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Community and International Nutrition

Intermittent Iron Supplementation Regimens Are Able to Maintain Safe Maternal Hemoglobin Concentrations during Pregnancy in Venezuela¹

Juan P. Pena-Rosas, Malden C. Nesheim², Maria N. Garcia-Casal^*, D. W. T. Crompton, Diva Sanjur, Fernando E. Viteri^**, Edward A. Frongillo and Paulina Lorenzana

Division of Nutritional Sciences, Cornell University, Ithaca, NY; ^* Instituto Venezolano de Investigaciones Cientificas, Centro de Medicina Experimental, Laboratorio de Fisiopatología, Caracas, Venezuela; WHO Collaborating Centre for Soil-transmitted Helminthiases, University of Glasgow, Glasgow, Scotland; ^** Nutritional Sciences and Toxicology, University of California, Berkeley, CA, and Children’s Hospital Oakland Research Institute (CHORI), Oakland, CA; and Departamento de Procesos Bioquimicos y Biologicos, Universidad Simon Bolivar, Caracas, Venezuela

²To whom correspondence should be addressed. E-mail: mcn2{at}cornell.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Daily iron supplementation programs for pregnant women recommend amounts of iron that are considered by some to be excessive, and either lower-dose or less frequent iron supplementation regimens have been proposed. A randomized, placebo-controlled study was performed to assess and compare the relative effectiveness of a weekly (WS) or twice weekly (TW) iron supplementation schedule in maintaining or achieving hemoglobin (Hb) levels at term considered to carry minimal maternal and fetal risk (90–130 g/L). Pregnant women (n = 116) at wk 10–30 of gestation (63 WS and 53 TW) were enrolled in the study (52 in WS and 44 TW completed the study). Women were randomly allocated to receive a 120-mg oral dose of iron as ferrous sulfate and 0.5 mg of folic acid weekly (n = 52) or 60 mg iron and 0.25 mg folic acid and a placebo twice weekly (n = 44). Hb, hematocrit, serum ferritin, and transferrin saturation were estimated at baseline and at 36–39 wk of gestation. Baseline dietary data and the presence and intensity of intestinal helminthic infections were assessed. The duration of supplementation was 14 ± 4 wk and the median level of adherence was 60.5%. Hb concentrations improved in women following the TW regimen and in women following WS who had low baseline Hb levels. About 89% of WS women and 95% of TW women maintained Hb levels at term (between 90 g/L and130 g/L), a range associated with optimal pregnancy outcomes. One woman in the TW group exhibited higher Hb levels that potentially carried perinatal risk (>130 g/L). Intermittent iron and folic acid supplementation may be a valid strategy when used as a preventive intervention in prenatal care settings.

KEY WORDS: • anemia • iron supplementation • pregnancy • Venezuela • randomized, controlled trial

Iron deficiency is recognized as the most prevalent specific nutrient deficiency in the world, particularly among pregnant women (1). The literature suggests that both low hemoglobin (Hb)³ levels (<90 g/L at sea level), indicative of moderate or severe anemia, as well as high Hb levels (>125–130 g/L) during gestation may be detrimental to pregnancy outcomes including low birth weight, increased frequency of prematurity and perinatal mortality, and maternal hypertension (2–5). However, a Cochrane systematic review (6) and a literature review (7) found no sufficient evidence to infer a causal relationship between iron supplementation during pregnancy and birth weight and other pregnancy outcomes. Yet most supplementation programs continue to be evaluated primarily on changes in Hb concentration during pregnancy.

Different modalities of oral iron supplementation programs have been used with relatively limited success as a strategy to overcome iron deficiency associated with low Hb levels throughout the world. The reasons for the lack of success are diverse, including the production of undesirable side effects (8,9), but this may also be the result of an arbitrarily high goal for such interventions regarding maternal Hb concentration (10).

Various organizations recommend diverse daily iron supplementation strategies during pregnancy. These strategies target mixed therapeutic and preventive effects of low Hb levels, including the administration of intermittent iron supplements for the prevention of anemia in pregnancy, using the following 2 basic mechanisms: 1) starting the supplementation before pregnancy through community organizations so that women enter pregnancy with iron reserves and continuing throughout pregnancy, and 2) permitting the proper regulation of iron absorption while avoiding the constant enrichment of the intestinal milieu and mucosa that may lead to oxidative stress and impair the absorption and metabolism of other divalent cations (11–15).

The intermittent supplementation approach was evaluated by its therapeutic rather than its preventive effect, as was originally proposed (16–18). The original idea came from studies with iron-normal or iron-deficient rats showing that in the latter the absorptive and iron retention capacities for iron declined rapidly when iron was given daily rather than intermittently (19). These studies gave rise to many human studies that generally showed adequate efficacy compared with daily iron supplementation in terms of Hb levels and safe increments of iron reserves (13). Beaton and McCabe (20), in an analysis of experiences with intermittent and daily iron, initially suggested that daily iron supplementation was superior to intermittent supplementation in pregnancy on the basis of Hb responses. Beaton later recognized that the original estimation of superiority of daily supplementation, if adjusted by the pregnancy stage at which the iron supplementation intervention started, essentially disappeared (10). Currently, preventive intermittent iron supplementation has been accepted except for antenatal programs, for which debate is ongoing (17,21). The weekly dosage schedule takes advantage of the turnover time for intestinal mucosal cells in humans, which is 5–6 d, favoring the regulation of iron absorption and avoiding the daily exposure of an iron-rich environment to such cells, which may cause oxidative stress (22) as well as reduced absorption of other cations, especially zinc and possibly copper (11,12). From the public health programmatic perspective, a weekly or twice weekly dose seems convenient compared with daily dosing, more economic, safer in terms of avoiding constant excess iron in the gastrointestinal tract, and having greater coverage if provided outside of the health system (18). Information about whether weekly or twice weekly dosing is preferred, however, is inadequate.

This paper reports a randomized, semisupervised, community study designed to evaluate the relative effectiveness of antenatal weekly and twice weekly iron and folic acid supplementation for maintaining or reaching safe iron nutrition and Hb levels at term, in a setting in which intestinal helminthic infections are endemic and the diet is relatively poor.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The study was carried out in a rural community in the Trujillo lowlands, southwestern Venezuela. The study population was randomly drawn from women attending prenatal care clinics at 6 main rural health centers and in their 8 satellite centers in the Betijoque Health District. Women first attending the antenatal clinics at wk 10–30 of pregnancy were invited to participate in the program and were informed of the purposes of the study and what participation would entail. They were free to withdraw from the study at any time without any disadvantage to themselves. Written consent was obtained from literate women and fingerprints in front of a witness were obtained from illiterate women. Before the study started, it was approved by the Cornell University Committee on Human Subjects as well as the Ministry of Health in Venezuela. Women with Hb < 80 g/L were referred for aggressive treatment, and those with current multiple pregnancy, chronic disease, or not pregnant were excluded from the study.

    Sample size, allocation of group, and tablet intake. A sample size of 44 subjects per group was estimated to be able to detect a difference of 5 g/L in Hb using an SD of 8 g/L from a similar study (23), allowing for a dropout rate of 20%, and using a standard formula (24). Subjects were randomly assigned to receive either a once weekly dose (WS) of 120 mg of elemental iron as ferrous sulfate and 0.5 mg of folic acid divided into a morning and an afternoon intake; or a twice weekly dose (TW) of 60 mg of elemental iron as ferrous sulfate and 0.25 mg of folic acid taken in the mornings and a placebo tablet in the afternoon. Placebos were made with lactose and cornstarch and had an appearance similar to that of the iron/folic acid tablets. The weekly supplemented group received 2 placebo tablets at midweek. Thus, both groups received the same total amount of iron per week, i.e., 120 mg elemental iron and 0.5 mg of folic acid and ingested 2 supplement tablets and 2 placebo tablets twice weekly.

The study nurses provided the iron tablets to the subjects at the health center and supervised the intake of 1 iron tablet while the women were fasting. They also provided the remaining 3 tablets in 2 small containers marked with the day and the indication they should be taken separately from meals at mid-morning and mid-afternoon. Nurses evaluated the occurrence of side effects and refilled the subjects’ supply of iron tablets for the week.

    Socioeconomic status. The subjects were interviewed during a home visit about family composition and socioeconomic status using a structured questionnaire. Socioeconomic status of the household was determined using the Modified Graffar method (25), an index used in Venezuela to categorize families into socioeconomic groups according to head of household’s occupation, maternal education, housing conditions, and source of income. This method classifies households as follows: high socioeconomic, medium-high, medium-low, poor, and very poor.

    Adherence to the regimen and side effects. Overall adherence was estimated by the number of weeks the women attended the centers and received tablets divided by the total number of weeks she should have received the supplementation, i.e., number of weeks enrolled in the program. General symptoms perceived by the woman, without making reference to supplement intake and thus attributable or not to iron supplements, were reported weekly to the nurse.

The nurses in the health centers provided the tablets weekly, supervised 1 tablet intake on site, and filled out reports on possible side effects. A Side-Effects Index was estimated by the sum of individual symptoms divided by the length of stay in the study.

    Parasitological examination. The Modified Kato-Katz technique (26) was used for stool examination by a trained medical technologist in Trujillo city. Eggs of hookworm, Ascaris lumbricoides, and Trichiuris trichiura eggs were identified and counted and expressed as eggs per gram of feces. A random 10% subsample of fecal preparations was reexamined for quality control.

    Dietary method. Baseline dietary data were collected using 2 nonconsecutive 24-h recalls. The mean of the 2-d data was used to estimate energy and micronutrient intakes and meal patterns (27).

    Iron status assessments. Venous blood samples from fasting subjects were drawn at the health centers at baseline on a nonspecified day during wk 36–39 of gestation after the ingestion of the previous supplement. Blood (15 mL) was collected into 2 tubes, 1 with NaEDTA anticoagulant and another evacuated tube that was trace element free. Samples were transported in coolers with ice to the laboratory, a journey taking 2 h. Hemoglobin and hematocrit determinations were performed using a Coulter S50 hematological autoanalyzer (Coulter Electronics). Of the daily samples, 10% were reexamined manually to check that the automated results were accurate. Determinations of serum ferritin (SF), total iron binding capacity, and transferrin saturation (TS) were performed following the recommendations of the International Committee for Standardization in Hematology ICSH (28,29).

    Statistical methods. The data were analyzed using SYSTAT for Windows (SPSS) and Nutritionist IV (The Harst Corporation) previously loaded with the Venezuelan food composition data (27). Significant differences in demographic characteristics and other baseline characteristics across groups (dropouts and stay-ins) were assessed using ANOVA with Tukey’s adjustment for multiple comparisons. Multiple regression analysis was used to assess the association between the following independent variables: supplementation groups, parasitic infections, dietary iron, socioeconomic status, adherence to the regimen, and side effects and the dependent variables, Hb and SF, after adjusting for baseline values, age, and gestational age at start of supplementation. The effect of each of the individual covariates was tested for significance by determining whether its coefficient was significantly different from 0 (P <0.05), thus rejecting the null hypothesis of ß_n = 0 where n represents a covariate. Because SF and TS were not normally distributed, their values were transformed using natural logarithms and reported as geometric means ± 1 SD.

To evaluate the effect of the different predictors on Hb levels, a regression model was designed that included the covariates in a forward stepwise fashion. Differences between the supplementation groups varied as covariates were controlled for in the model. Second-order interactions were checked and only those with significant P-values (P < 0.05) were retained in the final model.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Participation and characteristics of study sample. A total of 132 women were invited to participate. Of these, 13 (9.8%) had a gestational age > 30 wk; 3 women were excluded in the selection process: 1 was not pregnant, 1 had a twin pregnancy, and 1 had an Hb concentration of 69 g/L; 63 and 53 women were randomly assigned to the WS group and TW group, respectively. Of the 116 women enrolled, 96 (82.8%) completed the study protocol and had blood samples at baseline and after supplementation.

Of the women, 54% were classified as Graffar IV (poor), 42.6% as Graffar V (very poor), and 3.1% as Graffar III (middle-low). Table 1 shows the characteristics of the women upon entry to the study and compares those who completed the study and the dropouts. Maternal age ranged from 14 to 43 y. Characteristics of the dropouts did not differ from the stay-in subjects in the study. Of the women in the study, 31% were <20 y old. Mean gestational age at baseline, as estimated by the last ovulation, was 21 wk with a range of 10–30 wk. There were no significant differences among the groups. None of the subjects was infected with malaria. The mean prevalence of Ascaris lumbricoides, hookworm, and Trichiuris trichiura was 49, 15, and 32%, respectively. Of the women, 65% were infected with at least 1 of these helminths. Overall, hookworm and T. trichiura infections were all light, and a small percentage (12%) of A. lumbricoides infections were moderate.

    Adherence to program and duration of supplementation. The mean number of weeks that subjects came to the health centers for iron tablet refill visits was 7.9 ± 3.5 wk (WS) and 9.1 ± 3.9 wk (TW). The median of adherence was 60.5% with a 10th percentile of 31% and a 90th percentile of 100% adherence. Adherence ranged from 12.5% in the WS and 22.7% in the TW groups to 100%. The rate of adherence did not differ in the WS and TW groups (61.6 and 65.9% respectively). The duration of the supplementation period varied from 4 to 27 wk. Only 3 women were enrolled for <7 wk.

    Side effects. Some symptoms were reported by 72% of the supplemented women; 73% of women in the WS and 71% in the TW group reported any symptoms during the study period although no causation was necessarily attributable to the intake of iron tablets. Of these 35% reported anorexia, 30% reported fatigue, 28% reported nausea, and 21% reported vomiting. Abdominal pain and vomiting were reported more frequently by women in the WS group than in the TW group: 25 and 14% (P = 0.048), and 27 and 16% (P = 0.058), respectively.

    Iron status and relative effectiveness of iron supplementation regimens. Table 2 presents data for women who completed the study. No differences were found between WS and TW groups in final Hb, hematocrit, and ferritin concentrations. Only the percentage of serum TS differed between the groups (P < 0.05). In the total sample studied, 72% of the women had Hb level < 110 g/L at baseline. Of the 102 women with Hb < 110 g/L at baseline, 75 had complete measurements of SF and TS. Of this group with complete measurements, 34% had SF < 12 µg/L and 29% had serum TS values < 15% (data not shown). Using currently accepted Hb cutoff values for gestational anemia, SF, and % TS to estimate the prevalence of iron deficiency in women with low Hb levels at baseline (<110g/L), 23% of the women had iron deficiency anemia.

Coefficients and P-values of the final regression model for final Hb regressed on the covariates are presented in Table 3. After adjusting for all covariates, the main effect of regimen on final Hb concentration was 3.7 g/L higher in the TW group than in the WS group (P < 0.05). When the interaction term between type of supplementation regimen and baseline Hb was included in the model, 47.8% of the variation in final Hb concentration was explained by these compounded covariates in the model. The independent R² for type of supplementation was 0.295.

View larger version (18K): [in this window] [in a new window]   FIGURE 1 Effect of supplementation regimen and initial Hb concentration on final Hb concentration in pregnant women participating in a randomized, placebo-controlled study to assess and compare the relative effectiveness of a weekly or twice weekly iron-folic acid supplementation schedule. Values were adjusted by gestational age at enrollment, maternal age, adherence, duration of supplementation, presence and severity of parasitic infections, and dietary iron intake as modeled in Table 3.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The study was conducted to evaluate the relative effectiveness of weekly or twice weekly iron supplementation from a public health perspective on Hb and iron nutrition indicators in pregnant women living in rural areas of endemic helminthic infections. The focus was on the relative effectiveness, under field conditions, of either regimen to achieve and/or maintain desirable Hb concentrations among pregnant women consulting antenatal services at ages that are the reality in rural communities. The minimum sample size of 44 per group that we estimated to be required was achieved. This sample provided adequate power because the within-group variability found was about equal to that expected, and the substantively important differences observed were significant.

The literature indicates that levels of 90–100 g/L after gestational wk 30 have no effect on premature delivery and low birth weight, whereas Hb levels < 90 g/L and > 130 g/L by wk 26 are associated with these outcomes, thus suggesting that optimal birth weight and overall health of the newborn is achieved when maternal Hb levels remain between 90 and 130 g/L throughout pregnancy (2–5,32). Hemoglobin above that upper level, possibly indicating poor plasma expansion rather than better iron nutrition, also has been associated with increased incidence of maternal complications and poor pregnancy outcomes (33,34). Hemoglobin levels of this magnitude can be reached with daily iron supplementation, thus raising the question whether this form of periodicity could be hazardous to the mother and the fetus. The average Hb concentration was 4 g/L higher at the end of the study in the TW-supplemented group than in the WS group, but this difference was significant only after adjusting for gestational age, initial Hb concentration, adherence, duration of treatment, and dietary iron intake. Dietary iron tended to affect (P = 0.066) Hb concentration at term in both groups. Both supplementation regimens prevented a fall in Hb below the Hb levels associated with increased risk at term, and no maternal or perinatal consequences were reported. Consequently, the differences in Hb concentration between the TW and WS groups are most probably not biologically relevant.

Other studies evaluating intermittent iron supplementation in pregnant women reported a decrease in the prevalence of anemia defined as Hb < 110 g/L (35,36) after at least 8 wk of treatment. The comparisons were made with daily regimens as controls. The Guatemalan study, which was done under supervision and with an adherence > 89%, provided a higher dose than the one used in our study; the prevalence of Hb levels < 110 g/L decreased from 27 to 24.7% in the weekly supplemented women and increased to 32.9% in women under "usual" prenatal care (36). In the study in China (37), in which supplementation was supervised and the adherence was > 65%, a reduction in the prevalence of Hb levels < 110 g/L from 41 to 18% in the weekly supplemented group was reported, whereas daily supplementation reduced this prevalence from 39 to 22%. In the Indonesian study (35), the prevalence of Hb levels < 110 g/L decreased similarly between daily and weekly supplemented groups to 45.6 and 56.3% from 66.2 and 76.1%, with adherences of 54.3 and 62.2%, respectively. None of these studies reported controlling for gestational age. In all cases, differences between daily and weekly regimens were not significant.

Early in pregnancy, Hb concentration starts to decline and reaches a low point in the second trimester (38). This is explained by a hemodilution phenomenon due to an expansion of plasma volume that exceeds the accompanying increase in RBC mass. In the second and third trimesters, there is an increased iron requirement related to the expanding maternal RBC mass and the growth of maternal, placental, and fetal tissue. A rise in Hb concentration toward the end of the pregnancy occurs in those receiving iron supplements, at a time when expansion in plasma volume has slowed down (39).

The significance of the combination of levels of Hb and iron nutrition indicators to diagnose iron deficiency anemia in pregnancy is currently under scrutiny. If Hb alone was used to diagnose anemia, 72% of women in this sample were anemic at the basal evaluation, but only 23% were also iron deficient. The difference in these estimates casts doubts about the origin of anemia and about the chosen cutoff points for the diagnosis of anemia in pregnancy in a significant proportion of women who respond to iron supplement intake, even when nonanemic at baseline. The lack of an association between iron status indicators and helminthic infections in our study should not be generalized to consider them unimportant. For relationships between helminth infections and indicators of poor iron status to be evident, the intensity of helminthic infections must be high (40–42). Overall prevalence of helminthic infections was moderate in our sample, and the prevalence of hookworm was low. Additionally, the intensities of hookworm and T. trichiura infections were low in the study population.

Our data also suggest that among the 2 regimens used here, TW iron and folic acid supplementation would produce fewer associated symptoms than a similar dose consumed on the same day, even given hours apart only every 7 d. The possibility that women confused nausea and vomiting as symptoms attributed to pregnancy only and not related to supplementation is small. These symptoms occur generally during the first trimester of pregnancy and most of the women in this study were in their second or third trimester. Supplements were ingested when the women were fasting in the morning, and between lunch and dinner, which may accentuate gastrointestinal side effects. Experience shows that ingesting supplements before retiring at night, hours after the last meal, reduces the complaints of side effects. This added strategy may be important in improving adherence in public health programs.

Adherence to both WS and TW iron supplementation in this study was comparable with other similar studies and to adherence found in most daily iron supplementation regimes among pregnant women (9,35). Adherence rates are difficult to interpret in this study because women had to come to the health centers on a weekly basis to receive their supplements and 1 tablet weekly was ingested under supervision.

Weekly or twice weekly iron supplementation may not work as rapidly as daily iron in treating severe anemia in individuals irrespective of pregnancy. Intermittent iron-folic acid supplementation may be a desirable preventive strategy particularly if used among women of reproductive age and adolescent girls, long before they become pregnant or even in pregnant women with Hb levels > 90 g/L. A low-dose iron tablet given intermittently gave good results in adolescent girls and nonpregnant women (43–45). This study expands these results by demonstrating that twice weekly or weekly iron supplementation achieves essentially the same results among pregnant women. The twice weekly regimen appears to have minor advantages in Hb and iron nutrition indicators. On the basis of the Hb effects achieved in both groups, however, the biological repercussions (pregnancy outcomes) of these small differences would be minimal if present at all. The higher levels of serum TS may be artifactual, given that the probability of blood being obtained at a time closer to the ingestion of supplements in the TW women was greater than in the WS women. These advantages might be lost because, logistically, it would probably be easier to take iron supplements only once weekly. We cannot answer this question. In conclusion, intermittent iron and folic acid supplementation may be a valid strategy when used as a preventive intervention in prenatal care settings.

	ACKNOWLEDGMENTS

 
The authors thank the women who participated in this study, the nurses, and other staff of the clinics at which it was carried out. We also are grateful to the following collaborators in Venezuela: Jesus Benitez from the Trujillo Division of Rural Epidemics, Ministry of Health, J.V. Scorza from Universidad de los Andes as well as Lic. Elci Villegas from IPAS-ME and Lic. Jose Gregorio Rojas for their help in local laboratory set up and procedures. Iron-folic acid tablets were generously provided by UNICEF and placebos were prepared by Suyin Trujillo, Department of Pharmacology Universidad Central de Venezuela.

	FOOTNOTES

 
¹ Supported in part by the WHO Collaborating Centre for Soil-transmitted Helminthiases at the University of Glasgow, Scotland, and Cornell University, Ithaca, NY.

³ Abbreviations used: Hb, hemoglobin; RDI, recommended dietary intakes; SF, serum ferritin; TS, transferrin saturation; TW, twice weekly supplementation; WS, weekly supplementation.

Manuscript received 9 September 2003. Initial review completed 24 October 2003. Revision accepted 17 February 2004.

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TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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