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Article

Long-Term Weekly Iron Supplementation Improves and Sustains Nonpregnant Women's Iron Status as Well or Better than Currently Recommended Short-Term Daily Supplementation¹

Department of Nutritional Sciences, Morgan Hall, University of California, Berkeley, CA 94720-3104

²To whom correspondence should be addressed.

	ABSTRACT

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This 7-mo double-blind study compared the efficacy of two iron supplementation schemes in improving iron nutrition among 116 healthy fertile-age women. They were randomly distributed in three groups, receiving: Group 1, iron + folate (60 mg and 250 µg, respectively) daily for 3 mo (currently recommended scheme), and folate (250 µg) weekly the subsequent 4 mo. Group 2, folate daily, and 60 mg iron only once weekly for 3 mo, and then weekly iron + folate for 4 mo. Group 3, folate daily for 3 mo and then weekly for 4 mo. At baseline, 16% had depleted stores (plasma ferritin <15 µg/L) and 16% had hemoglobin levels <125 g/L. Eight percent had hemoglobin levels <120 g/L. In Group 1 hemoglobin and ferritin increased at 3 mo but returned to near basal conditions after 4 mo of weekly folate. In Group 2, hemoglobin and ferritin increased progressively throughout the 7 mo but mostly after 3 mo. Group 3 did not change. Side effects were highest with daily iron. Weekly iron supplementation over 7 mo (30 doses) improved and sustained iron nutrition at least as effectively and was better tolerated than 90 daily iron supplements consumed during 3 mo.

KEY WORDS: • iron • weekly supplementation • daily supplementation • women • iron-status

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Iron deficiency and anemia are prevalent among menstruating and pregnant women, even in the industrial world (Hallberg et al. 1995 , INACG 1981 , W.H.O. 1992 ). These women suffer from several functional limitations in their daily life (Li et al. 1994 ), give birth prematurely (Scholl et al. 1992 ) and their infants are at greater risk of developing early iron deficiency with all its negative consequences (Lozoff et al. 1991 , Preziosi et al. 1997 ). It is becoming more evident that prepregnancy iron stores are the most important determinant of iron status during pregnancy, even where antenatal iron supplementation programs are in place and that, most probably, pregnancy is not the most appropriate time for correcting preexisting iron deficiency (Kaufer and Casanueva 1990 , Scholl and Hediger 1994 , Sloan et al. 1992 , Viteri 1994a , Viteri 1994b ). These facts and many other reasons (including coverage, logistical factors and poor adherence, and the validity of hemoglobin cut-off points) may explain the documented low effectiveness of gestational iron supplementation programs in most developing countries (ACC/SCN 1991 ). Important among these reasons may be the high frequency of side effects associated with high daily iron doses given in an effort to correct iron deficiency late in pregnancy (ACC/SCN 1991 , Cook et al. 1990 , De Maeyer 1989 , Sölvell 1970 , Viteri 1995 , W.H.O./UNICEF/U.N.U. 1999 ).

As part of a global effort to control (correct and prevent) the problem of iron deficiency and anemia in women, the World Health Organization (W.H.O.) has recommended that antenatal daily iron supplementation with 120 mg of iron plus 500 µg of folic acid be a universal measure in countries where iron deficiency and anemia are prevalent (De Maeyer 1989 , W.H.O./UNICEF/U.N.U. 1999 ). W.H.O. has also recommended that if food-based strategies (including effective food fortification) are not foreseeable in the near future, daily iron supplementation for 2–4 mo/y be implemented for "population groups in greatest need of iron or at greatest risk of becoming iron-deficient," including "women likely to become pregnant" (De Maeyer 1989 , INACG 1998 , W.H.O./UNICEF/U.N.U. 1999 ).

A new strategy to control iron deficiency and improve iron reserves among groups at risk of this condition, particularly women prone to become pregnant, is derived from the concept of community-based, long-term weekly supplementation with iron or iron plus folic acid (Viteri 1994b , Viteri 1995b , Viteri 1997 , Viteri 1997b , Viteri 1998 ). Supplementation for 2–4 mo with adequate weekly iron doses proved nearly as efficacious as 2–4 mo of daily doses in improving iron nutrition and and correcting anemia, and in general, was better tolerated by children and other groups at risk (Angeles-Agdeppa et al. 1997 , Berger et al. 1997 , Gross et al. 1994 , Husaini 1996 , Liu et al. 1995 , Liu and Liu 1996 , Ridwan et al. 1996 , Tee et al. 1999 ). Folic acid is generally provided together with iron to improve folate nutrition and to insure that folic acid deficiency does not limit the response to iron. UNICEF tablets which are distributed worldwide at very low cost have both nutrients. Adequate folic acid nutrition in women likely to become pregnant is also highly desirable to reduce the risk of neural tube defects in their offspring (Wald and Bower 1995 ). Long-term weekly supplementation could be complementary to other preventive measures and is conceptualized as a surrogate for targeted fortification. It would be particularly indicated where effective iron fortification and/or significant dietary modifications appear highly improbable in the foreseeable future.

This paper compares the short-term (3 mo) and long-term effects (7 mo) of two schemes of indirectly supervised iron + folate supplementation (short-term daily and long-term weekly) on the iron nutritional status of healthy menstruating women in the University of California Berkeley community. A negative control group consumed iron-free tablets (please see the Methods section). The 7-mo time period would approach the results of long-term weekly supplementation in menstruating women.

	METHODS

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Healthy, menstruating women (n = 239) above 18 y of age, who responded to public notices at the University of California, Berkeley campus community, were screened. Fifteen were excluded from participating in the study and 224 were enrolled. Exclusion criteria included: blood donation during the previous 6 mo, pregnancy, pregnancy terminated during the previous year, lactation, meno-metrorrhagia, having a chronic condition interfering with normal iron metabolism, currently taking or having taken therapeutic iron in the previous 6 mo, and predicted impossibility to comply with the experimental protocol.

Enrollees visited our laboratory three times. On the first visit they filled out a consent form, a questionnaire to assess their general health, overall diet and gynecological function, and the basal blood sample was obtained (see below). Subjects were randomized into three groups in a double-blind design. Each study group participated in two consecutive phases: (i) Phase A, lasted 3 mo during which all subjects took a daily tablet. At the end of this Phase, the women were reevaluated clinically and a blood sample was obtained. (ii) Phase B, lasted four additional months, during which all subjects took only a weekly tablet. At the end of this Phase the women were again evaluated clinically and a final blood sample was obtained.

Subjects were fully informed about the objectives of the project and their requirements for participation. The study was approved by the Committee for the Protection of Human Subjects at the University of California at Berkeley.

There was no monetary or any other form of material compensation for participating in the study. Hb and ZPP values were immediately given to the participants at each evaluation point (basal, 3 and 7 mo). Those referring or demonstrating any substantial health alteration were asked to visit their preferred health-care provider.

In Phase A, the subjects were given a precise number of tablets distributed in two bottles and were instructed to take one tablet daily for 6 d/week from bottle No. 1, and one tablet the 7th d of the week from bottle 2. In Group 1 both bottles contained iron + folate; in Group 2, bottle 1 contained only folate and bottle 2 contained iron + folate. In Group 3 both bottles contained only folate. In Phase B, all subjects were again given a precise number of tablets in a single bottle containing their assigned weekly tablets: folate only for Groups 1 and 3, and iron + folate for Group 2.

The two types of tablets (containing only folate or folate + iron) were prepared by Chur-Suiza, (Guatemala City, Guatemala) and were indistinguishable in appearance. One type contained 250 µg of folic acid, and the other also contained 60 mg of iron as FeSO₄ · 7H₂O. Iron contents of both types of tablets (0 or 60 mg/tablet) were verified according to the method of Ceriotti and Ceriotti (1980) , and adequate solubility was confirmed by tablet dissolution in 0.1 mol/L of HCl.

The participants were told to take the tablets preferably at bedtime several hours after the last meal, or between meals, were carefully instructed and motivated to comply with the study schedule, were periodically contacted by Email, mail or phone to maintain their interest and adherence with the protocol, and were invited to visit the laboratory when they so desired during the study. Many did.

At the start of the study and between 5 to 7 d after the end of each Phase, during which time no tablets of any kind were ingested, finger-prick heparinized blood samples (0.6–0.8 mL) were collected in Caraway (Fisher; San Francisco, CA) heparinized tubes. The 5–7-d period without any supplement intake before blood sampling was chosen to avoid fictitiously elevated plasma ferritin (PF)³ levels from recently ingested iron supplements. Participants were asked to fill out calendar forms every day covering 1 mo to record the intake of tablets, changes in health and life routine, and side effects. These preaddressed forms were mailed back to us on a monthly basis. Bottles were returned to us at the end of each Phase, and the remaining tablets were counted and compared to the records in the calendar forms. Codes were broken only after all results were available.

Approximately 150 µL of blood was used to immediately determine hemoglobin (Hb) using the HemoCue system (HemoCue Inc., Angelholm, Sweden) and zinc erythrocyte protoporphyrin (ZPP) using a hematofluorometer (front-face fluorometric analysis, Helena Labs Inc., Beaumont Texas). Plasma was obtained from the remainder of the blood and stored frozen at -20°C. PF levels were measured using Spectro Ferritin MT kits (Ramco Labs, Houston, TX) calibrated for WHO standards. Cyanmethemoglobin (Sigma Chemical Co., St. Louis, MO) and HemoCue values correlated with an r of 0.998. Repeated measurements of ZPP yielded an interday coefficient of variation of 8.19%. Differences between duplicates in PF were always less than 4%, and the interrun precision had a coefficient of variation smaller than 9%.

Statistical analysis.

Statistical analyses using SPSS (SPSS Inc. Chicago, IL) were performed for Hb, and for logarithmically-transformed ZPP, and PF values. Logarithmic transformation was performed due to the skewedness of the distributions of these variables. The statistical procedures included analyses of variance (ANOVA) with repeated measurements with a grouping factor (groups) and a trial factor (Phase). When a significant group by Phase interaction was found, a repeated ANOVA was performed for each group to evaluate the effect of Phase within group for each variable and also to evaluate the effect of group within Phase. Significance of these comparisons was determined by using the Tukey's Studentized Range test with a procedure-wise error rate of 0.05. The statistical significance of the changes in Hb, PF and ZPP during Phase A was tested by covariance analysis, adjusting for their respective basal values. For Phase B the significance of changes was also tested by covariance analysis adjusting for their respective basal (for changes in 7 mo) or Phase A values (for changes in the last 4 mo). Data obtained from calendar forms and questionnaires were analyzed by nonparametric methods, and their influence on the outcome variables (basal Hb, ZPP and PF, and their change at Phases A and B) was explored by multiple regression analyses.

	RESULTS

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Recruits (224) began Phase A of the study. By the end of that Phase, 137 (61%) remained in the study and proceeded to Phase B; 85% of these women finished Phase B. Withdrawals were equally distributed among groups in both Phases, but the great majority took place within the first 2 wk of Phase A. One hundred and sixteen women (52% of those participating initially) completed both Phases with full data. These numbered 37, 35 and 44 in groups 1, 2 and 3, respectively, and were the object of analyses of results. Their characteristics at baseline are presented in Table 1. At baseline, the three study groups were similar in age, weight, height, body-mass index, dietary habits, usual intake of vitamin and vitamin/mineral supplements, gynecological history, history of having had anemia and overall health. Women who completed the study were also similar to those who withdrew from it at baseline in the above variables.

Among those completing the study, independent of group, 88% or more ingested over 90% of all tablets, and none ingested less than 80% in Phase A. In Phase B, all subjects ingested more than 90% of the required tablets, over 94% of subjects, independent of group, ingesting all the required tablets. Calendar forms and returned tablet counts coincided in determining compliance rates (r = 0.94).

During Phase A (daily tablet intake), the most commonly reported side effects were flatulence, mild diarrhea and/or constipation on one or more occasions, by 20, 14 and 17 women (54, 40 and 39% of subjects) in Groups 1, 2 and 3, respectively. In these same groups, occasional nausea was reported by 18, 12 and 2 women (49, 34 and 4% of subjects), and metallic taste and decreased appetite, by 2, 2 and 0 women, in groups 1, 2 and 3 respectively. During Phase B (weekly tablet intake) only 2 women in Group 1 (then taking only folic acid) and none in Group 2 (continued iron plus folic acid intake) reported side effects. In contrast, 16 women in Group 3 (continuing on folic acid only) reported flatulence, mild diarrhea and/or constipation, and 6 reported nausea.

The hemoglobin, ZPP and PF values before Phase A (basal), at the end of Phase A (3 mo) and at the end of Phase B (7 mo) are presented in Table 2.

Table 3 presents the means and standard errors of the individual changes for the subjects in the three groups during both phases. During Phase A, Group 1 showed significant increments in Hb (P < 0.05) and PF (P < 0.01). ZPP significantly in Group 3 (P < 0.05). In the course of Phase B, the Hb increments in Groups 2 and 3 were significant (values at 7 mo in relation to those at 3 mo, P < 0.05), while PF in Group 1 declined significantly (P < 0.01), and ZPP significantly declined in Group 3 (P < 0.05). The increment in PF levels between basal and final evaluations in Group 2 was also significant (P < 0.05).

At the end of Phase A, only 1 woman in each of the iron-supplemented groups and 9 in the control group had Hb levels <125 g/L (P < 0.01 vs. Group 3). At the end of Phase B there were no women with Hb levels below this cut-off in Group 2, while 13.5 and 9.1% of women in Groups 1 and 3 were below it (P < 0.01 vs. Groups 1 and 3). The proportion of women with PF <15 µg/L at the end of Phase B was significantly lower in Group 2 in comparison to the other groups but failed to reach significance (P < 0.055).

Table 4 presents the prevalence of three conditions: (i) ferropenic anemia based on the coincidence of Hb levels <125 g/L with PF <15 µg/L and/or ZPP values >70 mmol/mol heme. At baseline, 38% of these anemic women had both low PF and high ZPP; (ii) anemia without iron deficiency (nonferropenic anemia), when Hb levels were <125 g/L but PF and ZPP levels were 15 µg/L and 70 mmol/mol heme; and (iii) iron deficiency without anemia, defined by the presence of PF <15 µg/L and ZPP values >70 mmol/mol heme and Hb levels >125 g/L. The salient points in this analysis were that, by these criteria, at baseline the majority of anemias were ferropenic and equally distributed among the three groups. Anemia without ferropenia and ferropenia without anemia were each about half the prevalence of ferropenic anemia. At the end of Phase A, both iron-supplemented groups presented no ferropenic anemia (P = 0.044, Fisher exact test vs. Group 3), and by the end of Phase B the weekly supplemented group (Group 2) persisted without ferropenic anemia or nonferropenic anemia, while the daily group (Group 1) moved toward the baseline situation on both anemia types and the no-iron group (Group 3) lowered its anemia rate but still remained presenting both types of anemia. Statistical analysis exploring the patterns of anemia and iron deficiency from baseline to end of Phases A and B fails to reach significance with these small number of cases. A similar type of comparison should be made in a study involving a larger number of subjects. In this study, the use of multiple criteria to diagnose iron deficiency anemia falsely reduces prevalence figures for this condition based on response to iron. This coincides with Hallberg et al.'s experience (1993) .

The changes in proportion of women with ZPP values >70 µmol/mol of heme did not discriminate between groups and phases of study, although the trends were similar to those observed for low Hb (data not presented).

	DISCUSSION

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Weekly supplementation with 60 mg of iron + 0.25 mg of folic acid for 7 mo (30 tablets) has proven effective in controlling mild-moderate iron deficiency and anemia, and in progressively improving iron reserves in women of child-bearing age in Berkeley, CA. It has proven safe, well-tolerated, and given the Hb, ZPP and ferritin values at the end of the study, weekly iron supplementation appears at least as efficient as one tablet consumed daily for the first 3 mo of the study (for a total of 90 tablets). We do not know how long the improvements in iron status achieved by weekly supplementation would be maintained if iron supplements were stopped. This question has little relevance within the scheme of long-term preventive iron plus folate supplementation that calls for a sustained ingestion of weekly supplements by women prone to become pregnant and throughout the reproductive cycle, including during lactation.

Mean Hb levels in the three groups did not change with time (repeated measures ANOVA and ANCOVA) and variations in means can not be separated with confidence from regression to the mean. The fact that the greater Hb increment in Group 3 occurred during Phase B, when the weekly supplement contributed with only 0.25 mg of folic acid to the total weekly dietary folate intake and not when 250 µg of folic acid was ingested daily, argues against a folic acid effect.

The prevalence of anemia at baseline in the group of fertile-age women in Berkeley was found to be 17% based on the proposed 125 g/L cut-off for Hb (Viteri et al. 1972 ). The prevalence of iron deficiency (depleted iron stores) based on PF cut-off values <15 µg/L (Hallberg et al. 1993 ) was 16%. ZPP levels >70 µmol/mol heme were observed in 14% of women, suggesting they had iron-deficient erythropoiesis at the start of the study. Compared to the prevalences of anemia and of iron deficiency in women of childbearing age in other industrial countries (Hallberg et al. 1991 , Hallberg et al. 1993 , Hallberg et al. 1995 , Hercberg et al. 1985 , Hercberg et al. 1988 , W.H.O. 1992 ), the prevalence of anemia is higher but that of iron deficiency is within the reported ranges. The prevalence of anemia is higher because of the higher Hb cut-off derived from a well-nourished population without deficiencies in erythropoietic nutrients (Viteri et al. 1972 ). If the Hb cut-off level of 120 g/L recommended by W.H.O. is adopted, the prevalence of anemia is comparable (8%) to those reported in the studies cited above.

The disappearance of ferropenic anemia as a result of 3 mo of either daily or weekly iron supplementation strongly suggests a causal relationship between anemia and iron deficiency in this population (Table 4) . Similar results were reported in other studies (Angeles-Agdeppa et al. 1997 , Berger et al. 1997 , Gross et al. 1994 , Liu et al. 1995 ).

Only women in Group 2, however, maintained an Hb level >125 g/L at the end of Phase B (P < 0.05), women in Group 1 exhibiting again a 14% prevalence of anemia, classified either as ferropenic or not ferropenic, at the end of the study. However, no women had Hb <120 g/L in either of the iron-supplemented groups. This pattern of Hb regression during Phase B in Group 1 differs from the pattern of sustained Hb levels in Group 2.

Regarding PF levels, the significant increment at the end of Phase A in Group 1, where its geometric mean rose by nearly 15 µg/L over basal values, followed by an equally significant fall during Phase B, contrasts with the smaller increment that took place mostly during Phase B in Group 2 and with the stability of this variable in Group 3 during both Phases (Tables 2 and 3 ). It is important to reiterate that PF was measured in blood samples drawn after 5–7 d of the last iron dose. These significant differences between women receiving the two iron-supplemented groups in the distribution of Hb and PF at the end of both Phases argue in favor of long-term weekly supplementation (Group 2) rather than repeated short-term daily supplementation periods for improving iron reserves and controlling mild-moderate anemia. These results also suggest that iron reserves can be slowly increased and maintained by long-term weekly iron supplementation in women likely to becoming pregnant. The unexpected significant fall of PF during Phase B in Group 1 is hard to interpret. The following mechanisms may be implicated: (i) Diminished food iron absorption during and after daily supplementation; (ii) Increased iron losses following increments in iron stores, most probably in a "labile iron pool"; (iii) Increased PF as a reaction to gut mucosal inflammation due to the presence of a constant high iron environment leading to oxidative stress; and (iv) A combination of two or more of the above.

Even though we have no direct evidence for any of the above mechanisms, food iron as well as reference dose iron absorption is lower during iron supplementation (Hunt and Roughead 1999 , Viteri et al. 1999 ); an increase in iron losses (labile iron pool ?), was observed by Bjorn-Rasmussen et al. (1980) and Skikne et al. (1995) in short intervention studies where body iron has been temporarily increased; and elevated oxidative stress and peroxidative damage were observed in the intestinal mucosa of rats fed supplemental daily iron in food (Srigiridhar and Nair 1998 ).

Iron balance calculated on the basis of changes in Hb and in PF, following the formula published by Viteri et al. (1995) and assuming a constant food iron absorption during both daily or weekly iron supplementation, indicates that during Phase A, women in Group 1 gained 38 mg from the mean Hb change and 122 mg from the mean change in PF, for a total iron balance of +160 mg. Based on the mean intake of iron during Phase A, taking into account the mean adherence to daily iron supplementation, total mean intake is 5,184 mg. Mean iron absorption amounts to 3.1%. During Phase B this group had a negative balance of -107 mg (0.88 mg/d), resulting at the end of Phase B with a positive balance of +53 mg. Similar calculations for Group 2 result in an iron balance of +33 mg with a supplementary iron intake of 691 mg during Phase A and of +62 mg with a supplementary iron intake of 950 mg during Phase B. Mean iron absorptions are calculated to be 4.8 and 6.5% for each respective Phase, or 5.8% for the whole period. Mean absorption ratio of Group 2 during both Phases/Group 1 during Phase A = 1.87. Group 3 had a mean total iron balance of +24 mg in 7 mo (+0.1 mg/day).

The high proportion of women in Group 1 exhibiting PF values >50 and even >70 µg/L at the end of Phase A should not be overlooked, especially when PF levels above 70 µg/L are very improbable to occur normally in menstruating women from dietary iron absorption alone because of the effective down-regulation of food iron absorption (Hallberg et al. 1995 , Hallberg et al. 1997 ). There is general consensus that even temporary excess iron is undesirable because of its ability to promote oxidative damage (Halliwell and Gutteridge 1989 , Halliwell 1992 , Gutteridge 1996 ), and two recently completed human studies showed lipid peroxidation after 4 and 6 wk of 120 and 98.5 mg of iron daily, respectively (Knutson et al. 1999 , Mertz et al. 1999 ). This latter possibility may raise the question of safety of daily iron supplementation with doses of 60 mg or higher.

A high prevalence of elevated serum ferritin levels was also found among Chinese preschool children receiving daily iron, while none were observed with weekly iron supplementation (Liu et al. 1995 ). Serum ferritin levels above 50 µg/L were also reported among daily supplemented adolescent Indonesian girls for 12 wk by Angeles-Agdeppa et al. (1997) . Serum ferrirtin levels in these girls also showed a significant decline 6 mo after discontinuing daily iron supplementation, becoming very similar to the levels remaining in the weekly supplemented group.

Based on the percent of women who abandoned the study because of side effects during Phase A of the study (36% on daily iron and 19% on weekly iron), the former regimen was less tolerated than the latter. However, given the number of women in each group, the difference in percentages can only be considered as a tendency (P = 0.18). This tendency is similar to that observed among daily- and weekly-supplemented pregnant Chinese women (Liu and Liu 1996 ).

Side effects were more common, independent of group, during Phase A when tablets were ingested daily and were essentially absent during Phase B in Groups 1 and 2, when tablets with (Group 2) or without iron (Group 1) were ingested weekly. Only Group 3 reported the same prevalence of side effects during Phase B as during Phase A. We can not explain why Group 3, receiving only folic acid, persisted reporting side effects. This fact suggests that some side effects are related to tablet ingestion, and not exclusively to iron intake. The essential absence of side effects with weekly doses of iron was reported in studies in China where children received daily, bi-weekly and weekly iron supplements (Liu et al. 1995 ), and pregnant women received 120 mg of iron weekly (Liu and Liu 1996 ). Higher levels of side effects, leading to poor adherence to the supplementation regimens, were also reported among women in Indonesia with daily rather than with weekly iron supplement intake (Ridwan et al. 1996 , Angeles-Agdeppa et al. 1997 ).

In the last interview given to each woman, the difficulties associated with weekly tablet intake were explored. Most indicated no difficulties, remembering to take the tablet on a self-selected weekend day. A few chose a week-day activity or event (e.g., a favorite TV program) as effective remainders. Long-term weekly vitamin A supplementation was successful in India (Rahmathullah et al. 1990 ) and Nepal (Christian et al. 1999 , West et al. 1999 ). These experiences raise the possibility that weekly supplementation schedules can become a routine long-term practice if reminders are instituted together with community involvement in motivating, monitoring and assuring the supply of supplements (e.g., in Ecuador residents will be reminded by a proposed "iron-day" on spots in radio and TV stations).

Very encouraging results on adherence and effectiveness of school-based weekly iron supplementation in anemic and nonanemic adolescent school girls in Malaysia (Tee et al. 1999 ), Guatemala (Chew et al. 1997 ) and Panama (Sinisterra-Rodriguez et al. 1997 ) complement the findings being reported here.

The relevance of the findings of this and of other ongoing studies on preventive supplementation through weekly iron-folate doses and involving community resources has special significance if it is recalled that 47% of the rural population of the developing world has no access to health care and to centers through which iron supplements are currently dispensed (W.H.O. 1991 ).

Critics may indicate that the population we have studied is not representative of the fertile-age women of the developing world, who have the greatest need for correcting and preventing often moderate or severe iron deficiency. We propose that the present studies be followed by the implementation and evaluation of long-term field studies by community groups, with guidance from the health sector. These new studies should be aimed at testing the effectiveness (acceptability, sustainability and improvement of iron status) of long-term, weekly iron supplementation of targeted groups as a strategy that can complement other efforts to prevent iron deficiency and improve iron status in developing and industrial countries, particularly where food-based interventions, including food fortification, are presently out of reach (Viteri 1997 ). Only these studies can provide a definitive answer on long-term impact of this new strategy. By insuring prepregnancy iron reserves, the efficiency of antenatal iron supplementation will almost certainly be boosted (Kaufer and Casanueva 1990 , Scholl and Hediger 1994 ).

	ACKNOWLEDGMENTS

 
We want to acknowledge Dr. Mark Hudes for statistical advice and Dr. Mitchell D. Knutson for fruitful discussions and editorial advice.

	FOOTNOTES

 
¹ Partially supported by a grant from the International Nutrition Foundation for Developing Countries (INFDC) and by a Research Grant from the Agricultural Research Station, University of California.

³ Abbreviations: ANOVA, analysis of variance; Hb, hemoglobin; PF, plasma ferritin; ZPP, zinc erythrocyte protoporphyrins.

Manuscript received January 20, 1999. Initial review completed April 30, 1999. Revision accepted July 13, 1999.

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