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, and
The Center for Human Nutrition (CHN), Department of International Health and the Dana Center for Preventive Ophthalmology (DCPO), the Johns Hopkins Schools of Public Health and Medicine, Baltimore, MD 21205; * The Nepal Nutrition Intervention Project-Sarlahi (NNIPS) and the National Society for the Prevention of Blindness, Kathmandu, Nepal; and the Department of Pediatrics and Kanti Children's Hospital, Tribhuvan University, Kathmandu, Nepal.
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
FOOTNOTES
LITERATURE CITED
ABSTRACT 
Inconsistencies have been observed in the impact of vitamin A (VA) supplementation on early child growth. To help clarify this issue, a cohort of 3377 rural Nepalese, nonxerophthalmic children 12-60 mo of age were randomized by ward to receive vitamin A [60,000 µg retinol equivalents (RE)] or placebo-control (300 RE) supplementation once every 4 mo and followed for 16 mo. VA had no impact on annual weight gain or linear growth. However, arm circumference (AC) and muscle area (MA) growth improved in VA recipients, by 0.13 cm and 25 mm2, respectively, over controls. Growth of children with xerophthalmia, who were treated with 
120,000 RE at base line, was also compared to that of nonxerophthalmic children, stratified by initial wasting status, and adjusted for sex, baseline age and measurement status. Among initially nonwasted children (AC 13.5 cm), VA-treated xerophthalmic children (n = 86) gained 0.7 cm more in linear growth than nonxerophthalmic children. Among initially wasted children (AC < 13.5 cm), VA-treated children (n = 34) gained additional weight (672 g), height (~1 cm), muscle (76 mm2) and fat (79 mm2) areas, and subscapular skinfold (1.3 mm) compared to changes observed in nonxerophthalmic children. Relative increments in soft tissue growth occurred within 4 mo of VA treatment, while the effect on linear growth was gradual. Moderate-to-severe VA deficiency, marked by xerophthalmia, is likely to impair normal physical growth, but milder stages of deficiency may not have this effect in rural South Asia.
INTRODUCTION
Vitamin A deficiency is an important child health problem in many developing countries, with consequences ranging from potentially blinding xerophthalmia to increased risks of infection and mortality (Sommer and West 1996
). Increased vitamin A intake, achieved by supplementation or fortification of food stuffs, confers a clear survival benefit to young children (Beaton et al. 1993, Sommer and West 1996).
Vitamin A is an essential nutrient for mammalian growth (McCollum and Davis 1913) but it has been difficult to demonstrate the effect of vitamin A deficiency on the growth of children. The motivation to verify an effect of vitamin A deficiency on growth and hence extend the assertion of McCollum and Davis to the human, is less to influence public policy (since aims to prevent childhood blindness and mortality suffice in this regard) than to understand the sum of health effects that can be attributed to vitamin A deficiency and its prevention in populations where other nutritional deficiencies, infection and mortality are common in children. It is the working hypothesis of this paper that moderate-to-severe vitamin A deficiency, marked by the presence of night blindness or clinical eye signs, can and does impair physical growth in young children compared to the growth of generally wasted and stunted children who are also likely to be deficient in vitamin A, but lack eye signs of xerophthalmia.
Clinical vitamin A deficiency has long been linked to poor child growth on a cross-sectional basis; often the more severe the eye signs, the more severe the stunting and wasting (Sommer 1982). Children who develop mild xerophthalmia (night blindness or Bitot's spots) also show less weight gain and linear growth than their nonxerophthalmic peers. Conversely, improved weight gain can accompany spontaneous recovery from xerophthalmia, although catch-up linear growth is less evident (Tarwotjo et al. 1992). These associations may represent a direct effect of vitamin A nutriture on growth or they may be indirect, mediated by other co-varying nutritional and morbid states that can effect growth. Vitamin A supplementation trials have produced mixed results, ranging from improved ponderal (West et al. 1988) or linear (Muhilal et al. 1988) growth to little or no discernable effects (Brown et al. 1980, Fawzi et al. 1997, Lie et al. 1993, Rahmathullah et al. 1991, Ramakrishnan et al. 1995) in nonxerophthalmic children, casting doubt about the importance of vitamin A as a determinant of child growth in free-living populations (Ramakrishnan et al. 1995).
Here we report the impact of periodic vitamin A supplementation on ponderal, linear and body compositional growth of nonxerophthalmic children participating in a randomized, double-masked community trial. We also explore the hypothesis that vitamin A repletion of moderately-to-severely deficient children, marked by the presence of xerophthalmia, can improve growth under rural conditions where other forms of childhood malnutrition, infection and risk of mortality are moderately severe and widespread.
METHODS
), procedures (Pradhan et al. 1994) and findings of the trial related to the impact of vitamin A on mortality (Pokhrel et al. 1994, West. et al. 1991 and 1995) and xerophthalmia (Katz et al. 1995) have been reported. We have also attempted to assess the growth impact of vitamin A on moderately-to-severely vitamin A-deficient children by comparing within each supplement group the growth responses of children with xerophthalmia, who were treated with vitamin A at base line irrespective of their random assignment, with the growth of nonxerophthalmic children, adjusting for multiple potential confounders.
RESULTS
Table 1.
Numbers of children receiving anthropometry by visit, supplement-clinical status and initial arm circumference1
) and by probing for a history of nightblindness using a local term (rataundhi) (Khatry et al. 1995). Cases in both groups were treated with 120,000 µg RE of vitamin A (one capsule at presentation and a second taken the next day) and referred to local health posts for clinical follow-up and further treatment, if indicated. Masking was preserved for the purpose of the trial. Thus, children in the vitamin A group received a (coded) vitamin A supplement in their home just prior to examination, providing them with a total dose of 180,000 µg RE. Children in the control group received their assigned placebo supplement at home. Children continued to be visited at home every 4 mo and dosed according to their ward allocation in the trial. This design produced four supplement-clinical status groups: nonxerophthalmic children receiving vitamin A or placebo-control supplements every 4 mo and children with xerophthalmia at base line in each of these two groups (Fig. 1). Having all received at least 120,000 µg RE at the outset, cases of xerophthalmia in both supplement groups have been pooled for the growth analysis presented here, except where noted.
Fig. 1.
Study design and number of wards and children enrolled in the growth cohort, by supplement group and clinical status at baseline.
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24 mo) or recumbent length (12-23 mo) (HT), read to the nearest 0.1 cm on a steel tape attached to a wooden board with a foot-plate and sliding head block (Shorr Productions, Woonsocket, RI); 3 ) left mid-upper arm circumference (AC), read to the nearest 0.1 cm using a Zerfas insertion tape (Zerfas 1975); and 4 ) skinfold thickness, obtained to the nearest 0.1 mm after 2-4 seconds' application of a caliper to the left tricipital (TS) and subscapular (SS) sites (Holtain Ltd, Crosswell, Crymch, Wales, UK). The median of 3 or 5 independent readings was recorded for each measurement, except for weight which was usually read once after the pointer on the scale was steady for 2 s. Measurements were performed by a team of four trained anthropometrists: one observer-assistant pair assigned to measure WT and HT and a second pair to measure AC and skinfolds.
).
d2/2n, where d = the difference between paired measurements and n = the number of children) was 76 g for WT, 0.35 cm for HT, 0.14 cm for AC, 0.34 mm for TS and 0.27 mm for SS.
), respectively, were derived from AC and TS measurements by standard formulas (Frisancho 1981). Weight-for-height, height-for-age and weight-for-age values were expressed as standard normal deviates (Z-scores, or WHZ, HAZ and WAZ, respectively) based on the National Center for Health Statistics, median age-sex-specific values for American children (Hamill et al. 1977).
2 for discreet variables and analysis of variance for continuous variables. Differences in 4-, 8-, 12- and 16-mo growth increments were compared between 1 ) randomized groups of nonxerophthalmic children and 2 ) xerophthalmic and nonxerophthalmic children, by multivariable linear regression adjusted for age (in mo), the baseline value of the specific measurement or indicator being compared, and sex of the child (Kleinbaum and Kupper 1978). Beta-coefficients provided estimates of the adjusted cumulative growth effects of vitamin A supplementation relative to placebo receipt in the randomized groups. For comparisons between xerophthalmic and nonxerophthalmic children, the beta-coefficients represent the incremental growth of vitamin A-treated children with xerophthalmia over (or under) the growth rate of nonxerophthalmic children. It became apparent during analysis that, in this population, arm circumference (AC) size was an important effect modifier for observed growth responses to vitamin A. Therefore, growth comparisons were stratified by initial AC size, < 13.5 and 13.5 cm, representing children who were wasted and not wasted, respectively, at the outset. Ninety-five percent confidence limits (CL) for relative increments were derived from the standard errors (SEM) of the regression coefficients.
1 day of 4 loose watery stools the previous week as a proxy), breastfeeding status at the outset (visit 1) and at the relevant visit ending an interval (yes vs. no), and education of the head of household (any vs. none) as a proxy for socioeconomic status. These adjustments had no significant or discernable effects on growth outcomes, but decreased the effective sample size by about one-third for each comparison due to missing data obtained either by design (e.g., morbidity data were only collected for children who were under parental observation the entire previous week) or due to non-responses on some of these variables. Thus, only findings adjusted by age, baseline status and sex are presented to preserve sample size and power.
Table 2.
Baseline child and household characteristics (at visit 1) by randomized supplement group and xerophthalmia status
).
Table 3.
Cumulative differences in growth by interval and baseline arm circumference (AC) between nonxerophthalmic children, 12-60 mo of age at baseline, randomized to vitamin A or placebo control supplements every four months1
Fig. 2.
Baseline anthropometric status of children by arm circumference (AC < 13.5 cm, wasted; AC 13.5, nonwasted) and xerophthalmic status (Xero vs. Nonxero). A: Z-scores for height-for-age (HAZ), weight-for-age (WAZ) and weight-for-height (WHZ); B: arm circumference (AC) and subscapular skinfold (SS) thickness; and C: left mid-upper arm muscle (MA) and fat (FA) areas. All differences between nonwasted and wasted children are statistically significant, P < 0.0001. No comparisons between nonwasted Xero and Nonxero children are significant, all 0.15 < P < 0.90. All differences between wasted Xero and Nonxero children are significant (P 
0.03), except for WHZ (P > 0.1).
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0.16, 0.07)] than controls; the effect was comparable by baseline AC status (Table 3). This relative decrement was offset by relative weight gain over the next 8 mo (encompassing the late dry and early monsoon season) such that, after 12 mo, vitamin A recipients had gained an average of 38 g more than controls (not significant). After 16 mo (and a second peri-harvest interval) children receiving vitamin A had again gained less total weight than controls (72 g, 0.06 WHZ, 95% CL: 0.10, 0.02). Differences between groups in weight gain were comparable by baseline AC (Table 3), sex and age (not shown).
Table 4.
Differences in sixteen-month change in muscle and fat indicators by baseline arm circumference (AC)
in children 12-60 mo of age at baseline1
|
Table 5. Cumulative differences in growth by interval and initial arm circumference (AC) between xerophthalmic and nonxerophthalmic children, 12-60 mo of age at baseline1 |
HT in Table 5) of wasted xerophthalmics gradually accelerated over that of wasted nonxerophthalmic children, showing cumulative relative increments of 0.20, 0.49, 0.74 and 0.97 cm by 16 mo, representing a 10% increase over the mean linear growth (of 9.8 cm) in the latter group over this time.
13.5 cm) compared to the weight gain of their nonwasted, nonxerophthalmic peers (Table 5). Linear growth of xerophthalmics also improved, by 0.69 cm after 16 mo, representing 8% of the mean gain in height (of 9.2 cm) of nonxerophthalmic children. However, nonwasted xerophthalmics showed no advantage in changed weight-for-height (with relative increments varying from 0.04 to 0.01 WHZ, all not significant), AC (Table 5), MA, FA or SS (Table 4), indicating that the relative gain in weight was pondostatural. Supporting this interpretation, the 196 g weight gain advantage of VA-treated xerophthalmics was no longer evident once HT was introduced into the regression equation (b = 70 g) containing age, sex, baseline WT and other covariates suggesting that the differential in weight gain was largely due to a difference in height gain between groups.
WT, WAZ, WHZ and AC and insignificant interactions for HT and HAZ (P > 0.4 for all) during each cumulative interval, and strong interactions (P < 0.01 for all) for 16-mo differences in MA, FA and SS, as Tables 5 and 6, respectively, indicate. The size of interaction between effects in xerophthalmic children with a low vs. higher AC can be estimated by subtracting the coefficient values for children with AC > 13.5 cm from values for children with AC < 13.5 cm (e.g., 621 g difference in weight gain between AC groups from 0-4 mo).
2, 78) and SS increased by 0.42 mm (0.05, 0.89), while the relative increase in MA was less and not significant [29 mm2 (95% CL: 11, 69)].
DISCUSSION 
Fig. 3.
Growth by weight-for-age (WAZ) of children with xerophthalmia compared to children without xerophthalmia, supplement groups combined, by wasting status and age at baseline and adjusted for sex, age (in months) and baseline WAZ by linear regression. All differences in WAZ between wasted children and wasted nonxerophthalmic children are significant (P 0.005) except for 12-35 mo-olds after 12 mo (P 0.02) and 16 mo (P = 0.12). Only the WAZ growth of nonwasted children after 16 months is significantly different from nonwasted nonxerophthalmic children (P 0.01).
[View Larger Version of this Image (17K GIF file)]
).
) or as a periodic, high-potency supplement to children 6 to 36 mo of age (Ramakrishnan et al. 1995), failed to markedly influence 12-mo weight gain or linear growth, but seasonality was not examined. Thus, it appears that in South Asia, where moderate stunting and wasting (ACC/SCN Report, 1992) typically coexist with multiple micronutrient deficiencies (Gopalan 1989), vitamin A supplementation alone may have little effect on height or weight gain of most preschool children. This is in contrast to studies in Southeast Asia where improved weight gain (West et al. 1988) and linear growth (Muhilal et al. 1988) were observed in vitamin A-supplemented children in populations that were generally in better health and better nourished than the population in rural South Asia (UNICEF, 1997).
), shares high correlations with other indices of lean body mass, such as the creatinine/height ratio (Heymsfield et al. 1982; Trowbridge et al. 1982), and gradually responds to protein-energy deprivation and recovery (Wright and Heymsfield 1984). In the absence of an effect on subcutaneous arm and trunk fat, the change in muscle (and humoral bone) area may have reflected a positive shift in lean body mass with improved vitamin A nutriture. The effect was similar to the 36 mm2 relative increase in arm muscle area observed after a year of vitamin A supplementation in preschool boys in Indonesia (West et al. 1988). Improved lean body mass, assessed in this study by mid-arm anthropometry, may represent an infrequently evaluated aspect of child growth that responds to vitamin A, even in the absence of improved height and weight.
). Previous vitamin A-growth trials have excluded, either a priori or in the analysis, children with xerophthalmia (Fawzie et al. 1997, Rahmathullah et al. 1991, Ramakrishnan et al. 1995, West et al. 1988) who, being moderately-to-severely vitamin A-deficient (Sommer and West 1996), may have been expected to show a growth response to vitamin A. Mild xerophthalmia has been associated with decelerated linear and ponderal growth (Tarwotjo et al. 1992), low attained height, (Cohen et al. 1986, Khatry et al. 1995, Mele et al. 1991, Santos et al. 1983), mild wasting (Hussain et al. 1996, Khatry et al. 1995, Mele et al. 1991) and increased risks of morbidity (Milton et al. 1987, Sommer et al. 1984) and mortality (Sommer et al. 1983).
WHZ) was more highly correlated with age-adjusted change in upper arm muscle area in wasted xerophthalmics (r = 0.72) than in other wasted children (r = 0.43).
). In Indonesia, children spontaneously recovering from mild xerophthalmia regained all of their calculated weight decrement (~120 g) in a 3-mo period, but not height deficit even after 6 mo (Tarwotjo et al. 1992), suggesting the need for longer follow-up to discern a potential effect of vitamin A on linear growth. However, a more recent randomized, double-masked trial in Indonesia has also shown high-potency vitamin A to stimulate both linear and ponderal growth in severely vitamin A-deficient children (serum retinol < 0.35 µmol/L) (Hadi et al. 1997).
). It is unlikely that vitamin A supplementation elicits a typical growth response across populations or within the same population over different periods of time. Expectation of growth impact (or lack thereof ), in any event, should not drive policies to prevent vitamin A deficiency where reductions in the severity of morbidity and mortality of children can be realized (Beaton et al. 1993, Sommer and West 1996).
FOOTNOTES
Manuscript received 11 March 1996. Initial reviews completed 30 May 1996. Revision accepted 12 June 1997.
LITERATURE CITED
Subcommittee on Nutrition (ACC/SCN).
(1992)
Second Report on the World Nutrition Situation. Volume I. Global and Regional Results. World Health Organization (WHO), Geneva, Switzerland, pp. 1-50. an Indian experience.
Am. J. Clin. Nutr.
1987;
46:827-829
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