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Articles

Weekly Vitamin A and Iron Supplementation during Pregnancy Increases Vitamin A Concentration of Breast Milk but Not Iron Status in Indonesian Lactating Women¹

Siti Muslimatun^*,, Marjanka K. Schmidt^*,, Clive E. West^,**2, Werner Schultink, Joseph G. A. J. Hautvast and Darwin Karyadi^*

^* SEAMEO TROPMED Regional Center for Community Nutrition, University of Indonesia, Jakarta, Indonesia; Division of Human Nutrition and Epidemiology, Wageningen University, the Netherlands; ^** Department of Gastroenterology, University Medical Centre Nijmegen, the Netherlands; and Nutrition Section, UNICEF, New York, NY.

²To whom correspondence should be addressed. E-mail: Clive.West{at}staff.nutepi.wau.nl.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Studies on the effect of vitamin A and iron supplementation during pregnancy on maternal iron and vitamin A status postpartum are scarce. We investigated whether retinol and iron variables in breast milk and in serum postpartum were enhanced more with weekly vitamin A and iron supplementation during pregnancy than with weekly iron supplementation. During pregnancy, subjects were randomly allocated to two groups and received either (n = 88) a weekly supplement of iron (120 mg Fe as FeSO₄) and folic acid (500 µg) or (n = 82) the same amount of iron and folic acid plus vitamin A [4800 retinol equivalents (RE)]. Transitional milk (4–7 d postpartum) had higher (P < 0.001) concentrations of retinol and iron than mature milk (3 mo postpartum). Compared with the weekly iron group, the weekly vitamin A and iron group had a greater (P < 0.05) concentration of retinol in transitional milk (as µmol/L) and in mature milk (as µmol/g fat). Although serum retinol concentrations 4 mo postpartum did not differ significantly, the weekly vitamin A and iron group had significantly fewer (P < 0.01) subjects with serum retinol concentrations 0.70 µmol/L than the weekly iron group. Iron status and concentrations of iron in transitional and mature milk did not differ between groups. We have shown that weekly vitamin A and iron supplementation during pregnancy enhanced concentrations of retinol in breast milk although not in serum by 4 mo postpartum. However, no positive effects were observed on iron status and iron concentration in breast milk.

KEY WORDS: • iron • vitamin A • pregnant women • weekly supplementation • breast milk

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Approximately half of the women and preschool children in developing countries suffer from iron deficiency anemia (1) . The consequences of iron deficiency anemia during pregnancy include increased risk of perinatal mortality, low birth weight and preterm birth (2) . Low maternal iron nutrition during pregnancy has been shown to cause low iron stores in infants (3 ,4) . Although iron intake and status during pregnancy and lactation have not been shown to affect the iron concentration in breast milk significantly (5 –7) , healthy full-term breast-fed infants are unlikely to become iron deficient before 6 mo of age (5) .

Vitamin A–deficient lactating mothers may not have enough vitamin A in breast milk to maintain and build body reserves in their rapidly growing infants (8) . Also, vitamin A intake and status during the third trimester of pregnancy have been shown to affect the retinol concentration in breast milk (9) . In Indonesia, one third of pregnant and lactating women are marginally vitamin A deficient (10 ,11) . Among lactating women, supplementation with a single high dose of vitamin A (12 ,13) , a small daily dose of vitamin A (14) or a small daily dose of ß-carotene (11 ,12) has been shown to increase retinol concentrations in breast milk and in serum.

Vitamin A is essential for normal hematopoiesis (15) . Combining supplementation of vitamin A with that of iron during pregnancy has been shown to increase the hemoglobin concentration by 40% near term (10 ,16) ; however, the outcome on breast milk and maternal nutritional status postpartum have not been studied and reported.

Daily iron supplementation of pregnant women is an approach used universally to reduce anemia. With the rationale to increase compliance, reduce costs and avoid iron overload, weekly supplementation has been proposed as a method of choice to provide iron (17) . We have shown that weekly iron supplementation was as effective as daily iron supplementation in improving the iron status of pregnant women if compliance is ensured (16) . We investigated whether retinol and iron variables in breast milk and in serum postpartum were enhanced more with weekly vitamin A and iron supplementation during pregnancy than with weekly iron supplementation alone.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
A randomized double-blind, community-based trial among pregnant women was carried out from November 1997 until November 1999 in the rural subdistrict of Leuwiliang, West Java, Indonesia. This paper presents data on mothers postpartum. During pregnancy, these subjects had received supplements, i.e., either iron and folic acid alone, or together with vitamin A. Details of subject selection and supplementation procedures have been described elsewhere (16) . In brief, women who were 16–20 wk pregnant, aged 17–35 y, and parity <6 were assigned randomly to two groups on an individual basis. They were supplemented once weekly from enrollment until delivery with two tablets each containing 60 mg iron as ferrous sulfate and 250 µg folic acid or with two tablets each containing 2400 retinol equivalents (RE) vitamin A in addition to the same amount of ferrous sulfate and folic acid. Both of the supplements given were identical in physical appearance to the iron-folic acid tablets used for the national iron supplementation program and were provided by the same company, PT Kimia Farma, Indonesia. The subjects were instructed not to take iron-folic acid tablets from the national iron supplementation program, and village midwives were also advised not to give the tablets from the governmental program to the subjects.

Out of 243 pregnant women initially enrolled, 18 dropped out during pregnancy, 5 gave birth to a stillborn child, 1 had twins (only 1 survived), 7 had infants who died before reaching 3 mo of age and 11 moved from the research area. Among the remaining 201 eligible subjects, 182 subjects attended the postpartum examination. Data are presented for 170 subjects who had complete sets of biochemical and anthropometric data (Fig. 1 ). At the time of enrollment (16–20 wk pregnant), age, body weight, height, body mass index, parity, gestational age and iron status of these women did not differ from all subjects initially enrolled (data not shown).

View larger version (38K): [in this window] [in a new window]   Figure 1. Eligible subject enrollment and retention in a randomized double-blind, community-based trial to investigate the effect of vitamin A and/or iron supplementation during pregnancy on breast milk composition and maternal nutritional status postpartum.

Breast milk was collected in a standardized way 3 mo postpartum (referred to as mature milk) from 50% of the mothers chosen randomly. Breast milk 4–7 d postpartum (referred to as transitional milk) was also collected by means of a convenience sample from mothers whom we knew had given birth to a child within the previous week. Due to financial constraints, breast milk was collected only from a subsample. Between 0800 and 1100 h, all milk from the right breast, which had not been used to feed the child during the previous hour, was collected using a breast milk pump (White River Concepts, San Clemente, CA). The breast milk was stored in dark brown glass bottles and transported to the laboratory in a cool box with cooling elements. In the laboratory, two aliquots of 10 mL each were frozen at -79°C until analysis. Analyses were carried out within 1.5 y of breast milk collection.

Fat, iron and vitamin A status assessments in breast milk.

Breast milk was analyzed at the Central Laboratories Friedrichsdorf GmbH, Friedrichsdorf, Germany. Before analysis, breast milk was brought to room temperature (20°C), warmed in a water bath up to 40°C and homogenized. The temperature of breast milk at the time of analysis was 20°C. Fat was determined according to the Roese-Gottlieb method (18) . Water (8 mL) was added to a 1- to 2-mL sample plus 1.5 mL NH₄OH and 10 mL ethanol; 25 mL diethyl ether and 25 mL light petroleum were subsequently added with vigorous shaking. The organic layer was separated by centrifugation (700 x g, 1 min). The extraction was done twice, each with 5 mL ethanol, 15 mL diethylether and 15 mL light petroleum. The combined organic layers were evaporated and the remaining fat was weighed. The fat extraction was done in a Mojonnier extraction pipe (Funke-Gerber, Berlin, Germany). Iron was measured using atomic absorption spectrophotometry after dilution of samples (50 µL) with water (950 µL). Retinol was analyzed using HPLC after alkaline saponification with potassium hydroxide, ascorbic acid, ethanol and water, with retinyl acetate as internal standard. The between-run CV was 10%. All analyses in breast milk were performed singly.

Iron and vitamin A status assessments in serum.

Venous blood samples (5 mL) were collected 4 mo postpartum in a tube without anticoagulant between 0900 and 1200 h. Hemoglobin was determined using the cyanmethemoglobin method (Merck test 3317; Merck, Darmstadt, Germany) at the laboratory of the Nutrition Research and Development Center, Bogor. The within-assay variability, based on duplicate measurements performed on 5% of the samples, was 5.7 g/L. For preparation of serum, blood samples were allowed to clot before they were placed in a cool box with cooling elements for transport to the laboratory. Blood samples were centrifuged at 3000 x g for 10 min at room temperature and serum separated into three vials. Serum samples were kept for 1 mo at -20°C and subsequently at -79°C. All analyses were carried out within 1 y of blood collection.

Serum ferritin was analyzed by enzyme immunoassay using a commercial kit (IMX System, Abbott, Abbott Park, IL) at the SEAMEO TROPMED laboratory, Jakarta. On the basis of duplicate analyses performed on 15% of the samples, within-assay variability was 0.8 µg/L. Three control serum samples with low (20 µg/L), medium (150 µg/L) and high (400 µg/L) concentrations of serum ferritin were provided by the assay manufacturer. The between-day CV for low, medium and high concentrations were 4.4, 4.7 and 4.9%, respectively. Serum soluble transferrin receptor was measured by immunoturbidimetric assay (19) (IDeA sTfR-IT, Orion Diagnostica, Espoo, Finland) at Stichting Huisartsenlaboratorium Oost in Velp, the Netherlands. The within-assay variability, based on duplicate analyses on 10% of the samples, was 0.06 mg/L. Between-day CV for low (1.38 mg/L) and high (5.66 mg/L) serum controls were 2.5 and 3.6%, respectively. Serum retinol was analyzed using HPLC at the Division of Human Nutrition and Epidemiology, Wageningen University. Ten percent of the analyses were carried out in duplicate and the within-assay variability was 0.05 µmol/L. The between-day CV was 7.4%.

Anthropometric assessment.

At the same time as blood was collected, body weight was measured using a UNICEF electronic weighing scale (SECA 890, Hamburg, Germany) to the nearest 0.1 kg, mid-upper arm circumference was measured using a plastic measuring tape to the nearest 0.1 cm and height was measured at enrollment (16–20 wk pregnant) using a standing height measurement microtoise to the nearest 0.1 cm.

Statistics.

The normality of data distribution was checked using the Kolmogorov-Smirnov test. Serum ferritin and soluble transferrin receptor concentrations were not normally distributed; therefore, these data were logarithmically transformed and reported as geometric mean and 95% confidence intervals (CI). Normally distributed data are reported as mean and SD or SEM. Iron and retinol concentrations in breast milk are reported as mean and 95% CI. The differences in concentration between transitional milk and mature milk were tested using the Wilcoxon Signed Ranks test, except for fat, which was normally distributed, and thus tested using a paired t test. The differences between groups were tested using an independent t test for normally distributed data or the Mann-Whitney U test for not normally distributed data. When control for possible confounding variables was necessary in testing the differences between two groups, ANOVA was employed instead of an independent t test. Differences in proportions were tested with a ² test.

Determination of vitamin A status based on retinol concentrations in serum and in breast milk followed WHO recommendations (20) , whereas determination of iron status based on hemoglobin and serum ferritin concentrations followed International Nutritional Anemia Consultative Group recommendations (21) .

Correlation coefficients were calculated using Pearson correlation if both variables were normally distributed (such as the correlation between serum retinol and hemoglobin concentrations) or Spearman’s rank correlation if one or both variables were not normally distributed (such as the correlation between retinol concentrations in serum and in breast milk). Calculation of correlation coefficients was carried out independently in each group.

The SPSS software package (Windows version 7.5.2. SPSS, Chicago, IL) was used for all statistical analyses and a P-value of < 0.05 was considered as significant.

Ethical consent.

One of the authors (S.M.) explained the objectives and procedures of the study to the women in Bahasa Indonesia, which the women understood. Only women who gave written informed consent were allowed to participate in the study. Before the study commenced, the Medical Ethical Committees of the Medical Faculty of the University of Indonesia, the Indonesian Ministry of Health and Wageningen University had approved the research proposal.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Samples of blood were taken and anthropometric measurements made between 1.9 and 5.9 mo postpartum, with an average of 3.7 ± 0.6 (mean ± SD) mo. None of the subjects were pregnant. The general characteristics of the subjects did not differ between groups (data not shown). The proportions of subjects having body mass index <18.5 kg/m² and <21 kg/m² were 10 and 52%, respectively.

Breast milk composition.

Transitional milk (collected at 5.6 ± 1.2 d, mean ± SD) was available from 78 subjects and mature milk (collected at 3.0 ± 0.1 mo) from 92 subjects. However, we report data on transitional milk from 73 subjects and on mature milk from 85 subjects for whom all analytical data are available. In both groups, the concentrations of fat, iron, retinol and retinol per gram of fat in mature milk were not correlated with its concentrations in transitional milk (data not shown).

In both transitional and mature milk, iron and fat concentrations were similar in the two groups (Table 1 ). Compared with the weekly iron group, the weekly vitamin A and iron group had significantly higher (P < 0.05) concentrations of retinol in transitional milk (as µmol/L) and in mature milk (as µmol/g fat).

The proportions of all subjects having concentrations of retinol in mature milk 1.05 µmol/L and 0.028 µmol/g fat were 51 and 21%, respectively. On the other hand, 28% of subjects had retinol concentration in mature milk >1.40 µmol/L. The weekly vitamin A and iron group had a lower proportion (P < 0.01) of subjects with a mature milk retinol concentration 0.028 µmol/g fat (Fig. 2 ).

View larger version (18K): [in this window] [in a new window]   Figure 2. Proportion of women with low vitamin A status based on serum (4 mo postpartum) and mature milk (3 mo postpartum) measurements in the weekly vitamin A and iron group and the weekly iron group. Differences between groups were tested by 2 test. *P < 0.01 for weekly vitamin A + iron group vs. weekly iron group.

Hematological variables.

Hemoglobin, serum ferritin and serum soluble transferrin receptor concentrations did not differ between the two groups (data not shown). The proportion of anemic subjects (hemoglobin concentration <120 g/L) was 48%, whereas the proportion of subjects with low iron stores (serum ferritin concentration <12 µg/L) was 47%. The proportions of subjects with anemia and low iron stores did not differ between groups (data not shown).

Serum retinol concentrations in the weekly vitamin A and iron group were not significantly different from those in the weekly iron group (data not shown). However, compared with the weekly iron group, the weekly vitamin A and iron group had significantly fewer (P < 0.01) subjects with serum retinol concentration 0.70 µmol/L (18 vs. 5%) and tended to have fewer (P = 0.066) subjects with serum retinol concentration 1.05 µmol/L (52 vs. 38%; Fig. 2 ).

Serum retinol concentrations were significantly correlated with hemoglobin concentrations only in the weekly iron group (r = 0.256, P < 0.05). In both groups, serum ferritin concentrations were positively correlated with hemoglobin concentrations (r = 0.448 and 0.455, P < 0.01), but negatively with serum transferrin receptor concentrations (r = -0.628 and -0.434, P < 0.01). Compared with subjects with serum retinol concentrations 1.05 µmol/L, subjects with retinol concentrations >1.05 µmol/L had higher (P < 0.01, controlling for treatment group) hemoglobin concentrations (122.2 ± 1.2 vs. 116.7 ± 1.6 g/L; mean ± SEM) and higher (P < 0.05) serum ferritin concentrations [14.3 (11.6–17.7) vs. 9.9 (7.8–12.5) µg/L; mean (95% CI)].

None of the anthropometric indices (body weight, height, body mass index and mid-upper arm circumference) correlated with iron status or serum retinol concentrations. Parity was not associated with iron status nor with serum retinol concentrations (data not shown).

Correlations between retinol and iron concentrations in serum and in mature milk.

In the weekly iron group, serum retinol concentrations were significantly correlated with retinol concentrations in mature milk when expressed in term of volume or per gram of fat (r = 0.304 and 0.487, respectively, P < 0.01). In the weekly vitamin A and iron group, iron concentrations in mature milk were correlated with hemoglobin concentrations (r = 0.443, P < 0.01), with serum ferritin concentrations (r = 0.359, P < 0.05) and with serum soluble transferrin receptor concentrations (r = -0.325, P < 0.05).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
In this study, weekly supplementation of pregnant women with 4800 RE vitamin A and 120 mg iron (and 500 µg folic acid) during pregnancy enhanced the retinol concentration in breast milk 4–7 d postpartum, retinol concentration per gram of fat in breast milk 3 mo postpartum but not serum retinol 4 mo postpartum. It has been calculated (8) that a retinol concentration of 1.05 µmol/L in a mother’s breast milk during the first 6 mo postpartum provides enough vitamin A to meet the metabolic needs of her baby but provides insufficient vitamin A to build up liver stores. In vitamin A–sufficient populations, average retinol concentrations in breast milk range from 1.75 to 2.45 µmol/L (20) . The mean retinol concentration in the breast milk of the women we studied was <1.4 µmol/L, typical of vitamin A–deficient populations. The relatively high retinol concentration in transitional milk was also within the range of values reported from developing countries (22) . The 47% difference of retinol concentrations in transitional milk with vitamin A and iron supplementation administered weekly during pregnancy was reduced to 17% in a 3-mo period. A study carried out in Indonesia (13) showed that a single high dose supplementation with vitamin A (312 µmol retinyl palmitate) within 1 mo of parturition resulted in a 35% higher retinol concentration in breast milk at 3 mo, which was maintained until 8 mo compared with placebo. A 3.5 mg ß-carotene supplement from vegetables given daily for 3 mo did not increase the retinol concentration in breast milk compared with an increase of 67% with a similar amount of ß-carotene in a wafer (11) . It should be noted that our subjects were supplemented during pregnancy only, whereas the subjects in the other studies mentioned were supplemented during lactation. Although retinol concentrations in breast milk of women supplemented weekly during pregnancy were not as high and not retained longer as with a single high dose supplement, weekly supplementation of vitamin A during pregnancy has an additional advantage of preventing a decline of maternal vitamin A status during pregnancy as had been reported previously (16) . In addition, the effects were sustained until postpartum as shown by a lower proportion of women with serum retinol concentrations 0.70 µmol/L. However, we did not observe the positive effect of vitamin A supplementation during pregnancy on mean serum retinol concentration 4 mo postpartum. Three reasons may be proposed. First, the supplementation needs to be extended beyond pregnancy or the dose given was too small considering that the serum retinol concentration near term remained constant (16) . Second, the positive effect might be observed if it were measured at the same time as the breast milk measurement or earlier. Third, serum retinol concentration is not a responsive indicator of vitamin A status (23) . Provision of weekly vitamin A supplements to pregnant women can be channeled through existing systems, such as local health posts or women’s groups with which pregnant women have frequent contact.

The retinol concentration in breast milk is associated with that in serum in populations with relatively low vitamin A status (24) . Retinol concentration in breast milk was related to that in serum only in the groups that did not receive supplementary vitamin A.

Vitamin A in breast milk is found almost exclusively in fat; thus, factors that affect breast milk fat concentration may affect the vitamin A concentration as well (24) . Fat is the macronutrient in milk that varies most in concentration. Ruel et al. (25) showed that variability within individuals is influenced by the time of sampling through the day and the time elapsed since the last feeding. In our study, all breast milk samples were taken between 0800 and 1100 h from the right breast from which the baby had not been fed during the previous hour. This was done to reduce variation in nutrient concentrations of breast milk, particularly of fat. Fat concentration is higher in mature milk than in colostrum and somewhat higher in affluent than in poor societies (26) . Our population had lower fat concentrations in breast milk than those reported by Nommsen et al. (27) from the United States and Ruel et al. (25) from Guatemala but similar to those reported by Brown et al. (28) from Bangladesh. Fat concentration of breast milk has been shown to be higher in mothers with triceps skinfold thickness 11 mm or mid-upper arm circumference 22 cm than in their thinner counterparts (28) . We did not find such an association between fat concentration in breast milk and maternal nutritional status, probably because 90% of our population had mid-upper arm circumference 22 cm. Among well-nourished lactating women, Nommsen et al. (27) showed that maternal triceps skinfold thickness was related to the fat concentration of breast milk only at the later stage of lactation. Parity tended to be negatively related (P = 0.07) to the fat concentration in mature milk, as shown by others that lipid concentrations in breast milk are higher in primiparous women (27 ,28) .

Weekly iron (and folic acid) together with vitamin A supplementation during pregnancy did not increase the iron status postpartum and iron concentration in breast milk compared with supplementation with iron (and folic acid) alone. The improvement of hemoglobin concentration observed at near term with weekly iron (and folic acid) and vitamin A supplementation (16) was much less than that reported previously (10) . Therefore it is not surprising that the benefit of iron (and folic acid) and vitamin A supplementation during pregnancy was not sustained until the postpartum period. In the previous study (10) , daily administration of 60 mg elemental Fe and 2.4 mg (2400 RE or 8000 IU) retinol was used and the effects postpartum were not measured.

Studies reported so far do not indicate any relationship between maternal iron status and iron concentration in breast milk (6 ,7) . Similarly, provision of iron supplements during lactation does not increase the volume or iron concentration of breast milk (5) . We observed a significant correlation between maternal iron status and iron concentration in breast milk only in the group supplemented with vitamin A, which might be due to chance or to an increased iron absorption because of the better vitamin A status during pregnancy. The decrease in iron concentrations in breast milk as lactation proceeded, from 7.63–8.31 µmol/L (425–453 µg/L) at 4–7 d to 4.27–5.35 µmol/L (238–299 µg/L) at 3 mo postpartum, was similar to that reported earlier (29) . Although the concentration of iron in breast milk is low, its bioavailability is up to 70% compared with 30% for iron from cow’s milk and only 10% for iron from breast milk substitutes (30) . Lactoferrin, an iron-binding protein of bacteriostatic importance, which is present in high concentrations in human milk, has been proposed to account for the high iron bioavailability (31) .

In conclusion, we have shown that weekly supplementation during pregnancy with vitamin A and iron (and folic acid) compared with iron (and folic acid) alone increased the concentration of retinol in breast milk even though retinol concentrations in serum 4 mo postpartum did not increase. Postpartum maternal iron status and iron concentration in breast milk of those supplemented weekly during pregnancy with vitamin A with iron (and folic acid) did not differ from those supplemented weekly with iron (and folic acid) alone. Considering that the iron and vitamin A status of the women in all groups was poor, iron and vitamin A intake should be increased beyond pregnancy. Provision of additional iron and vitamin A sources can be obtained from pharmanutrients or food-based approaches with natural or enriched foods.

	ACKNOWLEDGMENTS

 
The authors thank Jacques Bindels (NUMICO Research Wageningen) for arranging and Günther Raffler (Central Laboratories Friedrichsdorf GmbH, Germany) for carrying out the breast milk analyses. We thank Siti Dhyanti Wisnuwardani (Medical Faculty, University of Indonesia) for advice on breast milk collection. The participation of health centers, midwives and postpartum mothers from Leuwiliang subdistricts is greatly appreciated.

	FOOTNOTES

 
¹ Supported by The Netherlands Organization for Scientific Research-Netherlands Foundation for the Advancement of Tropical Research (NWO-WOTRO) (WV 93–280) and Neys-van Hoogstraten Foundation (in 114), the Netherlands and German Agency for Technical Cooperation (GTZ)/South East Asian Ministers of Education Organization (SEAMEO), Indonesia.

Manuscript received January 31, 2001. Initial review completed March 13, 2001. Revision accepted June 20, 2001.

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