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Weekly Supplementation with Iron and Vitamin A during Pregnancy Increases Hemoglobin Concentration but Decreases Serum Ferritin Concentration in Indonesian Pregnant Women¹

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

^* SEAMEO TROPMED Regional Center for Community Nutrition, University of Indonesia, Jakarta, Indonesia; Division of Human Nutrition and Epidemiology, Wageningen University, The Netherlands; ^** UNICEF, New York, NY; Department of Gastroenterology, University Medical Center Nijmegen, The Netherlands; German Agency for Technical Cooperation (GTZ), Eschborn, Germany; and Nutrition Research and Development Center, Bogor, Indonesia

²To whom correspondence should be addressed. Division of Human Nutrition and Epidemiology, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands. E-mail: Clive.West{at}staff.nutepi.wau.nl.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
We investigated whether weekly iron supplementation was as effective as the national daily iron supplementation program in Indonesia in improving iron status at near term in pregnancy. In addition, we examined whether weekly vitamin A and iron supplementation was more efficacious than weekly supplementation with iron alone. One group of pregnant women (n = 122) was supplemented weekly with iron (120 mg Fe as FeSO₄) and folic acid (500 µg); another group (n = 121) received the same amount of iron and folic acid plus vitamin A [4800 retinol equivalents (RE)]. A third ("daily") group (n = 123), participating in the national iron plus folic acid supplementation program, was also recruited. Data on subjects with complete biochemical data are reported (n = 190). At near term, hemoglobin concentrations increased, whereas serum ferritin concentrations decreased significantly in the weekly vitamin A and iron group, suggesting that vitamin A improved utilization of iron for hematopoiesis. Iron status in the weekly iron group was not different from that of the "daily" group. However, iron status decreased with daily supplementation if <50 iron tablets were ingested. Serum transferrin receptor concentrations increased in all groups (P < 0.01). Serum retinol concentrations were maintained in the weekly vitamin A and iron group, but decreased in the other two groups (P < 0.01). Thus, delivery of iron supplements on a weekly basis can be as effective as on a daily basis if compliance can be ensured. Addition of vitamin A to the supplement improved hemoglobin concentration.

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

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
More than half of the pregnant women in Indonesia suffer from iron deficiency anemia (1) . Adequate iron status during pregnancy, particularly in early pregnancy, is crucial for reducing the risk of perinatal mortality, low birth weight and preterm birth (2) . Therefore, iron supplementation programs are common in areas in which the prevalence of iron deficiency anemia is high, particularly in developing countries.

Weekly iron supplementation has been shown to be as effective as daily iron supplementation with respect to the improvement of iron status in preschool children (3 4 5) , pregnant women (6) and nonpregnant women (7 ,8) . Therefore, weekly supplementation has been proposed as the method of choice for providing iron as a supplement. It has been argued that by reducing the frequency of iron tablet ingestion, side effects will be less and compliance will improve (7 ,9) .

A recent analysis by Beaton and McCabe (10) concluded that both weekly and daily iron supplementation are efficacious, but daily iron supplementation is consistently more efficacious than weekly iron supplementation across different age groups and with different levels of supervision. These authors concluded that weekly iron supplementation should not be recommended during pregnancy, regardless of the degree of supervision. However, it should be noted that the number of studies reviewed was small. Moreover, the difference in mean hemoglobin concentration as one of the outcome measures between groups supplemented weekly and those supplemented daily was relatively small. Because it is not yet clear whether there is a practical difference in effectiveness between daily and weekly supplementation with iron, further studies are required.

The relatively high prevalence of marginal vitamin A status among pregnant and lactating women has raised concern about its contribution to morbidity and mortality and to the etiology of anemia among women (11 ,12) . West et al. (13) showed a 40% reduction in maternal deaths related to pregnancy after 1.5 y of weekly supplementation with 7000 µg retinol equivalents (RE)³vitamin A or 42 mg (7000 RE) ß-carotene beginning before and continuing throughout pregnancy. Combining iron and vitamin A supplementation in pregnant women has been shown to improve both vitamin A and iron status (14 ,15) .

We conducted a community-based study to investigate the effect of weekly vitamin A and iron supplementation during pregnancy on infant growth in y 1 of life. This paper aimed to answer two questions with respect to the improvement of iron status at near term in pregnancy. The first question was whether weekly iron supplementation was as effective as the ongoing national iron supplementation program; the second question was whether weekly supplementation with vitamin A and iron was more efficacious than supplementation with iron alone, daily or weekly. Results on infant growth will be presented elsewhere.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
A randomized double-blind community-based trial was conducted from November 1997 until November 1999 to investigate the effect of weekly vitamin A and iron supplementation during pregnancy on infant growth in y 1 of life. A sample size of 63 per group was calculated on the bases of a 5% significance level (two-tailed test), a power of 80%, a difference in hemoglobin concentration of 5 g/L and a standard deviation of 10 g/L. For the infant, a sample size of 51 per group was calculated on the bases of a 5% significance level (two-tailed test), a power of 80%, a difference in length at 1 y of age of 1.5 cm and a standard deviation of 2.7 cm. A sample size of 120 women per group was chosen to allow for 50% dropout until their children reached 1 y of age.

Women who were 16–20 wk pregnant, aged 17–35 y and parity <6 were recruited from nine villages in the Leuwiliang subdistrict, Bogor district, West Java, Indonesia. The nine villages, each with 6500 inhabitants, had similar socioeconomic characteristics. The maximum distance between study villages was 20 km. The area was rural and hilly. Only the main road had asphalt; the remaining roads were made from stone or soil.

Allocation of group and tablet intake.

Subjects from five villages were assigned randomly to two weekly groups on an individual basis. They were supplemented each week from enrolment until delivery with two tablets each containing 60 mg elemental iron as ferrous sulfate and 250 µg folic acid, or with two tablets each of which contained 3000 RE vitamin A in addition to the ferrous sulfate and folic acid. PT Kimia Farma, Indonesia, prepared the supplements and both types of tablets were similar in physical appearance. The pregnant women received the supplement once a week between 0900 and 1200 h from volunteer health workers who ensured that the women swallowed the tablets in their presence. These volunteers also recorded the date tablets were taken, reasons why women did not take tablets and whether any other supplement or medication was ingested during the previous week. Every 4 wk, two of the authors (S.M. and M.K.S.) distributed the supplement to the voluntary health workers. Random supervision of tablet intake was carried out by two assistants who recorded any complaints of side effects in the preceding 4 wk. Compliance of tablet intake throughout pregnancy was assessed again through interview during the postnatal home visit.

Subjects from the other four villages were assigned to a third group referred to as the "daily" group. These subjects were participating in the ongoing national iron supplementation program. Government policy is that pregnant women receive 90–120 iron plus folic acid tablets throughout pregnancy distributed through medical services. PT Kimia Farma, Indonesia also produced the tablets for the government program. These tablets were similar in appearance and in iron and folic acid content to the tablets administered weekly but were packed in aluminum foil sachets each of 30 tablets. Adherence of iron tablet intake in the daily group was assessed through interview during the postnatal home visit.

There were three villages in the service area of the main health center and six villages in the service area of two smaller health centers supervised by the main health center. Groups were evenly distributed across the health centers.

Pregnancy and anthropometry assessment.

At baseline, demographic characteristics and pregnancy history of the subjects were assessed through interview by using a precoded questionnaire. Village midwives estimated gestational age by palpation and from the last menstruation date, which was later verified against the date of delivery. Body weight, midupper arm circumference (MUAC), and gestational age were measured at baseline (wk 16–20 of pregnancy) and at near-term assessments (wk 34–36 of pregnancy). Body weight was measured using a UNICEF electronic SECA 890 weighing scale (Hamburg, Germany) to the nearest 0.1 kg; MUAC was measured using a plastic measuring tape to the nearest 0.1 cm; and height was measured to the nearest 0.1 cm (only at enrolment) using a standing height measurement microtoise.

Iron and vitamin A status assessments.

Two blood samples were taken to evaluate the treatment, immediately before the intervention at 16–20 wk of pregnancy and at 34–36 wk of pregnancy. The days on which blood samples were taken were chosen to maximize the period of supplementation as well as to ensure that the second blood sample was taken before delivery. Venous blood samples ( 5 mL) were collected in a tube without anticoagulant at 0900–1200 h. Hemoglobin was determined using the cyanmethemoglobin method (Merck test 3317; Merck, Darmstadt, Germany) at the Nutrition Research and Development Center laboratory, Bogor. 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. After arrival at the laboratory, blood samples were centrifuged at 3000 x g for 10 min at room temperature and serum distributed among 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 laboratory of the South East Asian Ministers of Education Organization/Tropical Medicine, Jakarta, Indonesia. Duplicate analyses were performed on one eighth of the samples and the estimated variability was 0.9 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 4.5, 4.4 and 7.1, respectively. Serum soluble transferrin receptor was measured by immunoturbidimetric assay (IDeA sTfR-IT, Orion Diagnostica, Espoo, Finland) as described by Suominen et al. (16) at "Stichting Huisartsenlaboratorium Oost," Velp, The Netherlands. Duplicate analyses were performed for 10% of the samples and the estimated variability 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 estimated variability was 0.05 µmol/L. The between-day CV was 7.4%.

Parasite infestation and dietary assessment.

Subjects were requested to provide a stool sample for examination of intestinal parasites at 30 wk of pregnancy. Stool samples were collected in small plastic containers, and kept refrigerated at 4°C until examination. The intestinal parasites looked for were Ascaris lumbricoides, Trichuris trichiura and hookworm using a modified Kato-Katz method at the Parasitology Department, Agricultural Institute, Bogor. Dietary assessment was carried out using a single 24-h recall in 50% of the subjects at 30 wk of pregnancy.

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 transformed logarithmically and reported as geometric mean and 95% confidence interval (CI). Normally distributed data are reported as means and SD or SEM. To test the difference between baseline and near-term examination, the paired t test was used for continuous data, whereas McNemar’s test was used for dichotomous variables.

To answer the two research questions, each weekly group was compared with the "daily" group, and then the two weekly groups were compared. The independent t test was employed to test the difference between groups taking into account the equality of variance using the Levene test. The change of hemoglobin was correlated with its baseline concentration; therefore, baseline hemoglobin concentration was included as a covariate in the analysis. Pearson correlation coefficients were calculated for relationships between continuous variables.

Energy and nutrient intake data are presented as median and 25th–75th percentile, and the Mann-Whitney U test was employed to test the difference between groups. Energy and nutrient intake was calculated on the basis of Indonesian food composition tables. The SPSS software package (Windows version 7.5.2. SPSS, Chicago, IL) was used for all statistical analyses and a P-value <0.05 was considered 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 MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Initially, 366 pregnant women were enrolled in the study (Fig. 1 ) with age, 24.2 ± 4.6 y; parity, 1.4 ± 1.3 (30% were primiparous); height, 149.2 ± 4.8 cm; weight, 48.9 ± 6.4 kg; and body mass index, 21.9 ± 2.5 kg/m². We present data for 190 subjects on whom complete biochemical data at the baseline and near-term examinations are available (Fig. 1) . These subjects did not differ from the other subjects with respect to anthropometric and other biochemical variables at baseline. Compared with the other subjects, those included in the data analysis had (P < 0.05) lower serum soluble transferrin receptor concentrations [1.47 (95% CI: 1.41–1.54) vs. 1.64 (1.54–1.74) mg/L] and higher parity (1.6 vs. 1.3) at baseline.

View larger version (42K): [in this window] [in a new window]   Figure 1. Selection and retention of eligible subjects in a randomized double-blind community-based trial to investigate the effect of vitamin A and/or iron supplementation during pregnancy.

The supplements were produced in July 1997 and in February 1998. The tablets were analyzed at the Division of Human Nutrition and Epidemiology, Wageningen University in October 1998. The vitamin A content of the tablets was 2340 RE and 2475 RE as retinyl acetate in the first and second batches, respectively. The iron content of both tablets was 60 mg Fe as FeSO₄. The first batch of tablets was used from November 1997 until March 1998 and the second batch from April until October 1998.

The average duration of supplementation in the weekly groups was 20 wk; 63% of subjects took all tablets, whereas the remaining subjects reported that they took no supplements on one or two occasions. Nausea and dizziness were experienced by 25 and 13% of the subjects, respectively. Supplement compliance had no influence on hemoglobin, serum ferritin and soluble transferrin receptor concentrations.

Iron tablet intake in the daily group was assessed through interview. All subjects received iron tablets from one of the health services such as health centers, midwives or general practitioners. The median iron tablet intake was 50. Only 17% of the subjects took 90 tablets, and 43% took <30 tablets.

Observations on the mothers at baseline and near term.

Gestation, body weight and MUAC did not differ among groups either at baseline or at near-term examination (Table 1 ). The period between the two examinations was 17.3 ± 2.6 wk. The mean weight gain was 0.3 kg/wk. All three groups had similar energy, protein, fat, iron and vitamin A intake (P > 0.05). Median (25th–75th percentile) daily intake of energy and nutrient were as follows: energy, 5.1 (3.7–6.5) MJ; protein, 39 (30–57 g; fat, 35 (22–55) g; iron, 6.5 (3.8–8.6) mg; and vitamin A, 274 (76–648) RE. Heme iron intake was only 0.6 (0.3–0.9) mg/d and vitamin A intake from animal sources was 5 (0–36) RE/d.

The mean serum ferritin concentration decreased significantly in the weekly vitamin A and iron group and in the daily group at near term (Table 1) . The changes in serum ferritin were related to the baseline concentration (r = -0.67, P < 0.01). The proportion of subjects with low iron stores (serum ferritin concentration <12 µg/L) increased significantly in the daily group (Table 2 ). In all three groups, serum soluble transferrin receptor concentration increased significantly from baseline to the near-term examination by about one third (P < 0.01). At baseline, subjects with serum ferritin concentration <12 µg/L had a mean serum soluble transferrin receptor concentration of 1.74 mg/L, whereas subjects with serum ferritin concentration 12 µg/L had a mean serum soluble transferrin receptor concentration of 1.33 mg/L (P < 0.01). Compared with subjects with serum ferritin concentration <12 µg/L at both baseline and near term, subjects with serum ferritin concentration 12 g/L on both occasions had significantly lower (P < 0.01) mean serum soluble transferrin receptor concentrations at near term (1.61 vs. 2.44 mg/L).

In the subjects in the daily group who consumed <50 iron tablets during pregnancy, iron status decreased from baseline to near term as indicated by decreased hemoglobin and serum ferritin concentrations (P < 0.05) and increased serum soluble transferrin receptor concentrations (P < 0.01) (Table 3 ). On the basis of the same parameters, iron status did not differ between the weekly iron group and those women in the daily group who consumed 50 iron tablets. However, the weekly iron group performed better than those women in the daily group who consumed <50 iron tablets, on the basis of changes in concentrations of hemoglobin (P < 0.05) and serum soluble transferrin receptor (P < 0.05), but not serum ferritin.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
With respect to the improvement of iron status at near term in pregnancy, our study showed that supervised weekly iron supplementation did not differ in outcome from daily supplementation. However, further analysis revealed that iron status decreased in the daily supplementation group if <50 iron tablets were ingested. In addition, vitamin A and iron supplementation on a weekly basis increased hemoglobin concentrations but decreased serum ferritin concentrations, although the mean increase in hemoglobin concentration was not different from that with iron alone. The loss to follow-up at near-term examination was relatively high. However, we would not expect this to affect the results because the number of subjects in each group was still above that initially regarded as being required, except for the daily group. Moreover, characteristics at baseline were similar in subjects included in the analysis compared with those not included, except for serum soluble transferrin receptor concentration and parity.

In our study, the weekly dose of iron gave results that did not differ from those of the daily dose of iron when 50 tablets (median 70 tablets) were ingested. By comparison, the mean iron tablet intake in the weekly group was 34. If 20 mg iron was absorbed from 120 mg iron provided each week (17) , 340 mg of iron would have been absorbed over 17 wk of supplementation in the weekly iron group. Those in our daily group with iron tablet intake 50 would have absorbed higher amounts of iron compared with the weekly iron group. Hence it may be concluded that it is the regularity of iron tablet ingestion rather than the total number of tablets consumed that is important. This observation has been described earlier by others (7 ,8 ,18) .

Ridwan et al. (6) showed that loosely supervised weekly iron supplementation for 8–20 wk during pregnancy increased hemoglobin (by 6 g/L) but not serum ferritin concentrations. The increment in hemoglobin concentration was similar to that observed in our anemic subjects (initial hemoglobin concentration, 101.3 ± 6.9 g/L), considering that their initial hemoglobin concentration was higher. A recent study from a shanty town in Peru (19) revealed that daily supplementation with 60 mg iron and 250 µg folic acid from 10 to 24 wk gestation through 4 wk postpartum resulted in hemoglobin changes similar to those in our weekly iron group. In our weekly iron group, the fact that hemoglobin concentration did not improve significantly despite iron supplementation was due to the relatively high initial hemoglobin concentration.

It has been suggested that low serum soluble transferrin receptor concentration in early pregnancy reflects decreased red cell production, whereas the increase in serum soluble transferrin receptor concentration from early to late gestation reflects increased red cell production and also depleted tissue iron stores when the increase is above the reference interval (20 21 22) . The one third increase in serum soluble transferrin receptor concentration at near term in our population might reflect both increased red cell production and tissue iron depletion as shown by a consistently higher serum soluble transferrin receptor concentrations in subjects with low iron stores. In contrast to our findings, Carriaga et al. (23) did not see a significant increase of serum soluble transferrin receptor concentration as gestation proceeded. The serum soluble transferrin receptor concentration in our population was slightly lower than that reported by Choi et al. (20) , but this can be attributed to the different methods of analysis used.

Referring to the study carried out by Suharno et al. (15) , daily supplementation of 60 mg iron and 2.4 mg retinol (8000 IU) to anemic pregnant women increased hemoglobin concentration by 12.8 g/L and serum ferritin concentration by 1.8 µg/L. One third of the increment in hemoglobin concentration could be attributed to vitamin A supplementation. Similar results were found in our study, with the increment of hemoglobin concentration 42% higher in the anemic vitamin A–supplemented subjects compared with subjects supplemented with iron alone. However, this increment was not significant (P = 0.211). Hodges et al. (24) concluded that vitamin A is essential for normal hematopoiesis on the basis of studies in human subjects and in experimental animals. It is suggested that mobilization of iron from body stores into the circulation and into hematopoietic tissues is impaired in vitamin A deficiency (25) . Rats fed a vitamin A–deficient diet increased iron absorption, which was associated with increased tissue iron concentration, suggesting therefore that vitamin A deficiency is possibly associated with impaired erythropoiesis (26) . Another study indicated that the inhibiting effect of polyphenols and phytates on iron absorption is reduced by vitamin A (27) . In our study, the improvement of iron mobilization from body stores into the circulation and the increase of erythropoiesis with vitamin A supplementation were indicated by a sharp decline in serum ferritin concentration.

Although only 15% of our subjects had serum retinol concentrations <0.70 µmol/L, vitamin A status was considered to be low. In a study among poor pregnant women in India, similar results were found showing that plasma retinol concentration declined in the third trimester and daily 1800 RE vitamin A supplementation for 12 wk prevented this decline (28) . On the other hand, Sapin et al. (29) found that healthy, well-nourished pregnant women at term had the same absolute quantities of retinol as nonpregnant women, whereas the lower concentration of serum retinol in pregnant women at term was due to expansion in plasma volume.

The tablets used in this study had 20% less vitamin A than intended, which can be expected after 1.5 y of storage. Although this loss was not sufficient to affect our results, care should be taken in programs not to store such supplements for too long.

This study was conducted as closely as possible to the "real life" setting in the community. All pregnant women in the daily group had free access to iron tablets from the health services. In the weekly groups, the voluntary health workers distributed the supplements and supervised their intake. All pregnant women who were 16–20 wk pregnant were recruited without considering whether they were anemic or not. In our population, the proportion of pregnant women who were anemic was 46%. Because there is a program that provides iron supplements to pregnant women in Indonesia, it is not ethical to conduct a study in which pregnant women do not receive iron. Only 17% of the subjects took 90 iron tablets, suggesting that the compliance of iron tablet intake by pregnant women was low in the daily group.

In this setting, weekly iron supplementation during pregnancy is as effective as daily iron supplementation in improving the hemoglobin concentrations of pregnant women at term provided compliance can be ensured. Supplementation with vitamin A together with iron improved hemoglobin concentrations, whereas iron supplementation alone did not. In addition, the vitamin A supplement prevented a decrease in serum retinol concentrations. This effect of vitamin A supplementation on improving hemoglobin concentration and decreasing serum ferritin concentration may be due to increased iron mobilization from body stores and increased erythropoiesis.

	ACKNOWLEDGMENTS

 
We thank PT Kimia Farma, Indonesia, for providing the supplements. The participation of health centers, heads of villages, midwives and pregnant women from the 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, Tropical Medicine (SEAMEO TROPMED), Indonesia.

³ Abbreviations used: CI, confidence interval; MUAC, midupper arm circumference; RE, retinol equivalents.

Manuscript received 13 June 2000. Initial review completed 8 August 2000. Revision accepted 16 October 2000.

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