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Intermittent Iron Supplementation Regimens Are Able to Maintain Safe

Maternal Hemoglobin Concentrations during Pregnancy in Venezuela

Article  in  Journal of Nutrition · June 2004

DOI: 10.1093/jn/134.5.1099 · Source: PubMed

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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. Nesheim,2 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 Fisiopatologı́a, 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

ABSTRACT 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

Downloaded from jn.nutrition.org by guest on June 6, 2013

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. J. Nutr. 134: 1099 –1104, 2004.

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.
1
Supported in part by the WHO Collaborating Centre for Soil-transmitted
Helminthiases at the University of Glasgow, Scotland, and Cornell University,
Ithaca, NY.
2
To whom correspondence should be addressed. E-mail: mcn2@cornell.edu.
3
Abbreviations used: Hb, hemoglobin; RDI, recommended dietary intakes;
SF, serum ferritin; TS, transferrin saturation; TW, twice weekly supplementation;
WS, weekly supplementation.
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 through-
out 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 inter-
ventions regarding maternal Hb concentration (10).
Various organizations recommend diverse daily iron supple-
mentation 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

0022-3166/04 $8.00 © 2004 American Society for Nutritional Sciences.

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

1099
1100 PENA-ROSAS ET AL.
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 inter-
mittently (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 incre-
ments of iron reserves (13). Beaton and McCabe (20), in an
analysis of experiences with intermittent and daily iron, ini-
tially 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 interven-
tion started, essentially disappeared (10). Currently, preven-
tive 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 avoid-
ing 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 con-
stant 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, commu-
nity study designed to evaluate the relative effectiveness of
antenatal weekly and twice weekly iron and folic acid supple-
mentation 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
The study was carried out in a rural community in the Trujillo
lowlands, southwestern Venezuela. The study population was ran-
domly 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 ob-
tained 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 sub-
jects’ 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
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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 indi-
vidual 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 nonspeci-
fied 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 ac-
curate. Determinations of serum ferritin (SF), total iron binding
capacity, and transferrin saturation (TS) were performed following
the recommendations of the International Committee for Standard-
ization in Hematology ICSH (28,29).
Statistical methods. The data were analyzed using SYSTAT for
Windows (SPSS) and Nutritionist IV (The Harst Corporation) pre-
viously loaded with the Venezuelan food composition data (27).
Significant differences in demographic characteristics and other base-
line 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 be-
tween 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 ␤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
 INTERMITTENT IRON SUPPLEMENTATION 1101

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
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 base-
line 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
micronutrients (31), black beans, plantain, and eggs. Sausage,
sardines, bologna, tuna, or dry fish were also consumed in small
amounts, mainly on weekends. Fresh fruit juices (papaya,
guava, orange, and melon) were frequently consumed at lunch
and dinner.
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% respec-
tively). 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 in-
take 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

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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 preva-
lence 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 percent-
age (12%) of A. lumbricoides infections were moderate.
Dietary intake and usual diet. Using the recommended
dietary intakes (RDI) for Venezuela (30) as a reference for iron
(16 mg/d based on iron bioavailability in the diet for pregnant
adult women), it was estimated that 23.1% of the mothers
were consuming ⬍33% of the RDI for iron. Meats provided
14% of the iron consumed, and 68% came from cereals,
legumes, tubers, vegetables, and fruits, of which 14% came
from fortificant iron in the fortified cereal flours. The mean
intake of vitamin C met the Venezuelan RDI, whereas vitamin
A and calcium intakes were below the standards (94 and 60%
respectively). No significant differences were found in the
mean nutrient intakes of the subjects between supplementa-
tion groups. Meals consisted essentially of arepas made out of
precooked corn flour fortified with ferrous fumarate and other
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 supplemen-
tation 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 concen-
trations. 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 ␮g/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.
Both supplementation groups experienced a significant de-
cline in SF levels. The percentage of women with low TS
values also increased in both groups. The percentage of women
with low ferritin, low % TS, and Hb levels ⬍ 110 g/L increased

TABLE 1
Selected baseline characteristics of 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 and the groups’ dropouts1

Supplementation group WS TW WS dropouts TW dropouts

n 52 44 11 9
Age, y 24.5 ⫾ 7.5 24.5 ⫾ 6.9 26.8 ⫾ 9.3 23.0 ⫾ 8.6
Gestational age, wk 21.3 ⫾ 5.5 20.7 ⫾ 6.5 21.2 ⫾ 5.7 18.6 ⫾ 6.6
Parity, n 2.1 ⫾ 2.6 2.2 ⫾ 2.3 3.7 ⫾ 3.3 2.5 ⫾ 4
Initial Hb, g/L 104 ⫾ 8 105 ⫾ 7 110 ⫾ 9 110 ⫾ 5
Initial ferritin,2 ␮g/L 15.2 (6.2; 37.3) 15.6 (7.0; 34.8) 11.6 (3.3; 40.0) 20.1 (9.8; 43.8)
A. lumbricoides infection,3 % 45.7 47.6 66.7 50
Hookworm infection, % 4.3 16.7 22.2 25
T. trichiura infection, % 30.4 28.6 44.4 25

1 Values are means ⫾ SD, except for ferritin concentration, for which geometric means ⫾ 1 SD are presented.
2 For ferritin concentrations, sample sizes were WS (n ⫽ 43), TW (n ⫽ 35), WS dropouts (n ⫽ 9) and TW dropouts (n ⫽ 5).
3 For parasitic infections, group sample sizes were WS (n ⫽ 46), TW (n ⫽ 42), WS dropouts (n ⫽ 9) and TW dropouts (n ⫽ 8).
1102 PENA-ROSAS ET AL.

TABLE 2
Hematological and iron status indicators at baseline and end of the study in women receiving iron-folic acid
supplementation in the weekly or twice weekly dose regimen1

n Baseline End of Study Difference

Hb, g/L
WS 52 104 ⫾ 8 101 ⫾ 10 ⫺2.5 ⫾ 10
TW 41 105 ⫾ 7 105 ⫾ 10 ⫺0.4 ⫾ 7
Hematocrit
WS 52 0.349 ⫾ 0.030 0.347 ⫾ 0.032 0.0015 ⫾ 0.032
TW 41 0.354 ⫾ 0.021 0.356 ⫾ 0.030 ⫺0.0015 ⫾ 0.021
Ferritin, ␮g/L
WS 43 15.2 (6.2; 37.3) 4.1 (1.2; 13.7)* ⫺3.2 (⫺11.4; 1.1)
TW 35 15.6 (7.0; 34.8) 4.9 (1.5; 16.3)* ⫺3.2 (⫺10.6; ⫺2.9)
Serum TS, %
WS 37 19.7 (11.8; 32.8) 16.4 (9.9; 27.4) ⫺1.3 (⫺2.4; 1.5)
TW 30 19.9 (13.2; 29.9) 20.1 (11.5; 35.2) 1.0 (⫺1.6; 1.6)**

1 Values are means ⫾ SD and are unadjusted. For ferritin and serum TS, values are geometric means ⫾ SD (in brackets). * Significantly different
from baseline values, P ⬍ 0.05. ** Significantly different from WS group, P ⬍ 0.05.

slightly but not significantly in both supplementation groups not found to be an important predictor of Hb concentrations

Downloaded from jn.nutrition.org by guest on June 6, 2013

(data not shown).
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.
Only initial Hb, regimen, gestational age, and the interac-
tion term regimen ⫻ initial Hb were significant predictors of
final Hb concentration (P ⬍ 0.05). The significant influence
of supplementation regimen alone was superseded by the in-
teraction term regimen ⫻ initial Hb. Helminth infection was
at the end of the study (P ⬎ 0.05), independent of its severity.
The effect of supplementation regimen and baseline Hb ad-
justed for all covariates in the model shows that the supple-
mentation regimens behave differently at different levels of
baseline Hb concentration. Figure 1 graphically depicts the
trend in Hb change using baseline Hb means ⫾ 1 SD of the
data values, while maintaining all other variables constant in
the estimated model. At lower initial Hb levels, the estimated
difference in final Hb concentration was 1.1 g/L higher in the
WS than in the TW group. Levels of Hb increased in both

TABLE 3
Effect of initial Hb, regimen (WS vs. TW), adherence, duration
of treatment, helminth infections, and dietary iron on final Hb
concentrations: regression coefficients (␤-estimate) after
adjusting for gestational and maternal age1

Coefficient SE P-value

Constant 32.52 16.82 0.057

Initial Hb, g/L 0.440 0.155 0.006
Supplementation regimen2 ⫺54.16 24.64 0.031
Gestational age at enrollment, wk 0.71 0.19 0.000
Age, y 0.06 0.12 0.628
Adherence, % ⫺0.04 0.04 0.284
Duration of supplementation, wk 0.50 0.27 0.069
Hookworm infection 0.37 3.10 0.905
Whipworm infection ⫺1.17 2.14 0.586
Ascadum13 ⫺1.16 1.83 0.528
Ascadum23 2.42 2.87 0.402
Dietary iron intake, g/d 0.14 0.07 0.066 FIGURE 1 Effect of supplementation regimen and initial Hb con-
Supplementation regimen ⫻ initial Hb 0.550 0.233 0.021 centration on final Hb concentration in pregnant women participating in
a randomized, placebo-controlled study to assess and compare the
1 Adjusted R2 ⫽ 0.478; SEE ⫽ 0.725. relative effectiveness of a weekly or twice weekly iron-folic acid sup-
2 Supplementation regimen: WS (0); TW (1). plementation schedule. Values were adjusted by gestational age at
3 Ascaris lumbricoides infection: absent ascadum1 (0), ascadum2 enrollment, maternal age, adherence, duration of supplementation,
(0); mild infection ascadum1 (1) ascadum2 (0): severe infection asca- presence and severity of parasitic infections, and dietary iron intake as
dum1 (0) ascadum2 (1). modeled in Table 3.
 INTERMITTENT IRON SUPPLEMENTATION
supplementation groups compared with initial levels, but
women in the TW group had a slightly greater increase than
those in the WS group. At higher baseline Hb concentrations,
Hb values decreased in the WS group but increased in the TW
group compared with baseline values. At higher baseline Hb
values, the difference between supplementation regimens was
7.4 g/L in final Hb, higher in the TW group.
In our study, Hb concentrations improved slightly 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 their Hb levels
from the start of supplementation to term (between 90 and
130 g/L). Thus, both regimens were appropriate in maintain-
ing desirable Hb levels even when the basal evaluation sug-
gested a risk of developing biologically relevant low Hb levels.
One woman in the study, who was in the TW group, had Hb
concentrations ⬎ 130 g/L at 36 –39 wk, indicating that only a
very small percentage of the women might have risk associated
with excess iron. This woman was nonanemic at baseline (Hb
⫽ 120 g/L) and had an estimated adherence of 76% for the 17
wk she received the supplements.
DISCUSSION
The study was conducted to evaluate the relative effective-
ness 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 consult-
ing 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 pro-
vided 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 in-
creased incidence of maternal complications and poor preg-
nancy 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 hazard-
ous to the mother and the fetus. The average Hb concentra-
tion 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 di-
etary 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
1103
controls. The Guatemalan study, which was done under su-
pervision 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 re-
ported, 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 expan-
sion of plasma volume that exceeds the accompanying increase
in RBC mass. In the second and third trimesters, there is an
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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 nonane-
mic 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 possi-
bility that women confused nausea and vomiting as symptoms
attributed to pregnancy only and not related to supplementa-
tion 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 gastrointes-
tinal 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 impor-
tant 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
1104 PENA-ROSAS ET AL.
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 proba-
bility 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, inter-
mittent 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.
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