Vitamin A status and hemoglobin concentrations are improved in Indonesian children with vitamin A and deworming interventions.

OBJECTIVE: Anemia is a major public health problem caused by multiple factors. Vitamin A (VA) depletion can affect hemoglobin concentration (Hb). This study investigated the improvement in Hb and VA status in preschool Indonesian children following supplementation with 210 micromol VA and deworming with 400 mg albendazole. SUBJECTS AND DESIGN: Indonesian children (n = 131) infected with Ascaris lumbricoides and/or Trichuris trichiura were enrolled. The children were grouped by length of time since receiving 210 micromol VA through the local health system. Group 1 (VA administered > or = 4 month before baseline) included 51 children with Ascaris and 29 children with Trichuris. Group 2 had received VA < or = 1 month of baseline from the local health post and included 51 children. INTERVENTION AND METHODS: Immediately following baseline Hb and VA status assessment (modified relative dose response (MRDR) test), Group 1 children were given 210 micromol VA and 400 mg albendazole. Group 2 were randomized to be dewormed either 1 week before, at the same time or 1 week after baseline MRDR and Hb measures. Follow-up assessment was 3-4 weeks after baseline. RESULTS: VA status in Group 1 significantly improved in children with either Ascaris (P < 0.0001) or Trichuris (P = 0.028). Although the prevalence of anemia declined, the improvement in Hb was not significant (P = 0.08). In Group 2, improvement in VA status from the VA delivered through the public health system was maintained for more than 1 month. Hb improved (P = 0.0037) and this improvement appeared to be associated with the length of time between deworming and follow-up assessments. CONCLUSION: Public health supplementation programs to improve VA status may also increase Hb concentrations and decrease anemia prevalence, especially when linked to deworming. SPONSORSHIP: These studies were supported by the Thrasher Research Fund, SmithKline Beecham and Hatch-Wisconsin Agricultural Experiment Station number WIS04533.

Integration of vitamin A supplementation with the Expanded Programme on Immunization: lack of impact on morbidity or infant growth.

UNLABELLED: Vitamin A deficiency is associated with increased morbidity and mortality from diarrheal disease, measles, and malaria. It has been proposed that vitamin A supplementation could be linked with childhood immunization programs to improve child health. We conducted a randomized, double-blind, placebo-controlled clinical trial to evaluate the impact of linking vitamin A supplementation with the Expanded Programme on Immunization on morbidity and child growth. In West Java, Indonesia, 467 six-week-old infants were randomized to receive 7.5 mg retinol equivalent (RE), 15 mg RE, or placebo with childhood immunization contacts at 6, 10, and 14 wks and 9 mo of age. Child growth was assessed through anthropometry, and morbidity histories were obtained. Vitamin A supplementation had no apparent impact upon linear or ponderal growth or infectious disease morbidity in the first 15 mo of age when integrated with the Expanded Programme on Immunization. CONCLUSION: Although improving vitamin A nutriture is of general importance in reducing diarrheal and measles morbidity and mortality in developing countries, this clinical trial showed no apparent benefit of vitamin A capsules for infant health when given through childhood immunization programs.

Bioefficacy of beta-carotene dissolved in oil studied in children in Indonesia.

BACKGROUND: More information on the bioefficacy of carotenoids in foods ingested by humans is needed. OBJECTIVE: We aimed to measure the time required for isotopic enrichment of beta-carotene and retinol in serum to reach a plateau, the extent of conversion of beta-carotene dissolved in oil with use of beta-carotene and retinol specifically labeled with 10 (13)C atoms, and the intraindividual variation in response. DESIGN: Indonesian children aged 8--11 y (n = 35) consumed 2 capsules/d, 7 d/wk, for < or =10 wk. Each capsule contained 80 microg [12,13,14,15,20,12',13',14',15',20'-(13)C(10)]beta-carotene and 80 microg [8,9,10,11,12,13,14,15,19,20-(13)C(10)]retinyl palmitate. Three blood samples were drawn per child over a period of < or =10 wk. HPLC coupled with atmospheric pressure chemical ionization liquid chromatography-mass spectrometry was used to measure the isotopic enrichment in serum of retinol with [(13)C(5)]retinol and [(13)C(10)]retinol and of beta-carotene with [(13)C(10)]beta-carotene. The beta-carotene in the capsules used had a cis-trans ratio of 3:1. RESULTS: Plateau isotopic enrichment was reached by day 21. The amount of beta-carotene in oil required to form 1 microg retinol was 2.4 microg (95% CI: 2.1, 2.7). The amount of all-trans-beta-carotene required to form 1 microg retinol may be lower. CONCLUSIONS: The efficiency of conversion of this beta-carotene in oil was 27% better than that estimated previously (1.0 microg retinol from 3.3 microg beta-carotene with an unknown cis-trans ratio). The method described can be extended to measure the bioefficacy of carotenoids in foods with high precision, requiring fewer subjects than other methods.

Integration of vitamin A supplementation with the expanded program on immunization does not affect seroconversion to oral poliovirus vaccine in infants.

Childhood immunization programs may provide infrastructure for delivering vitamin A supplements to infants in developing countries. The effect of giving vitamin A, an immune enhancer, on antibody responses to trivalent oral poliovirus vaccine (TOPV) is unknown. A randomized, double-blind, placebo-controlled clinical trial was conducted to determine the effect of giving vitamin A simultaneously with TOPV on antibody responses to poliovirus. Infants (n = 467) received oral vitamin A, 15 mg retinol equivalent (RE), 7.5 mg RE or placebo with TOPV at 6, 10 and 14 wk of age. Antibody responses to poliovirus types 1, 2 and 3 were measured by a microvirus neutralization assay at enrollment and at 9 mo of age. Seroconversion rates to poliovirus types 1, 2 and 3 ranged from 98 to 100% in the three treatment groups, and there were no differences in mean antibody titers to poliovirus types 1, 2 and 3 among treatment groups. This study demonstrates that oral vitamin A does not affect antibody responses to poliovirus vaccine when integrated with the Expanded Program on Immunization.

Orange fruit is more effective than are dark-green, leafy vegetables in increasing serum concentrations of retinol and beta-carotene in schoolchildren in Indonesia.

The objectives of this study were to quantify the effectiveness of dietary retinol sources, orange fruit, and dark-green, leafy vegetables in improving vitamin A status, and to test whether orange fruit is a better source of vitamin A and carotenoids than are leafy vegetables. Anemic schoolchildren aged 7-11 y (n = 238) in West Java, Indonesia, were randomly allocated to 1 of 4 groups to consume 2 complete meals/d, 6 d/wk, for 9 wk: 1) 556 retinol equivalents (RE)/d from retinol-rich food (n = 48); 2) 509 RE/d from fruit (n = 49); 3) 684 RE/d from dark-green, leafy vegetables and carrots (n = 45); and 4) 44 RE/d from low-retinol, low-carotene food (n = 46). Mean changes in serum retinol concentrations of the retinol-rich, fruit, vegetable, and low-retinol, low-carotene groups were 0.23 (95% CI: 0.18, 0.28), 0.12 (0.06, 0.18), 0.07 (0.03,0.11), and 0.00 (-0.06, 0.05) micromol/L, respectively. Mean changes in serum beta-carotene concentrations in the vegetable and fruit groups were 0.14 (0.12, 0.17) and 0.52 (0.43, 0.60) micromol/L, respectively. Until now, it has been assumed that 6 microg dietary beta-carotene is equivalent to 1 RE. On the basis of this study, however, the equivalent of 1 RE would be 12 microg beta-carotene (95% CI: 6 microg, 29 microg) for fruit and 26 microg beta-carotene (95% CI: 13 microg, 76 microg) for leafy vegetables and carrots. Thus, the apparent mean vitamin A activity of carotenoids in fruit and in leafy vegetables and carrots was 50% (95% CI: 21%, 100%) and 23% (95% CI: 8%, 46%) of that assumed, respectively. This has important implications for choosing strategies for controlling vitamin A deficiency. Research should be directed toward ways of improving bioavailability and bioconversion of dietary carotenoids, focusing on factors such as intestinal parasites, absorption inhibitors, and food matrixes.

Effect of vitamin A supplementation on measles vaccination in nine-month-old infants.

OBJECTIVE: Childhood immunization programs have been suggested as an infrastructure to deliver vitamin A supplements to children in developing countries. The effects of giving vitamin A, a potent immune enhancer, with measles immunization to nine-month-old infants is unknown. METHODS: A randomized, double-masked, placebo-controlled clinical trial of vitamin A, 100,000 IU at the time of standard titer Schwarz measles immunization was conducted with nine-month-old infants in Bogor District, West Java, Indonesia. Antibody titers to measles were measured at baseline and one and six months following immunization. RESULTS: 394 infants received measles immunization, and 37 infants (9.4%) had baseline antibody titers > 1:120, which is consistent with previous natural measles infection. Of the remaining infants, 98.8% seroconverted to measles, and 99.3% had titers consistent with protection against measles six months postimmunization. Seroconversion rates were similar in vitamin A and placebo treatment groups. CONCLUSION: High dose vitamin A supplementation can be given without reducing seroconversion to standard titer Schwatz measles immunization in nine-month-old infants.

PIP: The feasibility of combining vitamin A supplementation and measles immunization was investigated in a double-masked, placebo-controlled clinical trial involving 394 9-months-old infants in Bogor district, West Java, Indonesia. Vitamin A, a potent immune enhancer, has been shown to reduce child mortality by 20-50% in developing countries and is among the most cost-effective child survival interventions. 130 infants received a placebo; 132 were given 25,000 IU of vitamin A at 6, 10, and 14 weeks and 100,000 IU at 9 months; and the final 132 were given 50,000 IU of vitamin A at 6, 10, and 14 weeks and 100,000 IU at 9 months. 37 (9.4%) of the study infants had pre-immunization measles titers greater than 1:120 at 9 months of age, indicative of a previous history of natural measles infection. 98.8% of the remaining infants had seroconverted to measles 1 month after immunization, regardless of whether they received vitamin A or placebo; after 6 months, 99.3% had titers consistent with protection against measles. Geometric mean titers were 1:1772 and 1:2298 at 1 month post-immunization and 1:1164 and 1:1900 at 6 months post-immunization in infants receiving vitamin A and placebo, respectively. Since vitamin A supplementation does not interfere with seroconversion to standard titer Schwarz measles immunization, its inclusion in Expanded Program on Immunization campaigns is recommended.

Infant survival is improved by oral iodine supplementation.

Although reports suggest that infant mortality is increased during iodine deficiency, the effect of iodine supplementation on infant mortality is unknown. A double-masked, randomized, placebo-controlled, clinical trial of oral iodized oil was conducted in Subang, West Java, Indonesia to evaluate the effect of iodine supplementation on infant mortality. Infants were allocated to receive placebo or oral iodized oil (100 mg) at about 6 wk of age and were followed to 6 mo of age. Six hundred seventeen infants were enrolled in the study. Infant survival was apparently improved, as indicated by a 72% reduction in the risk of death during the first 2 mo of follow-up (P < 0.05) and a delay in the mean time to death among infants who died in the iodized oil group compared with infants who died in the placebo group (48 days vs. 17.5 d, P = 0.06). Other infant characteristics associated with reduced risk of death included weight-for-age at base line, consumption of solid foods, female gender and recent history of maternal iodine supplementation. Oral iodized oil supplementation had a stronger effect on the mortality of males compared with females. This study suggests that oral iodized oil supplementation of infants may reduce infant mortality in populations at risk for iodine deficiency.

Refinement of the modified-relative-dose-response test as a method for assessing vitamin A status in a field setting: experience with Indonesian children.

The modified-relative-dose-response (MRDR) test, which has been used extensively throughout the world for assessing vitamin A status, has been simplified. The major methodologic change resulting from the current studies in Indonesia is the use of graded standard doses of 3,4-didehydroretinyl acetate (DRA) based on the age range of the population of interest. Instead of a dose of 0.35 mumol/kg body wt, standard doses of 5.3 mumol for children younger than 6 y, 7.0 mumol for children between 6 and 12 y of age, and 8.8 mumol for adults and children > 12 y of age are suggested for field use. The acceptable time between administering the oral dose and obtaining a blood sample was validated as being 4-7 h in a group of children (n = 84) by taking two blood samples per child between 3 and 7 h after dosing with DRA. Furthermore, DRA in vitamin E-containing corn oil, with or without the addition of 4.6 mmol all-rac-alpha-tocopheryl acetate/L, was found to be stable for > or = 18 mo at 2 degrees C and at -20 degrees C, but not at 22 degrees C or at 37 degrees C. When DRA was stored in amber glass vials, stability was affected more by temperature than by exposure to room light. In keeping with earlier studies in adults, the ratio of 3,4-didehydro-retinol to retino tends to be independent of body weight. Indeed, slower growing children (ie, those with lower weight-for-age) may have a somewhat better vitamin A status than their heavier counterparts.

Vitamin A status of Indonesian children infected with Ascaris lumbricoides after dosing with vitamin A supplements and albendazole.

In developing countries, both marginal vitamin A status and intestinal helminths are common among children. Indonesian children (n = 309, 0.6-6.6 y), known to be infected with Ascaris lumbricoides, were randomized into six different treatment groups (A-F). The treatments included 210 mumol vitamin A supplement and a dose of 400 mg albendazole (5-propylthio-1H-benzimidazol-2-yl carbamic acid methyl ester) administered orally either at the same health visit (Groups B and F) or at different contact times during a 1-mo period (groups A, C, D and E). Vitamin A status was assessed both before and 3-4 wk after the treatments by the modified relative dose response (MRDR) test. Vitamin A supplementation was most important in improving the vitamin A status (P < 0.0001) of these children, whereas treatment for ascariasis alone (P = 0.370) and the statistical interaction between treatment for ascariasis and vitamin A (P = 0.752) were not. Serum retinol concentrations marginally improved (P = 0.051) in two of the groups that received vitamin A and albendazole but not in the third group that received vitamin A only. The MRDR test proved a better discriminator of the effects of these treatments on vitamin A status than changes in serum retinol concentrations.

Daily supplements of vitamin A (8.4 mumol, 8000 IU) improve the vitamin A status of lactating Indonesian women.

The vitamin A statuses of lactating Indonesian women (n = 23) starting at 1-3 mo after delivery were determined at three monthly intervals (times 1, 2, and 3) during lactation and then again (time 4) after they had ingested vitamin A capsules (8.4 mumol, 8000 IU) daily for 35 d. Vitamin A status was determined by using the modified-relative-dose-response (MRDR) test and serum retinol concentrations. The mean MRDR ratio in these women rose from 0.084 +/- 0.047 (time 1) to 0.099 +/- 0.045 (time 2) and then to 0.100 +/- 0.054 (time 3). After supplementation the mean MRDR ratio fell to 0.040 +/- 0.021 (time 4) (P < 0.0001). Mean serum retinol concentrations at the first three times were 0.94 +/- 0.23, 0.87 +/- 0.20, and 0.80 +/- 0.20 mumol/L, but then rose to 1.10 +/- 0.31 mumol/L at time 4 (P < 0.04). After supplementation mean MRDR values and mean serum retinol concentrations were 60% lower and 38% higher, respectively, than those just before supplementation, MRDR values better distinguished the vitamin A statuses of the women than did serum retinol concentrations. Mean hemoglobin values increased during the study from 118 +/- 9 g/L at time 1 to 122 +/- 6 g/L at time 4 (P = 0.0187). The mean hematocrit also rose from 0.35 +/- 0.03 at time 1 to 0.361 +/- 0.17 at time 4 (P = 0.0478). Thus, iron status may also have improved marginally from time 1 to time 4, but most of the increase appeared before the vitamin A intervention.

Application of the modified relative dose response test to pregnant Indonesian women for assessing vitamin A status.

OBJECTIVE: To determine the prevalence of subclinical vitamin A deficiency (vitamin A inadequacy) in Indonesian pregnant women as assessed by the modified relative dose response test. DESIGN: Cross-sectional study of the vitamin A statuses of pregnant (second trimester) women randomly selected from ten different villages. SETTING: West Java, Indonesia. SUBJECTS: A group of 144 pregnant women recruited from the local health posts. INTERVENTIONS: Modified relative dose response (MRDR) test, serum retinol determination and gynecological examinations. RESULTS: The mean (s.d.) MRDR ratio was 0.039 +/- 0.031. Of the women tested, the vitamin A status of 17% was provisionally classified as being marginal (subclinically deficient) (MRDR ratio > or = 0.060), of 35% as being uncertain (MRDR ratio between 0.030 and 0.060) and of 48% as being satisfactory (MRDR ratio < or = 0.030). CONCLUSION: If the vitamin A statuses of the 'uncertain' group are also deemed to be unsatisfactory, approximately half of the pregnant Indonesian women tested could benefit from an increased intake of vitamin A.

Changing prevalence of xerophthalmia in Indonesia, 1977-1992.

OBJECTIVE: The primary objective of this analysis was to determine if the prevalence of xerophthalmia in Indonesia has changed over the period 1977-78 to 1992. DESIGN: The design was two cross-sectional prevalence surveys conducted in the same rural sample locations 14 years apart. SETTING: The studies were conducted in 15 provinces of Indonesia using a stratified random selection of villages. SUBJECTS: All persons in selected villages < 6 years of age were eligible for participation. Children were recruited during a door-to-door census of villages and invited to present for an eye examination at a central point in the village. A total of 19,032 subjects were included in the 1977-78 and 18,508 children in the 1992 survey. RESULTS: Overall, the prevalence of active xerophthalmia among preschool children declined by 75% (1.33% in 1977-78 to 0.34% in 1992). Active corneal disease declined by 95% (1/1000 in 1977-78 to 0.05/1000 in 1992). While the overall declines were dramatic and highly significant (P < 0.0001), selected provinces continued to show rates higher than the WHO criteria for a problem of public health significance. CONCLUSIONS: The prevalence of xerophthalmia has declined significantly over the past 14 years in Indonesia. The specific reasons for this decline cannot be ascribed to any particular intervention due to the multitude of health and social changes that have occurred during this period.

Assessment of the vitamin A status in lactating and nonlactating, nonpregnant Indonesian women by use of the modified-relative-dose-response (MRDR) test.

The vitamin A statuses of two groups of Indonesian women were compared by using the modified-relative-dose-response (MRDR) test: 1) lactating, nonpregnant women of lower socioeconomic status (n = 64) and 2) better-educated, premenopausal, nonpregnant, nonlactating women (n = 14). At times from 3 to 6 h after dosing, the mean ratio of dehydroretinol to retinol (DR/R) in the serum was approximately threefold higher in the lactating women than in the control group, eg, 0.109 +/- 0.073 and 0.034 +/- 0.015, respectively, at 5 h. At a provisional DR/R cutoff of 0.06, the vitamin A statuses of 70% of the lactating women and of 7% of the control women were judged to be inadequate. Only 7% of the variability in abnormal MRDR ratios could be attributed to body weight. Both abnormal and normal responses were highly reproducible when performed 0.5-3.25 mo after the first test.

PIP: The vitamin A statuses of two groups of Indonesian women recruited from the suburban areas surrounding Bogor in West Java, Indonesia, were compared by using the modified-relative-dose-response (MRDR) test: 1) 64 lactating nonpregnant women of lower socioeconomic status aged 17-37 years with 1-10 children; and 2) better-educated, pre-menopausal, nonpregnant, nonlactating women, 29-41 years old, with 0-4 children (n = 14) recruited from the staff at the Nutrition Research and Development Center in Bogor. The two groups differed significantly in weight (P 0.001) and age (P 0.001). At times from 3 to 6 hours after dosing, the mean ratio of dehydroretinol to retinol (DR/R) in the serum was approximately threefold higher in the lactating women than in the control group, e.g., 0.109 + or - 0.073 and 0.034 + or - 0.015, respectively, at 5 hours. The slopes of the response means between the groups showed a highly significant difference (P 0.001). The mean DR/Rs obtained by combining 5-hours and 5-hours-predicted values for lactating and control groups were 0.109 + or - 0.073 and 0.034 + or - 0.015, respectively. These two values also showed a highly significant difference (p 0.001). At a provisional DR/R cutoff of 0.06, the vitamin A statuses of 70% of the lactating women and of 7% of the control women were judged to be inadequate. The MRDR values of the control group also show a significant negative correlation with body weight (P 0.01). The slopes [(change in DR/R)/kg body wt] were -0.0055/kg (-0.0036/kg for n - 1) and -0.0015/kg for the lactating and control groups, respectively. Only 7% of the variability in abnormal MRDR ratios could be attributed to body weight. Both abnormal and normal responses were highly reproducible when performed 0.5 -3.25 months after the first test. Thus, safe, low-dose oral supplements of vitamin A ( 8000 IU) should be made available to lactating and pregnant mothers in at-risk populations. Nontoxic provitamin A carotenoids might be preferable as supplements.

Comparison of vitamin A status assessment techniques in children from two Indonesian villages.

The vitamin A statuses of preschool-aged children without clinical eye signs of vitamin A deficiency in two villages near Bogor, West Java, Indonesia, were studied by the modified-relative-dose-response (MRDR) test and the conjunctival impression cytology (CIC) method. In the second village the relative-dose-response (RDR) test was also applied. Of the children examined, 71% in the first village (group 1, n = 75) and 36% in the second village (group 2, n = 83) fell below the third percentile of the WHO reference standard of weight-for-age. The following provisional cutoff values for inadequate vitamin A status in Indonesia were used: MRDR (> or = 0.06), RDR (> or = 20%), CIC (an abnormal impression in one eye). The percent abnormal values were as follows: group 1--MRDR 48%, CIC 51%; group 2--MRDR 12%, RDR 11%, CIC 5%. Thus, the indicators gave concordant results for the two populations but did not necessarily identify the same individuals at risk. The consistency of the RDR test was much improved by increasing the oral dose of 3.5 mumol and by retesting only after a 3-wk interval.

Vitamin A status in preschool-age Indonesian children as assessed by the modified relative-dose-response assay.

The modified relative-dose-response (MRDR) assay has been validated in rats as a function of vitamin A status and tested in a group of American children. In this study the MRDR assay was applied to West Javan children who are at risk of being vitamin A deficient. Of 86 children enrolled, 75 were tested. In a time-course study involving 22 children aged 3.7-5.3 y, blood samples were taken at different times after doses of 0.35 mumol 3,4-didehydroretinyl acetate/kg body wt. Generally, the ratio of dehydroretinol to retinol (DR-R ratio) peaked between 4 and 8 h. Thereafter, in a survey of 53 children aged 0.6-4.8 y, single blood samples were drawn 5 h after the dehydroretinyl acetate dose. The DR-R ratio ranged from 0.0028 to 0.169. With a DR-R ratio of 0.03 as the cutoff value, 62% of the children were judged to be of marginal vitamin A status.