Modified Relative Dose Response Research Articles

Repeated High-Dose Vitamin A Supplements, Standard of Care for Treating Xerophthalmia, Leads to Hypervitaminosis A in Piglets

BackgroundVitamin A (VA) deficiency and excess negatively affect development, growth, and bone health. The World Health Organization’s standard of care for xerophthalmia due to VA deficiency, is 3 high-dose VA supplements of 50,000–200,000 IU, based on age, which may cause hypervitaminosis A in some individuals. ObjectivesThis study measured VA status following 3 VA doses in 2 piglet studies. MethodsIn Study 1, 5 groups of piglets (n = 10/group) were weaned 10 d postbirth to VA-free feed and orally administered 0; 25,000; 50,000; 100,000; or 200,000 IU VA ester on days 0, 1, and 7. On days 14 and 15, the piglets underwent the modified relative dose–response (MRDR) test for VA deficiency, and were killed. Tissues were collected for high-pressure liquid chromatography analysis. Study 2 used the same design in 3 groups (n = 13/group) weaned at 16 d and administered 0; 25,000; and 200,000 IU doses. ResultsIn Study 1 (final weight: 3.6 ± 0.7 kg), liver VA concentration was hypervitaminotic in 40%, 90%, and 100% of 50,000; 100,000; and 200,000 IU groups, respectively. The 25,000 IU group was 100% adequate, and the placebo group was 40% deficient. In Study 2 (final weight: 8.7 ± 0.8 kg), where 200,000 IU could be prescribed to infants with a similar body weight, 31% of the piglets were hypervitaminotic, the 25,000 IU group was 100% VA adequate, and the placebo group was 100% deficient. The MRDR test measured deficiency in 50% and 70% of the placebo group in each study but had 3 false positives among hypervitaminotic piglets in Study 1. ConclusionsRepeated high-dose VA may cause hypervitaminosis, indicating dose sizes may need reduction. The MRDR resulted in false positives in a hypervitaminotic state during malnutrition and should be paired with serum retinyl ester evaluation to enhance VA status assessment in populations with overlapping interventions.

Inflammation Adjustments to Serum Retinol and Retinol-Binding Protein Improve Specificity but Reduce Sensitivity when Estimating Vitamin A Deficiency Compared with the Modified Relative Dose-Response Test in Ghanaian Children.

ABSTRACTBackgroundSerum retinol and retinol-binding protein (RBP) concentrations are commonly used biomarkers of vitamin A deficiency (VAD); however, evidence indicates that they are not always accurate, especially in populations with high exposure to inflammation.ObjectiveThe aim was to assess sensitivity and specificity of serum retinol and RBP concentrations to predict VAD, with and without adjustment for inflammation (using categorical and regression-adjusted approaches), using the modified relative dose-response (MRDR) as the reference standard for liver reserves.MethodsThis secondary analysis of diagnostic accuracy used inflammation and RBP data and analyzed serum retinol and MRDR from a subsample of women of reproductive age (n = 178) and preschool children (n = 166) in the cross-sectional 2017 Ghana Micronutrient Survey.ResultsInflammation (elevated C-reactive protein and/or α1-acid glycoprotein) was present in 41% of children and 16% of women. Among children, estimates of VAD prevalence were as follows: 7% (MRDR), 40% (serum retinol), 29% (categorical-adjusted serum retinol), 24% (RBP), 13% (categorical-adjusted RBP), and 7% (regression-adjusted RBP). Sensitivity (95% CI) ranged from 22.2% (2.81%, 60.0%; both adjusted RBPs) to 80.0% (44.4%, 97.5%; serum retinol), whereas specificity ranged from 63.3% (54.7%, 71.3%; serum retinol) to 93.5% (88.0%, 97.0%; regression-adjusted RBP). Among women, VAD prevalence ranged from 1% (RBP) to 4% (all others); sensitivity was 0% and specificity was >96% for all indicators.ConclusionsSerum retinol and RBP had varying accuracy in estimating VAD, especially in children; adjustment for inflammation increased accuracy by increasing specificity at the expense of sensitivity. Effects of inflammation adjustment in the context of high inflammation and VAD prevalence need to be further explored. Especially in populations with high inflammation, the MRDR test should accompany serum retinol or RBP measurements in a subsample of subjects in population-based surveys. This trial was registered with the Open Science Framework registry (doi: 10.17605/OSF.IO/J7BP9).

Relation between Timing of High-Dose Vitamin A Supplementation and Modified-Relative-Dose–Response Values in Children 12–23 Months in Uganda

High-dose vitamin A (VA) supplements (VAS) can temporarily affect VA status. Hence, micronutrient surveys might need to be timed around VAS campaigns to accurately estimate VA deficiency (VAD) prevalence. Little is known about optimal timing of micronutrient surveys when the modified-relative-dose-response (MRDR) is used as a VA indicator. We evaluated the association between days since the end of a VAS campaign and MRDR values in children aged 12-23 mo in Uganda. We pooled data from 2 cross-sectional, population-based surveys in eastern Uganda conducted in 2015-2016 (n=118 children). We estimated the prevalence of VAD (MRDR≥0.060). Days since the end of a VAS campaign ("days since VAS") was calculated as the interview date minus the end date of the VAS campaign. The MRDR value was assessed using HPLC. We excluded children whose MRDR values were below the limit of detection (<0.007). We used linear regression to evaluate the association between days since VAS and log-transformed MRDR. In adjusted analyses, we controlled for potential confounders. Statistical analyses accounted for the surveys' complex design. The prevalence of VAD was 5.2% (95% CI: 1.1%, 9.3%). Mean days since VAS was 54.1 d (range 39-68 d). Days since VAS was not associated with log-transformed MRDR in unadjusted analyses ($\hat{\beta } = \ $0.0055; 95% CI:-0.009, 0.020; P=0.45) or adjusted analyses ($\hat{\beta } = $ -0.0073; 95% CI:-0.024, 0.010; P=0.39). MRDR measurement through a nutrition survey began as early as 1.3 mo after the end of a VAS campaign in eastern Uganda. Days since the end of a VAS campaign was not associated with MRDR in Ugandan children aged 12-23mo. Future studies should consider longitudinal designs and evaluate time since VAS and MRDR in children of different ages and in regions with higher VAD prevalence.

High-Dose Neonatal Vitamin A Supplementation to Bangladeshi Infants Increases the Percentage of CCR9-Positive Treg Cells in Infants with Lower Birthweight in Early Infancy, and Decreases Plasma sCD14 Concentration and the Prevalence of Vitamin A Deficiency at Two Years of Age

Vitamin A (VA) stores are low in early infancy and may impair development of the immune system. This study determined if neonatal VA supplementation (VAS) affects the following: 1) development of regulatory T (Treg) cells; 2) chemokine receptor 9 (CCR9) expression, which directs mucosal targeting of immune cells; and 3) systemic endotoxin exposure as indicated by changed plasma concentrations of soluble CD14 (sCD14). Secondarily, VA status, growth, and systemic inflammation were investigated. In total, 306 Bangladeshi infants were randomly assigned to receive 50,000 IU VA or placebo (PL) within 48h of birth, and immune function was assessed at 6 wk, 15 wk, and 2 y. Primary outcomes included the following: 1) peripheral blood Treg cells; 2) percentage of Treg, T, and B cells expressing CCR9; and 3) plasma sCD14. Secondary outcomes included the following: 4) VA status measured using the modified relative dose-response (MRDR) test and plasma retinol; 5) infant growth; and 6) plasma C-reactive protein (CRP). Statistical analysis identified group differences and interactions with sex and birthweight. VAS increased (P=0.004) the percentage of CCR9+ Treg cells (13.2± 1.37%) relative to PL (9.17± 1.15%) in children below the median birthweight but had the opposite effect (P=0.04) in those with higher birthweight (VA, 9.13± 0.89; PL, 12.1± 1.31%) at 6 and 15 wk (values are combined mean±SE). VAS decreased (P=0.003) plasma sCD14 (1.56± 0.025mg/L) relative to PL (1.67± 0.032mg/L) and decreased (P=0.034) the prevalence of VA deficiency (2.3%) relative to PL (9.2%) at 2 y. Neonatal VAS enhanced mucosal targeting of Treg cells in low-birthweight infants. The decreased systemic exposure to endotoxin and improved VA status at 2 y may have been due to VA-mediated improvements in gut development resulting in improved barrier function and nutrient absorption. This trial was registered at clinicaltrials.gov as NCT01583972 and NCT02027610.

Comparison of Serum Retinol and Retinol-Binding Protein with the Modified Relative Dose-Response Test in Estimating Vitamin A Deficiency Among Ghanaian Women and Children

Abstract Objectives To evaluate the sensitivity and specificity of serum retinol (SR) and retinol-binding protein (RBP) in determining vitamin A deficiency (VAD) using the modified relative dose-response (MRDR) test as the reference. Methods Subjects included a subset of women and children participating in the Ghana Micronutrient Survey 2017. VAD was determined by the following cut-offs: SR or RBP &amp;lt; 0.7 mmol/L; MRDR ratio of 3,4-didehydroretinol to SR ³0.060. Sensitivity, specificity and the area-under-the-receiver operating characteristic (ROC) curve were calculated for unadjusted and inflammation-adjusted VAD cut-offs (based on C-reactive protein (CRP) and a1-acid-glycoprotein (AGP) for SR and RBP using the MRDR test as the reference. Results In 167 children and 178 women, inflammation (elevated CRP and/or elevated AGP) was present in 41% and 16%, respectively. Prevalence of VAD ranged, depending on the indicator used, from 7% (MRDR) to 40% (unadjusted SR) in children and 1% (RBP) to 4% (SR and MRDR) in women. Among children, sensitivity and specificity of unadjusted and adjusted SR and RBP were highly variable among the children. Highest sensitivity was achieved by unadjusted SR (80% of children with VAD correctly identified), while highest specificity was achieved by adjusted RBP (86% of children without VAD correctly identified). The best predictor of VAD in children compared with MRDR was adjusted SR, with a sensitivity of 78%, specificity of 73%, and an area under the ROC curve of 0.76. Among women, specificity was 97% for unadjusted and adjusted SR with an area under the ROC curve of 0.48; additional values could not be calculated due to lack of VAD cases. Conclusions SR and RBP were only moderately sensitive and specific for identifying VAD in children in Ghana. Low specificity—falsely identifying VAD—is especially problematic when populations are covered by one or more vitamin A interventions. Overlapping sources of preformed vitamin A can lead to hypervitaminosis, which may affect bone metabolism and growth. More accurate measures should be used in conjunction with SR and RBP for evaluating VAD especially in vulnerable populations. Funding Sources UNICEF, Canada's Ministry of Foreign Affairs, Trade and Development.

Modified relative dose response values differ between lactating women in the United States and Indonesia.

Vitamin A (VA) deficiency is a major health issue globally, and lactating women are particularly vulnerable due to increased needs for milk production. Accurate detection of VA deficiency is important; however, most population surveys measure VA status using serum retinol, which is affected by inflammation and lacks sensitivity. The modified relative dose response (MRDR) test qualitatively distinguishes between VA deficiency and sufficiency and could improve population surveys if completed in a randomly selected subsample of individuals in surveys. The original relative dose response test required two blood samples, while MRDR requires only one, a significant improvement in accessibility of the technique by decreasing burden on subjects and investigators. This work demonstrates significant deficiency in Indonesian women compared with US women. In combination with previous research using lactating sows, these human data support milk as a surrogate for blood in the MRDR, which may be less invasive, but requires further validation.

Use of Modified Relative Dose‐Response to Examine Sensitivity and Specificity of Retinol Binding Protein as An Indicator of Vitamin A Deficiency among Nepali Children 6–23 Mo of Age

A population‐based survey in two districts of Nepal assessed retinol binding protein (RBP) and inflammation indicators among 2347 children 6–23 mo, and the modified relative dose‐response (MRDR) and serum retinol among 151 randomly selected children in a sub‐sample. In previous analyses, vitamin A deficiency(VAD) for RBP was defined as &lt;0.84 μmol/L, calculated by examining the serum retinol‐RBP relationship. MRDR assesses VAD as a qualitative measure of vitamin A liver reserves. MRDR defines VAD as ≥0.060. Retinol isotope dilution is the most sensitive biomarker of vitamin A status to vitamin A liver stores, but is not feasible to assess in cross‐sectional, population‐based surveys. Using MRDR as the standard, we examined RBP sensitivity and specificity to detect VAD among the sub‐sample, and also excluding those with any inflammation. RBP sensitivity was 34.6% and specificity was 75.0%. RBP was, and MRDR was not, influenced by inflammation. Excluding those with inflammation, RBP sensitivity was 23.1% and specificity was 81.2%. RBP showed poor sensitivity to identify VAD both with and without inflammation, while specificity of RBP was good. When feasible, including a sub sample of MRDR is useful in surveys because it provides more information about VAD status in children.

Vitamin A status and body pool size of infants before and after consuming fortified home-based complementary foods

BackgroundHome fortification using sachets of micronutrient powder (e.g. “Sprinkles”) is a food-based approach offering an alternative to high dose vitamin A (VA) supplements for infants. The primary objective was to investigate the impact of VA-home fortification on infant VA pool size. The secondary objective was to compare VA status of infants assessed by the modified relative dose response (MRDR) test before and the 13C-retinol isotope dilution (13C-RID) test in the same infants after vitamin A supplementation.MethodsA randomized-controlled trial was conducted in 7–9 month old infants in Ghana. Eligible children were randomly allocated to receive a daily sachet of “Sprinkles” with or without VA for 5 months added to complementary foods. The MRDR test indirectly determined VA liver reserves at baseline and the 13C-RID determined VA body pool at follow-up in the same cohort of children.ResultsAt baseline, the MRDR values (95 % CI) for infants were comparable in the intervention and control groups: normal at 0·032 (SD 0·018) (0·025–0·038) and 0·031 (SD 0·018) (0·024–0·038), respectively. After intervention, total body stores (TBS) and liver retinol concentrations did not differ between intervention and control groups; TBS were 436 (SD 303) and 434 (SD 186) μmol, respectively, and estimated liver concentrations were 0·82 (SD 0·53) and 0·79 (SD 0·36) μmol/g liver, indicating adequate reserves in all children.ConclusionsBoth the MRDR and 3C-RID tests confirmed that the infants had adequate VA status before and after home fortification of their complementary foods. These tests offered more information than serum retinol concentrations alone, which predicted VA deficiency using current suggested cutoffs not corrected for inflammation status.

International experiences in assessing vitamin A status and applying the vitamin A-labeled isotope dilution method.

Inadequate vitamin A (VA) nutrition continues to be a major problem worldwide, and many interventions being implemented to improve VA status in various populations need to be evaluated. The interpretation of results after an intervention depends greatly on the method selected to assess VA status. To evaluate the effect of an intervention on VA status, researchers in Cameroon, India, Indonesia, Mexico, Senegal and Zambia have used serum retinol as an indicator, and have not always found improvement in response to supplementation. One problem is that homeostatic control of serum retinol may mask positive effects of treatment in that changes in concentration are observed only when status is either moderately to severely depleted or excessive. Because VA is stored mainly in the liver, measurements of hepatic VA stores are the “gold standard” for assessing VA status. Dose response tests such as the relative dose response (RDR) and the modified relative dose response (MRDR), allow a qualitative assessment of VA liver stores. On the other hand, the use of the vitamin A-labeled isotope dilution (VALID) technique, (using 13C or 2H-labeled retinyl acetate) serves as an indirect method to quantitatively estimate total body and liver VA stores. Countries including Cameroon, China, Ghana, Mexico, Thailand and Zambia are now applying the VALID method to sensitively assess changes in VA status during interventions, or to estimate a population’s dietary requirement for VA. Transition to the use of more sensitive biochemical indicators of VA status such as the VALID technique is needed to effectively assess interventions in populations where mild to moderate VA deficiency is more prevalent than severe deficiency.

High Prevalence of Vitamin A Deficiency Is Detected by the Modified Relative Dose-Response Test in Six-Month-Old Senegalese Breast-Fed Infants ,

To alleviate vitamin A (VA) deficiency (VAD) in Senegal, understanding the relationship between VA status of lactating women and their 6-mo-old infants is important. This study measured 6-mo-old infants' VA intake from human milk and assessed the VA status of mothers and infants. A comprehensive study was undertaken in 34 mother-infant pairs. Nonpregnant lactating women and their infants were included. None of the infants had received a VA supplement. Mothers were grouped as supplemented with 2 doses of 200,000 IU (60,000 μg; 210 μmol) retinol as retinyl palmitate (n = 13) or nonsupplemented (n = 19) after delivery. Breast milk intake was measured by the deuterium dilution technique. Plasma and breast milk retinol concentrations were measured by HPLC. Infants' VA liver stores were assessed by the modified relative dose-response (MRDR) test. Plasma retinol detected 15% VAD among infants and the MRDR test (≥0.06) indicated 73.5% with low VA liver stores. Infants' milk VA intakes were close to estimated requirements (375 μg/d). No correlation was found between infants' plasma retinol and MRDR value. Infants' MRDR value was lower in the group from supplemented mothers (0.055 ± 0.017 vs. 0.073 ± 0.017; P = 0.009), but no difference was observed between plasma retinol concentrations of both groups of mothers; 8.8% of mothers were VA deficient based on plasma retinol (≤0.7 μmol/L). Low VA liver stores were prevalent among Senegalese infants at the beginning of the complementary feeding period. Postpartum VA-supplemented mothers significantly enhanced their infants' VA liver stores.

Vitamin A deficiency alters airway resistance in children with acute upper respiratory infection

ObjectiveTo assess whether vitamin A deficiency alters the recovery of total respiratory resistance (TRR) following acute upper respiratory tract infection (URI).MethodsThis is a case control study of children, age 4–6 years and grouped as: URI, (n = 74), URI and wheezing, (URI‐wheezing, n = 52), and healthy controls (n = 51). Vitamin A and total respiratory resistance (TRR) were assessed using the modified relative dose response (MRDR) and forced oscillometry, respectively.ResultsChildren with URI and URI‐wheezing had lower retinol, 32.4 ± 13.12 and 18.3 ± 6.83 µg/dl respectively, compared to controls, 56.9 ± 29.82 µg/dl (ANOVA, P < 0.001). The MRDR was elevated in children in the URI or URI‐wheezing groups 0.066 ± 0.045 and 0.021 ± 0.021, respectively, compared to controls 0.007 ± 0.006 (ANOVA, P < 0.0001). The TRR in the URI and URI‐wheezing groups differed from controls. During convalescence, the TRR failed to decline in the URI‐group only when the MRDR was >0.06. In the URI‐wheezing group, TRR declined independently of retinol and MRDR.ConclusionVitamin A contributes to preservation of airway function during and in recovery after upper respiratory infection in children. Pediatr Pulmonol. 2013; 48:481–489. © 2012 Wiley Periodicals, Inc.

Giardia lamblia Infection and Its Implications for Vitamin A Liver Stores in School Children

Background: Vitamin A deficiency (VAD) is a nutritional problem affecting the health of people in developing countries because VAD compromises innate and adaptive immunity, increasing a person’s predisposition toward infectious diseases. In addition, a high prevalence of infectious diseases continues to be a problem in developing countries, including Giardia lamblia. G. lamblia may be related to VAD because of its ability to change the intestinal architecture, thereby compromising the absorption of vitamin A. The aim of this study was to evaluate the effect of giardiasis on serum retinol levels and vitamin A liver stores in school children. Methods: Thirty Giardia-infected school children participated in this study. Vitamin A liver stores were evaluated with the modified relative dose response (MRDR) technique, and antiparasitic treatment was administered. In addition, anthropometric and dietary data were collected. Results: According to anthropometric indicators (age-appropriate Z scores for weight, height and body mass index) and daily vitamin A intake, the children had a normal nutritional status. Although the mean serum retinol levels did not change significantly after treatment for Giardia (p > 0.05), the MRDR values showed significant improvement (p < 0.002). Conclusion: Giardiasis not only compromises the vitamin A status through intestinal malabsorption, it also causes profound mobilization of liver retinol stores.

Assessment of Vitamin A Status of Preschool Children in a Sub-Saharan African Setting: Comparative Advantage of Modified Relative-dose Response Test

A nationally-representative sample of 2,696 preschool children living in Congo was examined during Au gust-September 2003 to determine the rates of vitamin A deficiency. Ninety clusters of 30 children, aged six months to six years, were selected, using a randomized two-level cluster-sampling method. Vitamin A deficiency was determined by assessing the prevalence of active xerophthalmia (nightblindness and/or Bitot spots) in the cross-over sample of 2,696 individuals. A semi-quantitative seven-day dietary questionnaire was concurrently applied to the mothers of children enrolled to estimate the latter's consumption of vitamin A-rich food. Vitamin A status was assessed by performing the modified relative dose-response test (MRDR) on dried blood spots (DBS) from a subsample of 207 children aged less than six years and the impression cytology with transfer (ICT) test on a subsample of 1,162 children. Of the children enrolled, 5.2% suffered from nightblindness, 8.0% had Bitot spots, and 2.5% had other vitamin A deficiency sequellae. Fifty-three percent of the ICT tests showed the presence of vitamin A deficiency. The biochemical MRDR test showed that the vitamin A status of 30% of the study children was critical. Twenty-seven of them had retinol levels of < 10 microg/dL [mean +/- standard deviation (SD) 7.02 +/- 2.0 microg/dL], and 50% had retinol levels of 10-20 microg/dL (mean +/- SD 14.2 +/- 2.83 microg/dL). The poor health status and low rates of consumption of vitamin A-rich food are the main factors determining critical status. Vitamin A deficiency, reflecting poor nutrition and health, is a serious public-health issue among children aged less than six years in Congo.

Plasma turnover of 3,4-didehydroretinol (vitamin A2) increases in vitamin A-deficient rats fed low versus high dietary fat

Relationships between increased adiposity and fat-soluble vitamin storage and metabolism are poorly understood. To examine these associations, 6% or 21% dietary fat was fed to rats for 11 weeks and tissue vitamin A storage determined. Two levels of supplemental vitamin A were administered. At the end of the tenth week, 3,4-didehydroretinol (DR) was administered orally, and its kinetics were followed for 1 week in serum and tissues. Model-based compartmental analysis was applied to these data. Kidney total retinol (R) concentrations were elevated in rats fed 6% compared with 21% dietary fat (n = 24/group). The fractional transfer coefficient (FTC) describing the movement of tracer from plasma to extravascular stores was two times higher in the 6% compared with the 21% fat group. Consistent with the elevated renal R in 6% fat fed rats, there was a 2-fold increase in the FTC representing tracer distribution from plasma to kidney in the 6% compared with 21% fat group. Taken together with a fat main effect on renal vitamin A, our data support the evidence that faster turnover of kidney R may help set the mechanism governing vitamin A tissue distribution during deficiency. Rats fed 21% versus 6% dietary fat conserved hepatic R more efficiently.

The Vitamin A Status of Zambian Children in a Community of Vitamin A Supplementation and Sugar Fortification Strategies as measured by the Modified Relative Dose Response (MRDR) Test

The main objective of the study was to determine the vitamin A status of Zambian children less than five years of age in a community where strategies of vitamin A supplementation and consumption of vitamin A fortified sugar have been introduced. In a cross-sectional study, a total of 537 children were enrolled. Their vitamin A status was measured using the modified relative dose response (MRDR) test. Their vitamin A status was compared to the status measured using a similar method in 1996, before vitamin A supplementation through capsule distribution and fortification of sugar was implemented as strategies to reduce vitamin A deficiency in the country. Results showed that the vitamin A status of children improved markedly as a result of these strategies.

Household Building Structure Impacts Hemoglobin and Hematocrit Values in Indonesian Children Infected with Intestinal Helminthes

ABSTRACT The links between socioeconomic status, nutritional status, and parasitic infection are difficult to clarify. This study investigated the correlations between household building materials, amenities, and head-of-household education with vitamin A status, hematocrit and hemoglobin (Hb) values in Indonesian preschool children infected with Ascaris lumbricoides and/or Trichuris trichiura. Children (N = 125, aged 3.3 ± 1.2 year) were enrolled at health posts in West Java. Anthropometric measures (i.e., gender, age, height, weight) and blood samples were collected. Vitamin A status was assessed with the modified relative-dose-response (MRDR) test and serum retinol concentrations, and iron status was assessed with Hb concentrations and hematocrit. A standard socioeconomic questionnaire was administered to the subjects' mothers by oral interview. Statistical analysis used multiple linear regression models for MRDR value, serum retinol concentration, hematocrit, and Hb with physical and socioeconomic factors as independent variables. Hb and hematocrit were negatively associated with the quality of walls (p = 0.032 and p = 0.0021, respectively) and floors (p = 0.0046 and p = 0.0032, respectively). Hb was positively associated with the quality of drinking water (p = 0.030) and serum retinol was positively associated with a higher level of head-of-household education (p = 0.035). Nutritional indicators correlated with household material quality and head-of-household education in Indonesian children and causality should be further investigated.

The effects of maternal and infant vitamin A supplementation on vitamin A status: a randomised trial in Kenya

Postpartum vitamin A supplementation of mothers and infants is recommended, but the efficacy has been questioned. In this double-blind, placebo-controlled trial, Kenyan mother-infant pairs were randomised to maternal vitamin A (400,000 IU) or placebo <24 h postpartum, and infant vitamin A (100,000 IU) or placebo at 14 weeks. Milk retinol was determined at weeks 4, 14 and 26, and maternal and infant serum retinol at weeks 14 and 26. Infant retinol stores were assessed at week 26, using a modified relative dose response (MRDR) test. Among 564 women, serum retinol at 36 weeks gestation was 0.81 (SD 0.21) micromol/l, and 33.3% were<0.7 micromol/l. Maternal serum retinol was not different between groups, but milk retinol was higher in the vitamin A group: (0.67 v. 0.60 micromol/l; 0.52 v. 0.44 micromol/l; 0.50 v. 0.44 micromol/l at 4, 14 and 26 weeks, respectively). When expressed per gram fat, milk retinol was higher in the vitamin A group only at 4 weeks. Infant serum retinol was not different between groups. However, although most infants had deficient vitamin A stores (MRDR>0.06%) at 26 weeks, vitamin A to infants, but not mothers, resulted in a lower proportion of infants with deficient vitamin A stores (69 v. 78 %). High-dose postpartum vitamin A supplementation failed to increase serum retinol and infant stores, despite modest effects on milk retinol. Infant supplementation, however, increased stores. There is a need for a better understanding of factors affecting absorption and metabolism of vitamin A.

The modified relative dose response (MRDR) test value predicts liver vitamin A reserves in a piglet model

The modified relative dose response (MRDR) test is an indicator of vitamin A (VA) status when defined by hepatic VA. Debate exists as to how accurately the MRDR test reflects hepatic VA or a change in VA status. We examined the MRDR test and serum retinol as indicators of hepatic VA in piglets using the following values to indicate deficient or marginal status: ≥ 0.060, < 0.70 μmol/L, and < 30 retinol equivalents/g, respectively. In piglets (n = 100) with a 78% prevalence of deficiency, the negative predictive value and sensitivity are higher using the MRDR test than serum retinol. The MRDR test more accurately indicated a change in VA status in groups of animals receiving supplementation than serum retinol. Serum retinol remains under homeostatic control throughout a wide range of liver values, but can be depressed due to protein-energy undernutrition, iron and zinc deficiency, and the acute-phase response even if hepatic VA is unaffected. Alternatively, the MRDR test reflects normal through severely depleted hepatic VA and is less affected by the acute-phase response and mild to moderate protein-energy undernutrition. Serum retinol and the MRDR test are correlated when hepatic VA is extremely low and when hepatic VA is ample. However, in groups with marginal status, the indicators are not correlated and the MRDR test gives a better definition of overall VA status. Supported by NIHNIDDK 61973 and USDA NRI 2003-35200-13754.

Evaluation of vitamin A supplementation regimens in Ghanaian postpartum mothers with the use of the modified-relative-dose-response test

Vitamin A deficiency is an important public health problem in many developing countries. Women of childbearing age and children are documented as the most affected groups. The objective was to determine the length of time mothers are protected postpartum against vitamin A depletion after receiving either 400,000 IU vitamin A in 2 divided doses or 200,000 IU as a single dose plus a placebo 24 h apart. Mothers (n = 168) were recruited by trained fieldworkers 7-10 d after delivery. Modified-relative-dose-response (MRDR) tests were performed at baseline in 167 women, and vitamin A was administered within 6 wk after delivery. The women were randomly assigned to 2 main treatment groups, and each treatment group was divided into 3 follow-up subgroups. Each subgroup was invited back once at month 1, 3, or 5 for a second MRDR test. The serum retinol concentration and the MRDR value were 1.4 +/- 0.5 micromol/L and 0.048 +/- 0.037, respectively, at baseline. A significant improvement in vitamin A status occurred after vitamin A treatment as assessed by the MRDR test (P < 0.0001). Serum retinol concentrations were not different after vitamin A treatment (P = 0.87). The mothers had marginally depleted liver reserves of vitamin A at baseline on the basis of MRDR test results. Liver reserves of vitamin A significantly improved in both treatment groups, and the improvement was maintained for >or= 5 mo.

The Modified-Relative-Dose-Response Values in Serum and Milk Are Positively Correlated over Time in Lactating Sows with Adequate Vitamin A Status

The modified-relative-dose-response (MRDR) test, which requires a blood sample after dosing with 3,4-didehydroretinyl acetate (DRA), has been used to determine vitamin A (VA) status of individuals and groups worldwide. Less invasive methods using milk are in development in a swine model. Swine are a good choice for studying VA metabolism because their gastrointestinal anatomy, morphology, physiology, and VA requirements are similar to those of humans. In this study, DRA was used as a VA tracer in lactating sows to follow the metabolism of newly ingested VA. Lactating sows (n = 6) were administered 35 micromol DRA after overnight food deprivation. Blood and milk were collected at 0, 1.5, 3, 5, 7, 9, 24, and 48 h; livers were obtained at the time of killing. Samples were analyzed for didehydroretinol (DR), retinol (R), and didehydroretinyl esters (DRE). Serum DR:R was compared with that in milk and other VA indicators. DRE rapidly increased in serum, corresponding to chylomicra, whereas DR increased at a slower rate corresponding to the holo-DR:retinol-binding protein complex released from the liver. An estimated 10-20% of the dose was irreversibly lost in milk over 48 h. The mean MRDR value was 0.018 +/- 0.013 at 5 h and the mean liver VA was 0.73 +/- 0.21 micromol/g, both signifying sufficient stores. Milk and serum DR:R values were directly correlated (r = 0.64, P < 0.0001). Thus, DR:R values in milk may be a potential alternative to serum in determining VA status in lactating women. Future work is required in VA-deficient sows and women of varying VA status to determine DR trafficking and to compare DR:R values in milk with those in serum.