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Division of Human Nutrition and Epidemiology, Wageningen University, The Netherlands;
Nutrition Research and Development Centre, Bogor, Indonesia; and the
Department of Gastroenterology, University Medical Center, Nijmegen, The Netherlands
**
*
2To whom correspondence should be addressed. E-mail: clive.west{at}staff.nutepi.wau.nl
ABSTRACT
In this study the effects of supplementation of iron and zinc, alone or combined, on iron status, zinc status and growth in Indonesian infants is investigated. Micronutrient deficiencies are prevalent in infants in developing countries, and deficiencies often coexist; thus, combined supplementation is an attractive strategy. However, little is known about interactions between micronutrients. In a randomized, double-blind, placebo-controlled supplementation trial, 478 infants, 4 mo of age, were supplemented for 6 mo with iron (10 mg/d), zinc (10 mg/d), iron + zinc (10 mg of each/d) or placebo. Anthropometry was assessed monthly, and micronutrient status was assessed at the end of supplementation. Supplementation significantly reduced the prevalence of anemia, iron deficiency anemia and zinc deficiency. Iron supplementation did not negatively affect plasma zinc concentrations, and zinc supplementation did not increase the prevalence of anemia or iron deficiency anemia. However, iron supplementation combined with zinc was less effective than iron supplementation alone in reducing the prevalence of anemia (20% vs. 38% reduction) and in increasing hemoglobin and plasma ferritin concentrations. There were no differences among the groups in growth. The growth of all groups was insufficient to maintain the same Z-scores for height for age and weight for height. There is a high prevalence of deficiencies of iron and zinc in these infants, which can be overcome safely and effectively by supplementation of iron and zinc combined. However, overcoming these deficiencies is not sufficient to improve growth performance in these infants.
KEY WORDS: • knemometer • insulin-like growth factor 1 • stunting
Micronutrient deficiency or hidden hunger is still a major threat to
health, growth and development of infants worldwide. Iron deficiency is
the most prevalent micronutrient deficiency globally, affecting more
than one half of the infants in developing countries (1
).
The same dietary factors of high phytate content and few animal
products, which lead to nutritional iron deficiency, contribute to
inadequate zinc nutriture, indicating that zinc deficiency is also
likely to be widespread (2
).
Iron deficiency is the most important cause of nutritional anemia, and
in Indonesia, approximately one-half of the children are anemic
(3
, 4
). Iron deficiency in infancy is associated not only
with impaired health, immunocompetence and performance, but also, very
importantly, with mental and motor development delays
(5
, 6
). Iron supplementation is currently the most
important tool to combat iron deficiency. However, high intake of iron,
especially as a supplement, has been shown to be an antagonist of zinc
absorption (7
).
Zinc is involved in many metabolic processes, and, consequently, zinc
deficiency leads to a wide range of manifestations, including decreased
growth, impaired immunocompetence and developmental delay
(8
, 9
). Zinc status is difficult to assess, because plasma
zinc concentrations do not sufficiently reflect individual zinc status
due to strong homeostasis. However, on population level, plasma zinc is
the most practical and reliable indicator of zinc status
(10
, 11
). In an earlier study in Indonesia, 25% of
lactating mothers and 17% of their infants had low plasma zinc
concentrations (3
).
Impaired growth is one of the most consistent signs of malnutrition,
and although it is in itself not hazardous to health, it is associated
with poverty and poor health. Studies on nutritional growth impairment
indicate that the onset of linear growth faltering probably occurs
within a few months of birth and that the most sensitive period for
intervention is before 18 mo of age (8
). Studies in
Indonesian children suggest that height growth failure begins directly
after birth, is most substantial in the first 6–8 mo of life and is
complete by the 1st year of life (12
). The measurement of
knee-heel length by knemometry has been suggested to be a more
sensitive measure of linear growth in infants than total body length
(13
).
Iron supplementation studies have shown clear positive effects on
anemia prevalence and iron status; however, the effects of iron
supplementation on zinc status or morbidity are more ambiguous. Iron
supplementation generally has no direct effect on growth
(8
). Zinc supplementation trials have shown a wide
range of effects, ranging from increased growth in stunted infants to
reduced morbidity from diarrheal diseases (14
–16
).
However, the findings are not very consistent throughout the different
studies, and in many studies the effects are small or only apparent in
specific subgroups. There is little information on interactions between
iron and zinc when supplemented together in infancy. A study in Mexican
preschool children found a small effect of iron and zinc
supplementation on morbidity but not on growth (17
).
However, micronutrient requirements and growth patterns are different
in young infants.
Deficiencies of micronutrients often coexist and have independent
as well as interacting effects (3
, 7
). Deficiencies can
share a common cause but can also aggravate each other. In populations
with a marginal iron and zinc status, the negative effects of high
intake of iron (e.g., with supplementation) on zinc uptake and vice
versa are important issues. Currently, in view of the serious
consequences of iron deficiency in children, large-scale iron
supplementation of children < 5 y of age is being
contemplated to combat iron deficiency. In this respect, however, the
possible negative effects on zinc status are a major concern.
The aim of this study was to investigate whether the supplementation of iron, zinc or iron and zinc combined can improve iron status and zinc status and reduce the prevalence of deficiencies of iron and zinc and whether supplementation can prevent growth faltering in the 1st y of life. In addition, the interaction between iron supplementation and zinc supplementation and possible negative effects of supplementation on iron status and zinc status were investigated. This study collaborated in the United Nations Children’s Fund-coordinated Multi-Country Iron and Zinc Intervention Trials Collaborative Group.
MATERIALS AND METHODS
Study design and location.
The study was designed as a randomized, double-blind,
placebo-controlled supplementation trial in infants 4 mo of age at
recruitment. Supplementation, not very different from the RDA
(18
), was given 5 d/wk for 6 mo by trained village health
volunteers. Infants were recruited from six adjacent villages in rural
West Java, Indonesia. Most people in the area depend on farming, with
rice as the primary crop. The area is free of malaria and lies at an
altitude of < 300 m above sea level.
A minimum required sample size of 34 infants was calculated to detect a difference in plasma zinc concentrations of 2.5 µmol/L (±4.5), with a confidence level of 95% and a power of 0.9. To detect a difference in height-for age Z-score of 0.2 (±0.8), with the same confidence level and power, a sample size of 168 infants was calculated. Because the study design allowed factorial analysis, a group size of 84 infants was selected. To allow for 25% drop-out, 119–120 infants per group were recruited.
Four groups of infants were supplemented with a syrup containing iron (10 mg/d), zinc (10 mg/d), iron + zinc (10 mg of each/d) or placebo. Supplements were made by a local pharmaceutical company (PT. Kenrose, Jakarta, Indonesia) in cooperation with United Nations Children’s Fund, Jakarta. The study was carried out in a rural area of Bogor District, West Java, Indonesia between October 1997 and March 1999.
Subjects and procedures.
Eligible infants were identified by the village health volunteers, and mothers were invited to participate in the study. Mothers were informed of the procedures and purpose of the study. After written informed consent was obtained from the mother, infants were assessed anthropometrically and a short history concerning socioeconomic status, dietary and lactation habits and the health of the mother and infant was taken.
Exclusion before recruitment was on the grounds of chronic or severe illness, severe clinical malnutrition or congenital anomalies. Infants were assigned to one of the four supplementation groups by individual randomization, using a block randomized group allocation list, which was computer-generated before the study began.
Supplementation was double-blind, the supplements were coded with a letter at production and the code-allocation was safe-kept at the Wageningen University, The Netherlands. The codes were not known at the study site in Indonesia. The code was revealed only after all subjects had completed the trial.
At recruitment, every subject received a personal bottle with a dosing syringe, labeled with the subject’s name, subject number, health volunteer’s name and the date. The bottles were monitored by the health volunteer who gave the supplement each day to prevent accidental intoxication or overdosing. Supplements (2 mL of syrup) were given 5 d/wk, and each dose given was tallied. Bottles were weighed before emission, replaced every month with a new bottle and weighed again after return to estimate the dose given to the infant as a measure of compliance.
At the monthly follow-up, the infant was assessed anthropometrically, and a short history concerning health, diet and lactation and possible adverse effects was taken. After 6 mo of supplementation, in addition to the usual follow-up procedure, a blood sample was taken of the infant for biochemical assessment of nutritional status, as well as a stool sample to check for parasite infestation. All infants with a hemoglobin concentration of < 110 g/L were given iron supplementation treatment.
Methods.
Anthropometry included measurement of weight, height and mid-upper-arm
circumference by trained anthropometrists using standard methods. In
addition, knee-heel length was measured with a knemometer.
Z-scores for weight and height [weight-for-age
(WAZ),3
height-for-age (HAZ) and weight-for-height (WHZ)] were calculated with
EPI-Info, Version 6.02, using WHO-recommended growth curves
(19
). Anthropometric measurements reflect long-term
growth performance, whereas current growth activity may be assessed
using plasma insulin-like growth factor 1 concentrations
(IGF-1) (20
).
A nonfasting 5-mL venous blood sample was taken from the infants. A closed tube heparanized vacuum system was used to avoid zinc contamination (Becton Dickinson, Leiden, The Netherlands). Blood samples were immediately stored at 4°C to prevent microhemolysis and separated within 5 h. Aliquots of plasma were stored at -30°C until analysis.
Hemoglobin concentrations were measured by the standard cyanoblue
method (Humalyzer, Wiesbaden, Germany). Plasma zinc concentrations were
analyzed with flame atomic absorption spectrophotometry (Varian,
Clayton South, Vic, Australia) using trace-element-free procedures, as
described in a previous article (3
). The coefficient of
variation (10% duplicate analysis and pooled control samples)
for zinc analyses was <5%. Ferritin and IGF-1 were measured using
commercial ELISA-kits (IBL, Hamburg, Germany) according to the
guidelines of the manufacturer. C-reactive protein (CRP) was
measured using immunoturbidimetric techniques at the Northern Ireland
Center for Diet and Health, University of Ulster, Northern Ireland
(Cobas Fara Analyzer; Roche Products, Welwyn, UK). The coefficient of
variation for the ferritin, IGF-1 and CRP assays was <10%. Plasma CRP
concentrations were analyzed to assess the occurrence of the acute
phase reaction, which lowers plasma concentrations of zinc and raises
plasma concentrations of ferritin (21
). Stool samples were
screened for the most commonly occurring parasites (hookworm,
Trichuras and Ascaris) by an experienced
microscopist. Parasitological examination of stool samples revealed an
infection rate of < 5% and was not different among the groups;
hence, intestinal parasite infestation was not considered a major
factor in the outcome of the study.
Ethical approval.
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.
Statistical analysis.
Data were checked for normal distribution using the Kolmogorov–Smirnov
test of normality. Plasma concentrations of ferritin and zinc were
transformed to logarithms before statistical analysis. Differences in
prevalence were tested with Pearson’s 
2 test,
differences between infants who did not complete the study and those
who did were tested with Student’s t test and
differences between baseline and endpoint anthropometry were tested for
each supplementation group with paired t tests.
Differences in plasma CRP concentrations between groups were tested
with the nonparametric Kruskal–Wallis test.
The primary effects of supplementation as well as treatment interactions were analyzed with full factorial ANOVA. All two- and three-way interactions were tested. In addition, differences for biochemical indicators among supplementation groups were analyzed using ANOVA or analysis of covariance (ANCOVA). Plasma concentrations of CRP were used as a covariate in the analysis of plasma concentrations of ferritin and zinc, to control for the effects of the acute phase response on plasma concentrations of both ferritin and zinc. Values reported, however, are not corrected or adjusted for acute phase response because there is currently no consensus on the quantitative effect of the acute phase response or on the manner of adjustment.
Differences among the supplementation groups for anthropometry at recruitment and after 6 mo of supplementation were analyzed with ANOVA and ANCOVA statistics. Age and sex were initially included in the statistical analysis as possible confounders but did not significantly contribute to the model.
When the overall F test was significant, differences among the groups were further investigated with posthoc multiple comparisons for ANOVA (Bonferroni’s multiple comparison t test for comparison among the groups and Dunnett’s t test for comparison with the placebo group) and in a general linear model for ANCOVA. Statistical analysis was performed with EPI-Info, Version 6.04b (Centers for Disease Control and Prevention, Atlanta GA) and SPSS, Version 7.5.2 (SPSS Inc., Chicago, IL) software packages.
RESULTS
A total of 478 infants were recruited and 360 infants completed the supplementation trial. A complete blood sample was collected from 348 infants upon completion of the trial.
Of the recruited infants, 26 (5%) never came back for follow-up
and were not considered sincere recruits. There is no additional
information available for these infants. An additional 92 infants
(19%) dropped out during the study for various reasons
(noncooperation, 13%; moving house, 5%; and mortality, three cases
(<1%; Fig. 1
). The infants who dropped out did not differ from the infants who
completed the trial in any of the characteristics at recruitment
(Student’s t test). Compliance was measured monthly by
comparing the weights of the bottles before emission with the weights
after return, and for every subject an overall compliance was
calculated. Mean overall compliance (±SD) was 86%
(±16%) of the total intended dose and was similar for all groups
(2 analysis). However, the dropout rate in the
group receiving the combination of iron and zinc was significantly
higher than that in the other groups (36% vs. 18–22%; P
< 0.01, 2 analysis). The number of
adverse effects reported was too small for meaningful statistical
analysis (one case of discoloration of teeth in the iron group and one
case of persistent regurgitation problems in the iron + zinc group).
|
2 analysis and
ANOVA; Table 1
). Over 90% of the infants were breastfed during the study. The number
of infants who were exclusively breastfed decreased to <10% during
the study. There were no differences in feeding practices among the
groups (2 analysis).
|
; P < 0.01 and P < 0.05,
respectively, ANOVA). Also, the hemoglobin concentrations of the
infants receiving iron alone were significantly higher than those of
the infants receiving zinc alone (Table 2
; P < 0.01,
ANOVA). The main effects and interactions of iron and zinc
supplementation were further tested with a factorial analysis. Iron
supplementation significantly affected hemoglobin concentrations
(P < 0.01), whereas the effect of zinc supplementation
was not significant (P = 0.09). The treatment
interaction between zinc and iron just failed to reach significance
(P = 0.06). The proportion of infants with anemia
(hemoglobin concentration < 110 g/L) in the iron group was
significantly lower than in the placebo and zinc groups (P
< 0.01, 2 analysis) but was also lower
than in the iron + zinc group (P < 0.05,
2 analysis; Table 2
). The prevalence of anemia
in the iron + zinc group was significantly lower than in the placebo
and zinc groups (P < 0.05,
2 analysis; Table 2
). The
prevalence of moderate to severe anemia (hemoglobin concentration
< 90 g/L) was lower in the groups receiving iron or iron + zinc
than in the groups receiving placebo or zinc, but numbers were too
small to allow meaningful statistical testing.
|
2 analysis, P
= 0.93) among the groups. Plasma ferritin concentrations were
significantly higher in the iron and iron + zinc supplementation groups
compared with the placebo and zinc groups (P < 0.01,
ANCOVA with CRP as covariate). With factorial analysis (with CRP as
covariate), both iron and zinc supplementation had a significant effect
on plasma ferritin concentrations (P < 0.01 for both),
but there was no significant treatment interaction (P = 0.47). The proportion of infants with iron deficiency anemia
(hemoglobin concentration < 110 g/L and plasma ferritin
concentration < 12 µg/L) was significantly lower in the iron
and iron + zinc supplementation groups (P < 0.01,
2 analysis; Table 2
).
Plasma zinc concentrations were significantly higher in the zinc and
iron + zinc supplementation groups than in the placebo and iron groups
(P < 0.01, ANCOVA with CRP as covariate; Table 2
).
Factorial analysis showed that zinc supplementation affected plasma
zinc concentrations (P < 0.01), but iron
supplementation had no effect (P = 0.49). In addition,
there was no significant treatment interaction (P = 0.13). The proportion of infants with a low plasma zinc concentration
(< 10.7 µmol/L) was significantly lower in the zinc and iron + zinc
groups than in the placebo group (P < 0.01,
2 analysis; Table 2
).
The effect of iron and zinc supplementation on hemoglobin and
plasma zinc concentration is clearly illustrated by the frequency
distribution curves (Figs. 2
and
3). For hemoglobin concentrations, the iron group curve is clearly
shifted to higher hemoglobin concentrations compared with the placebo
and zinc group curves, whereas the iron + zinc group curve is
intermediate between the iron and placebo group curves. The
distribution curves for zinc concentration are somewhat less smooth,
and the effect of supplementation is clearest when comparing the areas
under the curve below a plasma zinc concentration of <10.7 µmol/L
for the different groups. The placebo group curve has the largest area
with low plasma zinc concentrations, whereas both the zinc and iron +
zinc group curves have the smallest areas below the cutoff for zinc
deficiency. Interestingly, the zinc group curve seems to be more
shifted toward higher plasma zinc concentrations than the iron + zinc
group curve.
|
). Z-scores were based on the National Center for Health Statistics
(NCHS) reference data, although most infants were breastfed and,
therefore, might deviate from the NCHS-based growth curves.
However, transformation to Z-scores was done primarily to adjust
for variation in age, and the groups were compared among each other
with regard to treatment effect. At recruitment, the mean WHZ of the
infants were positive, whereas the mean HAZ were negative, indicating
that length growth might be suboptimal in these infants. Of the
infants, 25 (5%) had a HAZ of <-2, and only one infant had a WHZ
< -2 at recruitment. Mean knee-heel length
(±SD) at recruitment was 16.4 (±0.9) cm and did not
differ among the groups (ANOVA). During the study, HAZ, WAZ and WHZ
decreased significantly in all groups (P < 0.01,
paired t test). At the end of supplementation, there was no
difference among the groups for HAZ, WAZ or WHZ (ANOVA, P
> 0.5 for all). Factorial analysis also showed no effect of
either zinc or iron supplementation on any Z-score outcome at the
end of supplementation. Inclusion of sex or baseline Z-scores as
possible confounders did not change the outcome of the analysis. After
6 mo of supplementation, 74 infants (21%) were stunted (HAZ < -2.0). However, there was no difference in the prevalence of stunting
among the groups (Table 3
; 2 analysis). Also,
the knee-heel length did not differ among the groups after 6 mo of
supplementation (Table 2
; ANOVA). Plasma IGF-1 concentrations were
measured after 6 mo of supplementation as an indicator for growth
activity. There were no significant differences among the
supplementation groups [means ± SD: placebo group
(n = 24) 17.0 ± 9.5 µg/L, iron group
(n = 26) 21.0 ± 16.4, zinc group (n
= 28) 21.9 ± 12.8 and iron + zinc group (n = 26) 17.5 ± 10.2; ANOVA, P = 0.39]. Because of
the large interindividual variation, IGF-1 might not be a very
sensitive indicator for effects of supplementation on growth activity.
|
DISCUSSION
This study shows that anemia, iron deficiency anemia and zinc deficiency are very prevalent in these infants and that supplementation with iron and zinc is very effective in combating these deficiencies. The combined supplementation of iron and zinc was found to be less efficient than either supplement alone but was still effective in reducing both iron deficiency anemia and zinc deficiency.
An important finding is that iron supplementation does not have a negative effect on zinc status. The plasma zinc concentrations in the iron-supplemented infants were similar to those of the placebo group, and the prevalence of zinc deficiency was similar in both groups. In addition, there was no significant treatment interaction of zinc and iron supplementation on plasma zinc concentrations. This indicates that iron supplementation in young infants given daily in a dosage (10 mg/d), not very different from the RDA (8.5 mg/d), will not imperil zinc nutriture. In contrast, zinc supplementation does affect iron status but not to a large extent. Zinc supplementation significantly reduced plasma ferritin concentrations but did not significantly increase the prevalence of anemia or iron deficiency anemia.
Although it was not possible to assess micronutrient status at baseline and the prevalence of anemia, iron deficiency anemia and zinc deficiency at recruitment is not known, we would not expect any difference in these parameters among the groups, because the groups were similar in all parameters measured. Furthermore, indicators of especially iron status change considerably during the first 6 mo of life, with plasma ferritin concentrations being very high after birth and slowly declining thereafter. Therefore, the effect of supplementation on micronutrient status was compared with a placebo group.
In these infants, with a high prevalence of anemia (66%), iron deficiency anemia (30%) and zinc deficiency (24%) at 10 mo of age, combined supplementation with iron and zinc has the largest health benefits, reducing the prevalences of both iron as well as zinc deficiency to less than one-third of the prevalences in the placebo group. However, the effectiveness of combined supplementation seems to be less than supplementation of iron or zinc alone, because the combined supplement did not reduce the prevalence of anemia as much as did supplementation with iron alone. This effect is also apparent in the treatment interaction of iron and zinc supplementation on hemoglobin concentrations, which just failed to reach significance in the present study. Despite this antagonist interaction, combined supplementation is still effective in reducing the prevalence of iron deficiency anemia as well as of zinc deficiency.
A reason for concern is that the dropout rate in the iron + zinc supplementation group was nearly twice that of the other supplementation groups. This could indicate an acceptability problem of the combined supplement. Gastrointestinal complaints are the most likely cause of this higher dropout rate, because minor complaints, such as bad taste of the supplement, would have affected compliance also, but this was the same in all groups. In addition, there was no difference for any of the other baseline characteristics (age, sex or anthropometry) between the infants who dropped out and those who continued. Perhaps the composition of the supplement used, with iron and zinc as sulfate salts in a 1:1 weight ratio, has contributed to higher preferential dropout of the combined supplement. Sulfate salts are not well-tolerated because they are more likely to cause gastrointestinal complaints and a 1:1 weight ratio of iron and zinc might not be favorable. This study was not designed to investigate the optimal composition of the supplements, but this area certainly merits additional attention.
The anthropometrical assessment of the infants showed a striking decrease in Z-scores from the ages of 4–10 mo in all groups. The Z-scores were calculated with the NCHS reference data, which may not adequately reflect optimal growth performance of breastfed infants, leading to an overestimation of the growth faltering. However, this cannot fully explain the extent of growth faltering observed in this study. Furthermore, although supplementation with both iron and zinc was very effective in decreasing the prevalence of deficiencies of iron and zinc, there was no effect of supplementation of either iron or zinc on growth. Although supplementation was started before significant growth impairment had occurred, supplementation with iron, zinc or both was not able to improve growth performance. After 6 mo of supplementation, growth was impaired to the same extent in all groups, with 21% of the infants considered stunted using the NCHS reference data. The lack of effect of supplementation of iron and zinc on growth is further confirmed by the lack of effect on plasma IGF-1 concentration, which is an indicator of growth activity. There were no differences in growth activity among the groups. It would seem that in this population factors other than zinc deficiency are contributing to suboptimal growth in length and weight.
Ninh et al. (22
) showed that zinc supplementation of
Vietnamese children increased plasma IGF-1 concentrations as well as
growth performance, but only stunted children were supplemented. In
Ethiopia, the growth of both stunted and nonstunted infants benefited
from zinc supplementation, although the effect in stunted infants was
larger (15
). Iron intake in Ethiopia, however, is very
high, possibly creating exceptional conditions for zinc nutriture.
Rosado et al. (17
) found no effect of either zinc or iron
supplementation on growth in Mexican children > 1 y of age.
There was a small but significant effect of zinc supplementation on
morbidity but there was no interaction between iron and zinc. From a
meta-analysis of published randomized trials, Brown et al.
(16
) concluded that zinc supplementation had a significant
but small effect on growth, especially in stunted children. In the
present study, the infants were not selected for stunting, and
supplementation was started at an age when stunting is not yet
prevalent. This study aimed to prevent stunting, not to improve growth
in already stunted infants.
In conclusion, the results of this study show that although there is a high prevalence of deficiencies of iron and zinc, combating these deficiencies is not sufficient to allow optimal growth in these infants. There must be additional underlying factors in the diet or circumstances of these infants that effectively impair growth. In view of the detrimental effects of iron deficiency on development and of zinc deficiency on morbidity and possibly growth, supplementation of iron and zinc to combat the high prevalence of these deficiencies can play an important role in improving infant health. This study shows that supplementation with a combination of iron and zinc can be safe and effective.
|
ACKNOWLEDGMENTS
We thank all the mothers and the infants and the health volunteers who participated in this study. We are grateful for the enthusiastic support we received from Hendra, Anni and their staff at the Puskesmas Situ Udik. Furthermore, we thank the field team of Puslitbang Gizi and the laboratory staff from the Nutrition Research and Development Center, Bogor for their untiring efforts. We also thank D. Thurnham, C. Northrop-Clewes and J. Coulter from NICHE, University of Ulster for their help with the analysis of CRP. Finally, we thank P. Wieringa and H. Wieringa-Brants for providing invaluable logistic support.
FOOTNOTES
1 Supported by the Netherlands Foundation for the
Advancement of Tropical Research (WOTRO), Ter Meulen Fund (Royal
Netherlands Academy of Arts and Sciences) and United Nations
Children’s Fund-Jakarta. 
3 Abbreviations used: ANCOVA, analysis of
covariance; CRP, C-reactive protein; HAZ, height-for-age Z-score;
IGF-1, insulin-like growth factor 1; NCHS, National Center for
Health Statistics; WAZ, weight-for-age Z-score; WHZ, weight-for-height
Z-score.
Manuscript received 16 April 2001. Initial review completed 14 June 2001. Revision accepted 26 July 2001.
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