of children as measured by the relative dose response (RDR). Am J Clin Nutr 1987;46:91-94.

15. Scrimshaw NS, Taylor CE, Gordon JE. Interactions of nutrition and infection. Geneva: World Health Organization, 1968.

16. Sommer A. New imperatives for an old vitamin (A): vii E. V. McCollum international lectureship in nutrition. J Nutr 1989;119:96-100.

17. Chytil F, Ong DE. Intracellular vitamin A-binding proteins. Ann Rev Nutr 1987;7:321-35.

18. Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen retinoic acid. Nature 1987;330:62-29.

19. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988;240:889-95.

20. Umesono K, Giguere V, Glass CK, Rosenfeld MG, Evans RM. Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature 1988;336:262-65.

21. Bedo G, Santisteban P, Aranda A. Retinoic acid regulates growth hormone gene expression. Nature 1989;339:231-34.

22. Ahluwalia GS, Kaul L, Ahluwalia BS. Evidence of facilitory effect of growth hormone on tissue vitamin A uptake in rats. J Nutr 1980;110:1185-93.

23. Zile MH, Cullum ME. The function of vitamin A: current concepts. Proc Soc Exp Biol Med 1983;72:139-52.

24. McCollum EV, Davis M. The necessity of certain lipins in the diet during growth. J Biochem 1913;15:167-75.

25. Corey JE, Hayes KC. Cerebrospinal fluid pressure, growth, and hematology in relation to retinol status of the rat in acute vitamin A deficiency. J Nutr 1972; 102: 1585-94.

26. Anzano MA, Lamb AJ, Olson JA. Growth, appetite, sequence of pathological signs and survival following the induction of rapid, synchronous vitamin A deficiency in the rat. J Nutr 1919;109:1419-31.

27. Zile MH, Bunge EC, DeLuca HF. On the physiological basis of vitamin A-stimulated growth. J Nutr 1979;109:1787-96

28. Sherman BS. The effect of vitamin A on epithelial mitosis in vitro and in vivo. J Invest Dermatol 1961 ;37:469-80.

29. Kohlmeier RH, Burroughs W. Estimation of critical plasma and liver vitamin A levels in feed lot cattle with observations upon influences of body stores and daily dietary requirements. J Animal Sci 1970;30:1012-19.

30. Mayer J, Krehl WA. influence of vitamin A deficiency on the gross efficiency of growth of rats. Yale J Biol Med 1948;20:403-05.

31. Olson JA. Serum levels of vitamin A and carotenoids as reflectors of nutritional status. J Natl Cancer Inst 1984;73:1439-44.

32. Hicks VA, Gunning DB, Olson JA. Metabolism, plasma transport and biliary excretion of radioactive vitamin A and its metabolism as a function of liver reserves of vitamin A in the rat. J Nutr 1984;114:1327-33.

33. Mohan PS, Rao KSJ. Sulphate metabolism in vitamin A deficient rats. J Nutr 1980;110:868-75.

34. Sherman BS. Blood vessels in the epiphyseal cartilage of vitamin A-deficient rats. Calcif Tissue Res 1967; 1:19296.

35. Zile M. Vitamin A deficiency and urinary calcium excretion in rats. J Nutr 1972;102:1255-58.

36. De Luca LM, Payson E, Wolf G. Vitamin A and protein synthesis by rat intestinal mucosa. J Biol Chem 1969;244:701-08.

37. Howell JH, Thompson JN. Lesions associated with the development of ataxia in vitamin A deficient chicks. Br J Nutr 1967;21:741-48.

38. Smith SM, Hayes CE. Contrasting impairments in IgM and IgG responses of vitamin A deficient mice. Proc Natl Acad Sci USA 1987;84:5878-82.

39. Smith SM, Levy NS, Hayes CE. Impaired immunity in vitamin A deficient mice. J Nutr 1987;117:857-65.

40. Glover J, Goodwin TW, Morton RA. The relationship between blood vitamin A levels and liver stores in rats. Biochemistry 1947;41:97-100.

41. Strum JM, Latham PS, Schmidt ML, McDowell EM. Vitamin A deprivation in hamsters. Virchows Arch (Cell Pathol) 1985;50:43-57.

42. Nielsen W, Mills JHL, Rousseau E, Woelfel CG. Parotid duct metaplasia in marginal bovine vitamin A deficiency. Am J Vet Res 1966;27:223-33.

43. Eaton HD, Lucas JJ, Nielsen SW, Helmboldt CF. Association of plasma or liver vitamin A concentrations with the occurrence of parotid duct metaplasia or of ocular papilledema in Holstein male calves. J Dairy Sci 1970;53:177579.

44. Zile MH, Bunge EH, DeLuca HF. Effect of vitamin A deficiency on intestinal cell proliferation in the rat. J Nutr 1977;107:552-60.

45. Rojanapo W, Lamb A, Olson JA. The prevalence, metabolism and migration of goblet cells in rat intestine following the induction of rapid, synchronous vitamin A deficiency. J Nutr 1980; 110: 178-B8.

46. Wolbach SB, Howe PR. Tissue changes following deprivation of fat-soluble A vitamin. J Exp Med 1925;42:75377.

47. McDowell EM, Keenan KP, Huang M. Effects of vitamin A-deprivation on hamster tracheal epithelium. Virchows Arch (Cell Pathol) 1984;45:197-219.

48. De Luca LM, McDowell EM. Effects of vitamin-A status on hamster tracheal epithelium in vivo and in vitro. Food Nutr Bull 1989;11(3):20-24.

49. Patterson JM, McHenry EW, Crandall WA. The physiological properties of vitamin A. Biochem J 1942; 36:79294.

50. Brown EF, Morgan AF. The effect of vitamin A deficiency upon the nitrogen metabolism of the rat. J Nutr 1948;35:425-38.

51. Schone F, Ludke H. Investigations into the vitamin A requirement of the growing pig: 1. The influence of vitamin A supply on the growth of piglets and fattening pigs. Arch Tierenahr Berlin 1984;34:205-17.

52. Rechcigl M, Berger S, Loosli JK. Williams HH. Dietary protein and utilization of vitamin A. J Nutr 1962;76:435 40

53. Nauss KM. Influence of vitamin A status on the immune system. In: Bauernfeind JC. ed. Vitamin A deficiency and its control. Orlando, Fla, USA: Academic Press, 1986:207-43.

54. Chandra RK, Vyas D. Vitamin A, immunocompetence, and infection. Food Nutr Bull 1989;11(3):12-19.

55. West KP Jr, Howard G, Sommer A. Vitamin A and infection: public health implications. Annu Rev Nutr 1989;9:6386.

56. Stephenson M, Clark AB. A contribution to the study of keratomalacia among rats. Biochem J 1920;14:50221.

57. Guilbert HR, Hart GH. Minimum vitamin A requirements with particular reference to cattle. J Nutr 1935;10:409-27.

58. Gil A, Briggs GM, Typpo J, Mackinney G. Vitamin A requirement of the guinea pig. J Nutr 1968;96:359-62.

59. Baumann CA, Riising BM. Steenbock H. Fat soluble vitamins: XLII. The absorption and storage of vitamin A in the rat. J Biol Chem 1934;107:705-15.

60. Booth VH. Liver storage of vitamin A by male and female rats. J Nutr 1952;23:459-71.

61. Lewis JM, Bodansky O, Falk KG, McGuire G. Vitamin A requirements in the rat, the relation of vitamin A intake to growth and to concentration of vitamin A in the blood plasma, liver and retina. J Nutr 1942;23:351-63.

62. Paul HE, Paul MF. The relation of vitamin A intake to length of life, growth, tooth structure and eye condition. J Nutr 1946;31:67-78.

63. May BJ, Calhoun MC, Engdahl GR. A re-evaluation of the minimum vitamin A requirement of growing-finishing iambs. J Anim Sci 1987;65:1626-32.

64. Sherman HC, MacLeod FL. The relation of vitamin A to growth, reproduction and longevity. J Am Chem Soc 1925;47:1658-62.

65. Zaklama MS, Gabr MK, Maraghy SE, Patwardhan VN. Liver vitamin A in protein-calorie malnutrition. Am J Clin Nutr 1972;25:412-18.

66. Muhilal H, Glover J. Effects of dietary deficiencies of protein and retinol on the plasma level of retinol-binding protein in the rat. Br J Nutr 1974;32:549-58.

67. Underwood BA. Effect of protein quantity and quality on plasma response to an oral dose of vitamin A as an indicator of hepatic vitamin A reserves in rats. J Nutr 1980;110:1635-40.

68. Jagannathan SN, Patwardhan VN. Dietary protein in vitamin A metabolism: Part 1. Influence of level of dietary protein on the utilization of orally fed preformed vitamin A and beta-carotene in the rat. Ind J Med Res 1960;48:77584.

69. Carney SM, Underwood BA, Loerch JD. Effects of zinc and vitamin A deficient diets on the hepatic mobilization and urinary excretion of vitamin A in rats. J Nutr 1976;103:1773-81.

70. Bhattacharya RK, Esh GC. Inter-relationship of dietary protein and vitamin A metabolism. Part IV. Am Biochem Exptl Med 1962;22:83-90.

71. McLaren DS. Influence of protein deficiency and sex on the development of ocular lesions and survival time of the vitamin A-deficient rat. Br J Ophthalmol 1959;43:234-41.

72. Hess AF, McCann GF, Pappenheimer AM. The failure of rats to develop rickets on a diet deficient in vitamin A. J Biochem 1921;47:395-412.

73. Wolbach SB. Vitamin A deficiency and excess in relation to skeletal growth. J Bone Joint Surg 1947;29:17192.

74. Wolbach SB, Hegsted DM. Vitamin A deficiency in chick: skeletal growth and the central nervous system. AMA Arch Pathol 1952;54:13-29.

75. Wolbach SB, Hegsted DM. Vitamin A deficiency in the duck: skeletal growth and the central nervous system. AMA Arch Pathol 1952;54:548-63,

76. Baume LJ. Differential responses of condylar, epiphyseal, synchondrotic, and articular cartilages of the rat to varying levels of vitamin A. Am J Orthod 1970;58:537-51.

77. Gallina AM, Helmboldt CF. Frier Hl, Nielsen SW, Eaton HD. Bone growth in the hypovitaminotic A calf. J Nutr 1970;100:129-42.

78. Hayes JC, Cousins RJ. Vitamin A deficiency and bone growth: 1. Altered drift patterns. Calcif Tissue Res 1970;6: 120-32.

79. Orr JB, Richards MB. Growth and vitamin A deficiency. J Biochem 1934;28:1259-73.

80. Stewart RJC. Bone pathology in experimental malnutrition. World Rev Nutr Diet 1975;21:1-74.

81. Melanby E. Vitamin A and bone growth: the reversibility of vitamin A-deficiency changes. J Physiol 1947;105:38299.

82. Cousins RJ, Eaton HD, Rousseau JE, Hall RC. Biochemical constituents of the aura mater in vitamin A deficiency. J Nutr 1969;97:409-18.

83. Oreffo ROC, Teti A, Triffitt TJT, Francis MJO, Carano A, Zallone AZ. Effect of vitamin A on bone resorption: evidence for direct stimulation of isolated chicken osteoclasts by retinol and retinoic acid. J Bone Mineral Res 1988;3(2):203-10.

84. Donoghue S, Kronfeld DS, Berkowitz SJ, Copp RL. Vitamin A nutrition of the equine: growth, serum biochemistry and hematology. J Nutr 1981;111: 365-74.

85. Menon K, Vijayaraavan K. Sequelae of severe xerophthalmia: a follow-up study. Am J Clin Nutr 1980;33: 218-20.

86. Sommer A, Muhilal. Nutritional factors in corneal xerophthalmia and keratomalacia. Arch Ophthalmol 1982;100:399-403.

87. Sommer A. Nutritional blindness: xerophthalmia and keratomalacia. New York: Oxford University Press, 1982: 107-84.

88. Arroyave G, Aguilar JR, Flores M, Guzman MA. Evaluation of sugar fortification with vitamin A at the national level. PAHO Scientific Publication no. 384. Washington, D.C.: Pan American Health Organization, 1979.

89. Demeke T, Wolde-Gabriel Z. Vitamin A status of preschool children in Ethiopia (an estimate of national prevalence). Addis Ababa: Ethiopia Nutrition Institute, 1985.

90. Stoll BJ, Banu H, Kabir 1, Molla A. Nightblindness and vitamin A deficiency in children attending a diarrheal disease hospital in Bangladesh. J Trop Pediatr 1985;31:36-39.

91. Mele L, West KP Jr, Kusdiono et al. Nutritional and household risk factors for xerophthalmia in Aceh, Indonesia: a case-control study. Am J Clin Nutr 1991 ;53: 1460-65.

92. Tarwotjo 1, Sommer A, Soegiharto T, Susanto D, Muhilal. Dietary practices and xerophthalmia among Indonesian children. Am J Clin Nutr 1982;35:574-81.

93. Brink EW, Perera WDA. Broske SP et al. Vitamin A status of children of Sri Lanka. Am J Clin Nutr 1979;32:8491.

94. Santos LMP, Dricot JM, Asciutti LS. Dricot-d'Ans C. Xerophthalmia in the state of Paraiba, northeast of Brazil: clinical findings. Am J Clin Nutr 1983;38:13944.

95. Waterlow JC, ed. Linear growth retardation in less developed countries. Nestle Nutrition Workshop Series, vol. 14. New York: Raven Press, 1988.

96. Lloyd-Puryear MA, Humphrey JH, Siren N et al. Xerophthalmia, vitamin A deficiency, anemia and stunted growth: a statewide survey in Truk, Federated States of Micronesia (FSM). Nutr Res (in press).

97. Brown KH, Black RE, Becker S, Hoque A. Patterns of physical growth in a longitudinal study of young children in rural Bangladesh. Am J Clin Nutr 1982;36:294302.

98. West KP Jr. Peri-urban malnutrition in Bangladesh: differential energy, protein, and growth status in children. Ecol Food Nutr 1986;19:99-112.

99. Bangladesh Nutritional Blindness Study 1982-83. Nutritional findings. Dhaka: Helen Keller International and Institute of Public Health Nutrition, 1985.

100. West KP Jr, Chirambo M, Katz J, Sommer A. Breast-feeding, weaning patterns, and the risk of xerophthalmia in southern Malawi. Am J Clin Nutr 1986;44:69097.

101. Bloch CE. Clinical investigation of xerophthalmia and dystrophy in infants and young children (xerophthalmia et dystrophia alipogenetica). J Hygiene 1921; 19:283-304.

102. Bloch CE. Blindness and other diseases in children arising from deficient nutrition (lack of fat-soluble A factor). Am J Dis Child 1924;27:139-48.

103. West KP Jr, Djunaedi E, Pandji A, Kusdiono, Tarwotjo 1, Sommer A. Vitamin A supplementation and growth: a randomized community trial. Am J Clin Nutr 1988;48: 1257-64.

104. Hamill PVV, Drizd TA, Johnson CL, Reed RB, Toche AF, Moore WM. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 1979;32:607-29.

105. Sommer A, Tarwatjo 1, Djunaedi E et al. Impact of vitamin supplementation on childhood mortality: a randomized controlled community trial. Lancet 1986;1:1169-73,

106. Tarwotjo 1, Sommer A, West KP Jr, Djunaedi E, Mele L, Hawkins B. Influence of participation on mortality in a randomized trial of vitamin A prophylaxis. Am J Clin Nutr 1987;45:1466-71.

107. Tielsch JM, Sommer A. The epidemiology of vitamin A deficiency and xerophthalmia. Annu Rev Nutr 1984;4: 183-205.

108. Muhilal, Permeisih D, Idjradinata YR, Muherdiyantiningsih, Karyadi D. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. Am J Clin Nutr 1988;48:127176.

109. Forman MR. Research priorities and strategies for investigation of the influence of vitamin-A supplementation on morbidity. Food Nutr Bull 1989; 11(3):25-35.

110. Dennert G. Retinoids and the immune system: immunostimulation by vitamin A. In: Sporn MB, Roberts AB, Goodman DS, eds. The retinoids. Vol. 2. Orlando, Fla, USA: Academic Press, 1984:373-90.

111. Chew BP. Vitamin A and beta-carotene on host de. fense. J Dairy Sci 1987;70:2732-43.

112. Brown KH, Gaffar A, Alamgir SM. Xerophthalmia, protein-calorie malnutrition, and infections in children. J Pediatr 1979;95:651-56.

113. Foster A, Sommer A. Corneal ulceration, measles, and childhood blindness in Tanzania. Br J Ophthalmol 1987;71 :331-43.

114. McLaren DS, Shirajian E, Tchalian M, Khoury G. Xerophthalmia in Jordan. Am J Clin Nutr 1965;17: 11730.

115. Bloem MW, Wedel M, Egger RJ et al. Mild vitamin A deficiency and risk of respiratory tract disease and diarrhea in preschool and school children in northeastern Thailand. Am J Epidemiol 1990;131:332-39.

116. Lloyd-Puryear M, Humphrey JH, West KP Jr et al. Vitamin A deficiency and anemia among Micronesian children. Nutr Res 1989;9:1007-16.

117. Stanton BF, Clemens JD, Wojtyniak B, Khair T. Risk factors for developing mild nutritional blindness in urban Bangladesh. Am J Dis Child 1986;140:584-88.

118. Shahid NS, Sack DA, Rahman M, Alam AN, Rahman N. Risk factors for persistent diarrhoea. Br Med J 1988;297: 1036-38.

119. Sommer A, Katz J, Tarwotjo 1. Increased risk of respiratory disease and diarrhea in children with preexisting mild vitamin A deficiency. Am J Clin Nutr 1984; 40: 1090-95.

120. Sommer A, Tarwotjo 1, Hussaini G, Susanto D. Increased mortality in children with mild vitamin A deficiency. Lancet 1983;2:585-88.

121. Milton RC, Reddy V, Naidu AN. Mild vitamin A deficiency and childhood morbidity: an Indian experience. Am J Clin Nutr 1987;46:827-29.

122. Underwood BA, Rahmathullah L, Thulasiraj RD, Milton RC. Morbidity and growth are not affected by a weekly low-dose vitamin A supplement to children in southern India. FASEB J 1991;5:A1080.

123. Sommer A, West KP Jr. Vitamin A and childhood mortality. (Letter) Lancet 1991;337:925.

124. Ellison JB. Intensive vitamin therapy in measles. Br Med J 1932;2:708-11.

125. Barclay AJG, Foster A, Sommer A. Vitamin A supplemeets and mortality related to measles: a randomized clinical trial. Br Med J 1987;294:294-96.

126. Hussey GD, Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990;323:160-64.

127. West KP, Pokhrel RP, Katz J et al. Efficacy of vitamin A in reducing preschool child mortality: a randomized, double-masked community trial in Nepal. Lancet 1991; 338:67-71.

128. Vijayaraghavan K, Radhaiah G, Prakasam BS, Sarma KVR, Reddy V. Effect of massive dose of vitamin A on morbidity and mortality in Indian children. Lancet 1990;336: 1342-45.

129. UN-ACC Subcommittee on Nutrition. Statement on vitamin A and mortality. Food Nutr Bull 1986;8(2): 65.

130. IVACG releases statement on role of vitamin A in child health and survival. Am J Publ Health 1990; 80:1217.

131. West KP Jr, Sommer A. Delivery of oral doses of vitamin A to prevent vitamin A deficiency and nutritional blindness. ACC/SCN State-of-the-Art Series, Nutrition Policy Discussion Paper no. 2. Geneva: UN ACC Subcommittee on Nutrition, 1987.

132. Wallingford JC, Underwood BA. Vitamin A deficiency in pregnancy, lactation and the nursing child. In: Bauernfeind JC, ed. Vitamin A deficiency and its control. Orlando, Fla, USA: Academic Press, 1986:11)1-52. 133. Gebre-Medhin M, Vahlquist A, Hofvander Y et al. Breastmilk composition in Ethiopian and Swedish mothers: 1. Vitamin A and beta-carotene. Am I Clin Nutr 1976;29:441-51.

134. Villard L, Bates CJ. Dietary intake of vitamin A precursors by rural Gambian pregnant and lactating women. Humn Nutr 1987;41(A): 135-45.

135. Bates CJ. Vitamin A in pregnancy and lactation. Proc Nutr Soc 1983;42:65-79.

136. El-Karib AO, Laryea MD, Mayatepek E, El-Amin EO, Ahmed HM, Bremer HJ. Plasma retinol and tocopherols of breast-feeding Sudanese women. Trop Med Parasit 1989;40:405-08.

137. Brown KH, Black RE, Becker S, Nahar S, Sawyer J. Consumption of foods and nutrients by weanlings in rural Bangladesh. Am J Clin Nutr 1982;36:878-89.

138. Dualeh KA, Henry FJ. Breast milk - the life saver: observations from recent studies. Food Nutr Bull 1989;11(3):43-46.

139. Oomen HAPC, Grubben GJH. Tropical leaf vegetables in human nutrition. Communication 69. Amsterdam: Department of Agricultural Research, Royal Tropical Institute, 1978:36-37.

140. Butao RP. A study to determine the carotene content of local used vegetables, both wild and domesticated, and the effect of traditional sundrying: MS thesis, Bunda College of Agriculture, University of Malawi, Lilongwe, Malawi, 1981.

141. Rahman M, Wahed WA, Ali A. Beta-carotene loss during different methods of cooking of green leafy vegetables eaten by people of different socio-economic groups of Bangladesh. Report of the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh, 1988.

142. Nagra SA, Khan S. Vitamin A (b-carotene) losses in Pakistani cooking. J Sci Agric 1988;46:249-51.

143. Kahn HA, Sempos CT. Statistical methods in epidemiology. New York: Oxford University Press, 1989:72-84.

Contents - Previous - Next