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ORIGINAL RESEARCH COMMUNICATIONS |
1 From the Division of Human Nutrition and Epidemiology, Wageningen University, Netherlands; the Nutrition Research and Development Centre, Bogor, Indonesia; and the Division of Gastroenterology, University Medical Centre Nijmegen, Nijmegen, Netherlands.
2 Supported by the Dutch Foundation for the Advancement of Tropical Research (WOTRO), the Ter Meulen Fund (Royal Netherlands Academy of Arts and Sciences), and UNICEF–Jakarta.
3 Address reprint requests to CE West, Division of Human Nutrition and Epidemiology, Wageningen University, PO Box 8129, 6700 EV Wageningen, Netherlands.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: The aim was to investigate the extent to which deficiencies of vitamin A, iron, and zinc coexist and the nutritional relation between lactating mothers and their infants.
Design: In a cross-sectional survey in rural West Java, Indonesia, 155 lactating mothers and their healthy infants were assessed anthropometrically and blood, urine, and breast-milk samples were obtained.
Results: Marginal vitamin A deficiency was found in 54% of the infants and 18% of the mothers. More than 50% of the mothers and infants were anemic and 17% of the infants and 25% of the mothers were zinc deficient. There was a strong interrelation between the micronutrient status of the mothers and infants and the concentrations of retinol and ß-carotene in breast milk. Vitamin A deficiency in infants led to an increased risk of anemia and zinc deficiency (odds ratios: 2.5 and 2.9, respectively), whereas in mothers the risk of anemia and iron deficiency (odds ratios: 3.8 and 4.8, respectively) increased. In infants, concentrations of insulin-like growth factor I were related to concentrations of plasma retinol and ß-carotene but not to zinc.
Conclusions: Micronutrient deficiencies were prevalent in West Java. The micronutrient status of lactating mothers and that of their infants were closely related; breast milk was a key connecting factor for vitamin A status. Furthermore, concurrent micronutrient deficiencies appeared to be the norm.
Key Words: Vitamin A • iron • zinc • deficiency • infants • lactating mothers • anthropometry • plasma • human milk • retinol • ß-carotene • retinol binding protein • ferritin • hemoglobin • insulin-like growth factor I • Indonesia
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Deficiencies of vitamin A, iron, and zinc often coexist and have independent and interacting effects on health, growth, and immunocompetence (2, 3). It is well known that severe vitamin A deficiency leads to xerophthalmia. However, vitamin A is important in many other tissues and metabolic processes and the considerable effects of vitamin A deficiency on morbidity and mortality have become clearer. It is important to note that in populations with only marginal vitamin A deficiency, effects on metabolism and immune function are already present (4). Also, vitamin A deficiency was shown to contribute to the development of anemia and stunting (6, 7). People in developing countries derive most of their vitamin A from provitamin A carotenoids, of which ß-carotene is the most important. However, absorption, conversion, and mobilization of carotenoids and retinol are variable and dependent on many factors (8).
Iron deficiency is the most important cause of nutritional anemia and is the most common micronutrient deficiency worldwide; it leads to impairment of health, growth, development, and performance (9). Iron supplementation is currently the most important tool for combating iron deficiency. However, a high intake of iron, especially as a supplement, was shown to be an antagonist to zinc absorption (3, 10).
The extent of zinc deficiency and its consequences are not yet clear. Zinc status is difficult to assess because plasma zinc concentrations do not sufficiently reflect individual zinc status because of strong homeostasis (11). In infants, improved growth performance after zinc supplementation is the most accurate measure of preexisting zinc deficiency but, on a population level, plasma zinc is still the most practical and reliable indicator of zinc status (12).
The manifestations of zinc deficiency range from an increased incidence and severity of infection and impaired growth and development of children to pregnancy complications, low birth weight, and increased perinatal mortality (13–16). Zinc is also thought to play a role in vitamin A and ß-carotene metabolism. Zinc supplements were shown previously to improve dark adaptation and intestinal integrity and zinc deficiency was found to aggravate the clinical effects of vitamin A deficiency (2).
Most public health and nutrition programs focus on one micronutrient only, whereas many populations can be expected to be deficient in several micronutrients at the same time. The aim of this study was to investigate the prevalence of concurrent micronutrient deficiencies in lactating mothers and their infants to elucidate the nutritional interrelation between the mothers and their infants and the relation of micronutrient deficiencies with growth.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mothers were informed of the procedures and purpose of the study. After written, informed consent was given by the mothers, infants and mothers were anthropometrically assessed and a short history concerning socioeconomic status, dietary and lactation habits, and health was taken. Furthermore, a series of breast-milk samples from the mothers and blood and urine samples from both the mothers and the infants were obtained as completely as possible. The protocol was approved by the Ethical Committee of the National Health Research and Development Institute of Indonesia and by the Ethical Committee of the Royal Netherlands Academy of Arts and Sciences.
Methods
Anthropometry included measurement of weight, height, and midupper arm circumference by a trained anthropometrist using standard methods; z scores for weight and height [weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ)] were calculated by using EPI-INFO (version 6.02; Centers for Disease Control and Prevention, Atlanta) with the use of World Health Organization recommended growth curves (17). A fasting 3-mL venous blood sample was taken from the mothers and a nonfasting 5-mL venous blood sample was taken from the infants. A closed-tube heparin-containing vacuum system was used to avoid zinc contamination. Blood samples were stored immediately at 4°C to prevent microhemolysis and were separated within 5 h.
Breast milk was obtained from the right breast 45–60 min after the last feeding from that breast. The breast was completely expressed and all milk was collected. The manual breast-milk pumps and containers were washed with acid to prevent zinc contamination (18). Urine samples were collected in acid-washed containers (mothers: midstream samples; infants: samples taken after the genital area was washed).
Zinc in blood, urine, and breast milk was analyzed with flame atomic absorption spectrophotometry (Varian Australia Ltd, Clayton South, Australia) by using certified control sera (J Versieck, Department of Internal Medicine, University Hospital, Gent, Belgium) as a quality control. For plasma and urinary zinc, the interassay CV was typically <5%; however, breast-milk zinc analyses showed more variability (10%), probably because of matrix effects. Urinary zinc concentrations were measured in casual urine samples from 104 infants and 130 mothers.
Retinol and ß-carotene were analyzed by using standard HPLC procedures. Hemoglobin concentrations were measured by using the standard cyanoblue method (Humalyzer, Tanusstein, Germany). Hematocrit in blood and creamatocrit in breast milk—a measure of breast-milk fat—were determined according to standard practices. The fat content of breast milk was calculated on the basis of the creamatocrit content according to the method of Lucas et al (19). Ferritin, C-reactive protein (CRP), and insulin-like growth factor I (IGF-I) were measured by using commercial enzyme-linked immunosorbent assay kits (MP-products, Amersfoort, Netherlands). Urinary creatinine was measured colorimetrically (Randox, Antrim, United Kingdom) and retinol binding protein (RBP) turbidimetrically (Behring Diagnostics Benelux NV, Rijswijk, Netherlands). Because a close interrelation between indicators of micronutrient status of mothers and their infants was expected, the relation between hemoglobin and plasma retinol, ß-carotene, and zinc concentrations in the mother-infant pairs was examined.
Because many commonly used indicators of micronutrient status [eg, plasma concentrations of zinc, retinol, ferritin, and RBP (20)] are altered by the acute phase response, subjects were screened for the presence of inflammation (12, 20). Because a clinical examination often does not exclude the presence of minor or low-grade chronic infections, subjects with an acute phase response—as indicated by CRP concentrations >10 mg/L or ferritin concentrations >150 µg/L (>400 µg/L in infants aged <6 mo) (21)—were excluded from the statistical analyses.
Statistical analysis
Data were checked for normal distribution by using the Kolmogorov-Smirnov test of normality. Relations were analyzed by using multiple linear regression analysis; confounders were controlled for when necessary by using a backward deletion procedure (threshold: P > 0.1). When no confounders were found, Pearson's correlation coefficients were used. Odds ratios and CIs were determined by using chi-square tests. Differences between groups were checked by using Student's t test for parametric or log-transformed variables. Statistical analysis was carried out with EPI-INFO (version 6.04b) and SPSS (version 7.5.2; SPSS Inc, Chicago) software packages.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), with an equal age distribution for both sexes; the sample included 78 males and 77 females. The mean HAZ was negative (-0.73) whereas the mean WHZ was positive (0.24), indicating that in general the infants were short but not wasted. Eleven infants (7%) had an HAZ < -2, whereas one infant (0.6%) had a WHZ < -2. An HAZ > 2 and a WHZ > 2 were found in 1% and 3% of the infants, respectively. Furthermore, all z scores were significantly negatively correlated with age after sex was controlled for (HAZ: r = -0.34; WHZ: r = -0.29; WAZ: R = -0.48; P < 0.01 for all), implying that growth faltering in these infants started within the first months of life and progressed with age, as is observed frequently in developing countries.
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). Seventeen infants and 12 mothers were excluded because of having an acute phase response: either elevated CRP concentrations only or both elevated CRP and ferritin concentrations; none had elevated ferritin concentrations only. As expected, plasma retinol concentrations were significantly lower and plasma ferritin concentrations were significantly higher in the excluded subjects. Plasma zinc and RBP concentrations, however, did not differ significantly in the excluded subjects.
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). There was a positive correlation between concentrations of plasma zinc and urinary zinc (related to creatinine) in infants only (r = 0.23, P < 0.05; Spearman's rank test). The urinary zinc concentration is considered a more sensitive indicator of early zinc deficiency than is the plasma zinc concentration (14); however, in the present study it was found to be less suitable in the field setting, where sampling conditions were difficult. Usually, only casual urine samples can be obtained in a field setting and it is often difficult to obtain samples from young infants. These factors contribute to the large variation in urinary zinc concentrations; therefore, this measure is not very useful as an indicator of zinc status.
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). Similarly, in lactating mothers, breast milk was an important link between the nutritional status indicators of mothers and infants. Breast-milk concentrations of retinol and ß-carotene were significantly correlated with those in the plasma of both mothers and infants (Table 3), accounting to a large extent for the strong interrelation between the vitamin A status of the mothers and infants. Concentrations of zinc in breast milk, however, were not significantly correlated with those in the plasma of either the mothers or infants. The fat content of breast milk [calculated on the basis of a median creamatocrit content of 3.7% (interquartile range: 2.8–5.0%)] was significantly positively correlated with both breast-milk retinol and ß-carotene concentrations (r = 0.53 and r = 0.24, respectively; P < 0.01 by multiple regression analysis). However, conflicting findings on changes in micronutrient concentrations during lactation were reported previously (22–25). In the present study, there was no significant effect of the duration of lactation on retinol, ß-carotene, or zinc concentrations in breast milk.
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). Furthermore, a clear relation was observed between IGF-I and plasma retinol and ß-carotene concentrations but not with zinc. No relation was found between the indicators of micronutrient status and the anthropometric measurements.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Even though the population studied was not very deprived, merely rural and having traditional habits and diets, they had a high prevalence of marginal-to-severe micronutrient deficiencies, especially of iron and vitamin A. On the basis of the current cutoff indicating zinc deficiency (plasma zinc < 10.7 µmol/L; 26), the prevalence of zinc deficiency in the present study population was almost similar to the prevalence of iron deficiency. This is despite the fact that zinc deficiency is less readily assessed than is iron deficiency. At the population level, the plasma zinc concentration is a useful indicator of zinc status (12). However, current cutoffs for deficiency have been defined without considering the effect of infection on plasma zinc concentrations. Hence, the estimate of zinc deficiency in this population was conservative because subjects with an acute phase response were excluded.
The plasma RBP concentration was advocated recently as an alternative to the plasma retinol concentration for assessing vitamin A status. However, the relation between the plasma retinol concentration and the retinol-RBP ratio (Figure 2) showed that this ratio is constant and close to 1 only above marginal concentrations of retinol: the ratio is <1 at lower plasma retinol concentrations. This lower ratio probably reflects an increase in plasma apo-RBP concentrations in vitamin A deficiency (27). Hence, RBP becomes a less-sensitive indicator of vitamin A status at lower plasma retinol concentrations. Therefore, substituting RBP for retinol as an indicator of vitamin A status may lead to an underestimate of deficiency. Methods that specifically measure holo-RBP circumvent this drawback (28), but are not yet generally available. It is important to establish reliable indicators for micronutrient status, especially when assessing a population for multiple micronutrient deficiencies, because confounding factors such as infection can easily complicate the overall picture.
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The nutritional status of mothers is an important factor both prenatally and after birth. Prenatal maternal nutritional status affects birth weight, neonatal morbidity and mortality, and the micronutrient status of newborns. Postnatal maternal status can affect the quality of breast milk and thus the nutrient intake of infants (31). In the present study, indicators of the micronutrient status of the lactating mothers were clearly related to those of the infants. Concentrations of hemoglobin, plasma retinol, plasma ß-carotene, and plasma zinc were all strongly correlated between the mother-infant pairs. For retinol and ß-carotene, this relation was attributable to the breast-milk link referred to above The close relation between maternal vitamin A status and vitamin A concentrations in breast milk was described previously (32, 33), but few data are available on the link between vitamin A concentrations in breast milk and the vitamin A status of infants. The present study showed clearly that the concentrations of vitamin A and ß-carotene in breast milk were closely related to those in the plasma of the infants. No relation was found between zinc concentrations in the plasma of the mothers and in breast milk, reflecting earlier evidence that mammary zinc secretion is independent of maternal zinc status (23, 24).
Impaired growth in infants is in itself not hazardous to health but is associated with higher morbidity and mortality and with impaired cognitive and psychomotor development (34). The findings of the present study indicate that growth was suboptimal in these infants, with length more affected than weight. In accordance with findings in similar populations, HAZ scores were lower with increasing age. Growth failure is a consistent sign of zinc deficiency, and zinc supplementation was shown to improve growth, especially in stunted children (35). Ninh et al (36) reported increased IGF-I concentrations after zinc supplementation in stunted Vietnamese infants. In the present study, however, IGF-I was found to be related to plasma concentrations of retinol and ß-carotene in the infants, and to a lesser extent to hemoglobin concentrations, but not to plasma zinc concentrations.
There is clear evidence of a direct effect of vitamin A on cellular and tissue growth (37). However, supplementation with either retinol or ß-carotene improved growth performance in some studies but not in others, and the underlying mechanisms are not clear (7, 38–40). IGF-I is a relatively new indicator of growth activity and the relation between plasma concentrations of retinol and ß-carotene and those of IGF-I has not been reported. Thus, further investigation is required to establish whether this relation can be confirmed and to test whether the effect is causal. Other factors such as infection, nutrient status with respect to other nutrients, and genetic background could also be implicated (41). For instance, vitamin A status has profound effects on morbidity and could thereby indirectly influence growth (4).
The results of this study provide clear evidence that the concurrent occurrence of deficiencies of many micronutrients is the norm rather than the exception. Of special significance is the strong interrelation between the micronutrient status of the mothers and that of their infants; however, the mechanisms involved have not yet been elucidated satisfactorily. In a future trial of ß-carotene, iron, and zinc supplementation, we will investigate interactions between vitamin A, iron, and zinc and interrelations between micronutrient deficiencies in infants and pregnant women in West Java, Indonesia.
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ACKNOWLEDGMENTS |
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REFERENCES |
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