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*
Department of International Health, The Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205;
Nepal Nutrition Intervention Project-Sarlahi (NNIPS), Nepal Netra Jyoti Sangh, Nepal Eye Hospital Complex, Tripureswor, Kathmandu, Nepal and
Schistosomiasis and Intestinal Parasites Unit, Division of Control of Tropical Diseases, World Health Organization, Geneva 27, Switzerland
2To whom correspondence should be addressed at Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONRisk factors for anemia...Implications for control of...REFERENCES |
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KEY WORDS: • anemia • iron deficiency • pregnancy • Nepal
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONRisk factors for anemia...Implications for control of...REFERENCES |
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, World Health Organization 1992
).
When iron deficiency is sufficiently severe, red blood cell synthesis
becomes impaired, and anemia results. Approximately 50% of women and
children in less developed countries are anemic (DeMaeyer and Adiels-Tegman 1985
), and 60% of anemic women in the world
reside in South Asia (ACC/SCN 1992
). Globally, the most
common cause of anemia is believed to be iron deficiency due to
inadequate dietary iron intake, physiologic demands of pregnancy and
rapid growth and iron losses due to parasitic infections. However, iron
deficiency is not the only cause of anemia. Other prevalent causes of
anemia include malaria, chronic infections and nutritional deficiencies
of vitamin A, folate and vitamin B-12. The relative contributions of
these causes of anemia and iron deficiency vary by sex, age and
population and are not well described in many populations.
During pregnancy, iron requirements exceed storage iron for most women
(Bothwell and Charlton 1984
). The increased need by the
body for iron is due to increases in the red cell mass, iron needs of
the fetus and iron losses during delivery (Bothwell and Charlton 1984
). Although hemodilution from expansion of the plasma
volume leads to a "physiologic pregnancy anemia" (DeLeeuw et al. 1966
), inadequate iron supply can limit red cell mass
expansion and lead to further deterioration in iron status during
pregnancy (Viteri 1994
) that may pose risks for the
pregnant woman and her infant (Allen 1997
). Severe
anemia during pregnancy is associated with a woman’s increased risk of
death (Llewellyn-Jones 1965
), and moderate to severe
anemia is associated with an increased risk of low birth weight
(Garn et al. 1981
, Murphy et al. 1986
)
and preterm delivery (Klebanoff et al. 1991
,
Scholl et al. 1992
, Zhou et al. 1998
).
Iron deficiency and anemia during pregnancy are associated with lower
iron stores in the fetus, which may result in iron deficiency anemia
(Agarwal et al. 1983
, Kaneshige 1981
,
MacPhail et al. 1980
, Milman et al. 1987
,
Puolakka et al. 1980
). In several studies, iron
supplementation during pregnancy resulted in greater iron stores in
young infants (DeBenaze et al. 1989
, Milman et al. 1994
, Preziosi et al. 1997
).
We assessed a cohort of pregnant women in the rural plains of Nepal to determine the prevalence, severity and infectious and nutritional causes of anemia and iron deficiency. Our goal was to estimate the relative contributions of several causes of anemia and iron deficiency in this population to provide a basis for more effective prevention and control.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONRisk factors for anemia...Implications for control of...REFERENCES |
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The study was conducted in Sarlahi District in the east-central
plains (terai) of Nepal bordering India. Most of the
population is involved in subsistence agriculture, sanitation is very
poor, health care services are not widely available and protein–energy
and micronutrient malnutrition is prevalent among adults and children
(Christian et al. 1998b
, West et al. 1991
and 1999
). Ancylostoma duodenale (hookworm) and
Ascaris lumbricoides are two species of geohelminths
endemic in the area (Navitsky et al. 1998
).
Historically, malaria is hyperendemic in the terai. An aggressive
control program during the 1960s and early 1970s reduced the incidence
of malaria to very low levels (Shrestha et al. 1988
),
but the incidence increased again during the early 1980s.
Plasmodium vivax is the more common species of malaria
parasite in Nepal, but P. falciparum is also present
(Nepal Malaria Eradication Organization 1986
).
The study population consisted of women 12–45 y old who were
participating in a randomized community intervention trial of the
effect of vitamin A or ß-carotene supplementation in women of
childbearing age on maternal, fetal and early infant mortality and
morbidity rates (West et al. 1999
). All women from a
10% subsample composed of 27 of 270 participating wards (local
administrative units) in three subdistricts who reported being pregnant
during weekly home interviews were enrolled in the main trial and
invited to a local clinic, after verbal consent was obtained, for a
health and nutrition examination conducted by trained study staff. The
three subdistricts were centrally located in the study area and
represented the general characteristics of the larger trial area.
This analysis includes data collected from August 1994 through March 1997 from women allocated to placebo and living in the clinic substudy area. Of 621 eligible pregnant women, 388 (62%) visited the clinic; of the 388 women, 368 (95%) had pregnancies confirmed with a ß-human chorionic gonadotropin urine test. Twenty-four women visited the clinic for two different pregnancies, but only their first pregnancies were used for analysis, leaving 344 pregnancies. Among these women, 336 (98%) provided a blood specimen for assessment of iron status, and this is the final sample size for this analysis. Clinic attendance was affected by women’s refusal to participate and extended absences from home due to a common practice of women returning to their parents’ home during pregnancy. Also, women who reported a miscarriage, stillbirth or live birth between the time of pregnancy ascertainment and their scheduled clinic visit were not enrolled in the clinic study. Women who did not enroll were similar in age (24.5 versus 24.4 y, P = 0.91) and nutritional status [mid-upper arm circumference (MUAC)3 21.3 versus 21.2 cm, P = 0.61) to those who did enroll in the study. However, nonparticipants were more likely to be <20 y old (25.5% versus 18.9%, P = 0.05), possibly because women are most likely to return to their parents’ home for a first pregnancy.
Assessment of nutrition and health status.
Age, report of last menstrual period (LMP) and a pregnancy history were collected during the initial home interview for enrollment of pregnancies into the supplementation trial. Date of LMP was based on a combination of prospectively reported menstrual histories and LMP recall. Data on socioeconomic status, including literacy and household possessions, were obtained at a second interview conducted later in pregnancy.
Anthropometric measurements were obtained during the clinic visit.
Weight was measured to the nearest 0.1 kg with a battery-powered
digital scale (Seca, Columbia, MD). Height was measured to the nearest
0.1 cm with a stationary height board fastened to the clinic wall. MUAC
was measured to the nearest 0.1 cm at the midpoint of the left arm with
an insertion tape (Zerfas 1975
). Triceps and subscapular
skinfolds were measured to the nearest 0.2 mm with skinfold calipers
(Holtain; Seritex, Carlstadt, NJ). The median of three measurements was
recorded for each measure, except for weight, which was measured once.
Iron status was assessed with hemoglobin, erythrocyte protoporphyrin
(EP) and serum ferritin concentrations, and vitamin A status was
assessed with serum retinol concentration. Blood was collected via
venipuncture. Hemoglobin was measured with a Hemocue hemoglobinometer
(Mission Viejo, CA), and EP was measured with a hematofluorometer (AVIV
Biomedical, Lakewood, NJ). Blood samples were centrifuged at 1530
x g for 10 min at room temperature, and serum was
collected in 1-mL cryotubes. Serum was immediately stored in liquid
nitrogen freezers until transported to Baltimore, where they were
stored at -70°C until analysis. Serum ferritin was assessed with a
fluorometric immunoassay (Delfia System; Wallac, Gaithersburg, MD). The
assay within-day and between-day coefficients of variation were
7.9 and 11.5%, respectively. Serum retinol was determined with reverse
phase, isocratic high performance liquid chromatography (Craft 1996
), and the assay within-day and between-day
coefficients of variation were 2.3 and 3.0–5.7%, respectively.
To detect malaria parasitemia, a thick blood film and a thin blood film
were collected, fixed and stained with Giemsa. Blood films were not
available for 31 women because they visited the clinic before
start-up of the protocol for malaria assessment. An additional 17
women had unreadable blood films, leaving a total of 288 (94% of
available specimens) women with blood films available for the detection
of malaria. Malaria parasites were counted as a ratio to leukocytes. If
<10 parasites were seen after 200 leukocytes were counted, then 500
leukocytes were counted. At least 100 microscope fields were examined
in all blood films. The calculation of parasite density was based on
8000 leukocytes/µL of blood (World Health Organization 1991
). Malaria species were identified from thick and thin
blood films; all infections were identified as P. vivax.
All specimens identified as positive for malaria parasites were later
reread by an experienced malariologist or by another microscopist under
his supervision. Only those specimens confirmed positive in the second
reading were considered positive in these analyses. A systematic random
10% subsample was reread by the malariologist. Agreement was moderate
for the presence of malaria parasitemia (percent agreement = 81%,
= 0.47).
For assessment of helminth infections, women were asked to collect a
stool specimen in provided containers the evening before or the morning
of their clinic visit. Thirty-two of the 336 study subjects have no
helminth data because they visited the clinic before start-up of
the protocol for helminth assessment. Among the remaining 304 women,
190 (62% of available specimens) returned a stool sample. The
Kato-Katz method was used to stain the samples on the day of the
clinic visit, and they were read within 1 h of staining
(World Health Organization 1994
). Specimens were
examined by an investigator (M.L.D.) or one of two trained
microscopists for the presence of hookworm, A.
lumbricoides and Trichuris trichiura eggs. A
subsample of specimens (n = 71) were reread by
M.L.D. for quality control purposes. Agreement between egg counts in
categories of 1000 eggs/g of feces was very good for A.
lumbricoides (percent agreement = 87%, = 0.83)
and good for hookworm (percent agreement = 77%, = 0.60). T. trichiura infection was not prevalent enough
to estimate agreement.
Women with a hemoglobin concentration of <70 g/L were given a 30-d course of ferrous fumarate capsules containing 120 mg of elemental iron each. P. vivax malaria infection was treated with 600 mg of chloroquine on the 1st d, followed by 300 mg/d for the following 3 d. All women found to have helminth eggs in their stool sample at the pregnancy clinic visit were treated with a single 400-mg dose of albendazole when they returned for a second clinic visit 3 mo postpartum. However, women with a hemoglobin concentration of <70 g/L who were also infected with hookworms were immediately given anthelminthic treatment if they were in the second or third trimester of pregnancy.
The study protocol was reviewed and approved by the Nepal Health Research Council in Kathmandu, Nepal, and the Committee on Human Research at the Johns Hopkins School of Hygiene and Public Health in Baltimore, MD.
Data analysis.
Our analytic approach to the iron status data involved descriptions of anemia and iron deficiency and their causes. First, we estimated the prevalence and severity of anemia, defined by hemoglobin concentration, and of iron deficiency, defined by serum ferritin and EP concentrations. Second, iron deficiency was examined as a cause of anemia. Finally, we investigated other risk factors as causes of anemia and iron deficiency.
Multiple hemoglobin cutoffs were examined to explore the possibility
that some risk factors might be associated with milder anemia and
others might be associated with more severe anemia. This is an
important possibility because the relationship of anemia to health
outcomes depends on the severity of anemia. Anemia was defined as
hemoglobin of <110 g/L, and moderate to severe anemia was defined as
hemoglobin of <90 g/L (World Health Organization, UNICEF and UNU 1998
). We defined severe anemia as hemoglobin of <80 g/L
because only 14 women (4.2%) had values below the more conventional
cutoff of 70 g/L.
Serum ferritin and EP concentrations were skewed to high values and
were log-transformed for analysis. Serum ferritin concentrations
were extremely low in this population, and therefore we chose a
relatively low cutoff of 10 µg/L to define depleted iron stores
(Levin et al. 1993
, Romslo et al. 1983
).
Iron-deficient erythropoiesis was defined as EP of >70 µmol/mol
heme (World Health Organization, UNICEF and UNU 1998
).
Iron deficiency was defined as either serum ferritin of <10 µg/L or
EP of >70 µmol/mol heme, and iron deficiency anemia was defined as
the presence of iron deficiency with hemoglobin of <110 g/L.
Low serum retinol was defined as <1.05 µmol/L. Parasitic infections were categorized according to their severity and relationship to iron status. Parasite densities for P. vivax malaria and T. trichiura were uniformly low, so these data are presented as present or absent. For A. lumbricoides and hookworm infections, standard cutoffs were used to characterize the population. However, because no relationship was found between A. lumbricoides worm burden and iron status, data on this infection were dichotomized for multivariate analyses. Hookworm egg counts were linearly related to all three iron status indicators, so data were analyzed in increasing 1000 eggs/g feces categories for multivariate analyses.
For dichotomous risk factors, differences in hemoglobin, EP and serum
ferritin concentrations were compared by Student’s t
test, and differences in anemia and iron deficiency were compared by
the 
2 test. Fisher’s exact test was used instead of the
2 test in cases where the number of subjects in two or
more categories was less than five. Linear trends for continuous and
categorical iron status variables were tested by linear regression and
by the 2 test for trend, respectively. To investigate
iron deficiency as a risk factor for anemia, relative risks with 95%
confidence intervals (CI) were calculated for indicators of iron
deficiency with prevalence rather than incidence data (Kahn and Sempos 1989
). Statistical significance was defined as a
P-value of <0.05.
Adjusted odds ratios (AOR) and 95% CI for anemia, iron-deficient
erythropoiesis and depleted iron stores were estimated from logistic
regression models, and adjusted mean differences in hemoglobin, EP, and
serum ferritin concentrations were estimated from linear regression
models. All regression models included variables for intensity of
hookworm infection, P. vivax malaria parasitemia and low
serum retinol regardless of statistical significance. Trimester of
pregnancy was retained in all models because iron status and serum
retinol were strongly associated with gestational age. Socioeconomic,
demographic, anthropometric and other parasitologic variables were
retained in models only if statistically significant (P
< 0.05). Interactions among hookworm infection, P.
vivax malaria parasitemia and low serum retinol were
investigated by stratified bivariate analyses and by inclusion of
interaction terms in multivariate regression models. Interaction terms
were retained in models if their P-value was 
0.15.
To estimate the maximal proportion of anemia in the population that
might be prevented by the elimination of a risk factor, we calculated
the attributable fractions of all anemia and moderate to severe anemia
for each risk factor. Attributable fraction is the same as attributable
risk (Kahn and Sempos 1989
) except prevalence ratios are
used instead of risk ratios. Adjusted prevalence ratios were calculated
from a conversion formula using AOR (Osborn and Cattaruzza 1995
). These were then used to calculate attributable fractions
with a formula that produces valid estimates when adjusted prevalence
ratios are used (Kleinbaum et al. 1982
, Rockhill et al. 1998
). Data were analyzed using SAS software (SAS
Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONRisk factors for anemia...Implications for control of...REFERENCES |
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Women ranged in age from 15 to 40 y, with 64% between 20 and
29 y (Table 1
). Few women were literate, and only 29% came from a household in which
a radio was owned. Approximately one fifth of the women smoked
cigarettes, but alcohol consumption was rare. Twenty-one percent of
the women were nulliparous, and 36% had given birth to three or more
children. Two thirds of the women visited the clinic during the second
trimester of pregnancy (13–24 wk) with the other third split between
the first and third trimesters. The women were stunted and thin. The
height and MUAC of the study sample were 149.9 ± 5.4 and 22.3
± 1.7 cm, respectively. The vitamin A status of women was poor,
with more than half having a serum retinol concentration of <1.05
µmol/L. Only one woman reported the consumption of iron supplements
during the past month.
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. T. trichiura
infection was rare (5.3%). P. vivax malaria parasitemia was
present in 19.8% of women, was uniformly low and was not associated
with other infections, and its prevalence did not differ by nulliparity
(20.3 versus 19.8%, P = 0.93). The prevalence of
parasitic infections did not vary significantly by trimester of
pregnancy.
Anemia was prevalent, and the iron status of the study subjects was
poor. Seventy-three percent of the women were anemic, with 19.9%
having moderate to severe and 7.4% having severe anemia (Table 2
). Iron-deficient erythropoiesis was present in 66.0% of the women,
and 58.5% had depleted iron stores. The prevalence and severity of
anemia and iron deficiency were progressively greater in women examined
later in pregnancy (Table 2)
. Of women examined during the third
trimester, 14.3% were severely anemic and 79.7% had depleted iron
stores.
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The overall prevalence of iron deficiency was 80.6%; 64.0% had iron
deficiency anemia, which accounted for 88% of anemia in this
population. The relative risk of anemia associated with elevated EP was
1.41 (95% CI 1.19–1.68), and that associated with low serum ferritin
was 1.50 (1.28–1.76). When iron deficiency was classified by either or
both EP and serum ferritin, there was an increasing linear trend in the
prevalence of anemia and of moderate to severe anemia with increasing
severity of iron deficiency (Fig. 1
). These data indicate that iron deficiency was strongly associated with
both mild and moderate to severe anemia in this population.
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Nulliparous women had a lower prevalence of anemia (62.0 versus 75.7%,
P < 0.05), but the prevalence of moderate to severe
anemia did not differ by parity (19.7 versus 20.2%, P
= 0.94). The prevalence of anemia appeared higher among women
20 y old than among women < 20 y old (74.7
versus 63.1%, P = 0.06). Anemia was not associated
with maternal weight, height or MUAC, but women with moderate to severe
anemia had significantly smaller triceps and subscapular skinfold
measurements (triceps 7.9 ± 2.6 versus 8.7 ± 2.5 mm,
P < 0.05; subscapular 11.4 ± 3.9 versus 12.5
± 3.6 mm, P < 0.05). Depleted iron stores were
associated with significantly higher maternal weight (44.1 ± 5.4
versus 42.6 ± 5.1 kg, P < 0.05). Among
socioeconomic characteristics, both literacy and radio ownership were
inversely associated with anemia but not with indicators of iron
deficiency (data not shown).
Risk factors for anemia and iron deficiency: unadjusted analyses.
In bivariate analyses, hookworm infection was the most important
contributor to anemia and iron deficiency in this population. There was
a strong linear trend toward worse values for all three iron status
indicators by hookworm intensity of infection (Table 3
). For example, hemoglobin concentration decreased from 106 g/L among
uninfected women to 90 g/L among women with moderate to severe
infection (P < 0.0005). Hookworm infection intensity
was strongly associated with anemia at various levels of severity. At
2000 eggs/g of feces, the prevalence of moderate to severe anemia was
four times that of uninfected women, and severe anemia was 12 times
more prevalent. The prevalence of elevated EP and of low serum ferritin
concentrations also increased with increasing hookworm infection
intensity. Neither A. lumbricoides nor T.
trichuris infection was related to any iron status indicator.
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. There also was evidence that
malaria was associated with iron deficiency. Serum ferritin
concentration was lower (P < 0.05) among women with
P. vivax malaria parasitemia, and the proportion of women
with low serum ferritin tended to be higher.
Low serum retinol concentration was strongly associated with all three
iron status indicators in this cohort (Table 3)
. Women with low serum
retinol were more likely to be anemic, to have iron-deficient
erythropoiesis and to be iron depleted.
Risk factors for anemia and iron deficiency: multivariate analyses.
AOR for anemia and iron deficiency, calculated from multivariate
logistic regression models, are presented in Table 4
. As in the bivariate analyses, hookworm infection was the strongest
predictor of poor iron status for all three indicators. The strongest
risk factor for anemia varied by the severity of the anemia being
modeled. For example, the risk of anemia associated with hookworm
infection increased as hemoglobin cutoffs for more severe anemia were
used. In contrast, low serum retinol concentration was most strongly
associated with mild anemia. The relative odds of anemia by any cutoff
were approximately doubled with P. vivax malaria
parasitemia, but the 95% CI included 1. In stratified
analyses, malaria was strongly associated with moderate to severe
anemia among the small proportion of women not infected with hookworms
(25.0 versus 2.9%, P = 0.08 by Fisher’s exact test).
However, the small numbers in some of the subgroups did not allow for
adequate analysis of this interaction.
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1000 eggs/g of feces was
2 compared with women without hookworm infection, but this
association was not statistically significant because the CI for the
AOR included 1.
In multivariate regression models of iron status indicators as
continuous variables, hookworm infection intensity remained the
strongest predictor of all three iron status indicators. The bivariate
associations of hookworm infection intensity with hemoglobin and serum
ferritin concentrations (Table 3)
were essentially unchanged by
adjustment for other risk factors and maternal characteristics. Serum
retinol of <1.05 µmol/L and P. vivax malaria parasitemia
were each associated with a hemoglobin decrement of 5 g/L after
adjustment. When the hemoglobin model was run with serum retinol as a
continuous variable instead, a 1-µmol/L increase in retinol was
associated with a 9-g/L increase in hemoglobin (P < 0.001). In the multivariate model for EP, there was a trend of
progressively larger increments in EP with increasing intensity of
hookworm infection, and the increment associated with a hookworm egg
count of 2000 eggs/g of feces was significant (P < 0.05).
Interaction between low serum retinol concentration and P.
vivax malaria was found in both the hemoglobin and EP linear
regression models (P-value for retinol x malaria
interaction terms: hemoglobin, 0.06; EP, 0.07). Malaria was associated
with a much larger hemoglobin decrement (-10.6 g/L, P
< 0.005) among women with low serum retinol than among those with
serum retinol of 1.05 µmol/L (-1.3 g/L, P = 0.70).
Conversely, low serum retinol was associated with a larger decrement in
hemoglobin (-12.3 g/L, P < 0.01) among women with
malaria parasitemia than among uninfected women (-2.9 g/L,
P = 0.18). The interaction of these two risk factors
for EP was similar in type and magnitude to the interaction for
hemoglobin.
Attributable fractions for the causes of anemia (Table 5
) were calculated to assess their importance at a population level.
Approximately 40% of all cases of anemia and 85% of all cases of
moderate to severe anemia were attributable to iron deficiency, making
it the most important cause of anemia identified in this population.
Among the other risk factors, hookworm infection was the next most
important contributor to anemia, with more than half of all cases of
moderate to severe anemia attributable to hookworm infection. Vitamin A
deficiency was also an important contributor to anemia at the
population level, with attributable fractions of 14 and 29% for all
cases of anemia and moderate to severe anemia, respectively. Although
the attributable fraction for all cases of anemia was small, 16% of
cases of moderate to severe anemia were attributable to P.
vivax malaria.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONRisk factors for anemia...Implications for control of...REFERENCES |
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Anemia is a serious public health problem among pregnant women in the
rural plains of Nepal (World Health Organization, UNICEF and UNU 1998
). The observed prevalence of 73% was nearly identical to
a South Asian regional anemia prevalence estimate of 75% among
pregnant women, the highest in the world (World Health Organization 1992
). In India, 88% of pregnant women are anemic
(World Health Organization, UNICEF and UNU 1998
). A
survey of pregnant women in Bihar State, India (across the border from
Sarlahi district, Nepal), found an anemia prevalence of 81%
(Agarwal et al. 1987
).
Our findings provide a population-based picture of iron status
during pregnancy among rural South Asian women living in conditions of
chronic malnutrition and endemic infections. Iron deficiency appeared
to be the dominant cause of anemia, especially moderate to severe
anemia. Eighty-five percent of cases of moderate to severe anemia
were attributable to iron deficiency. However, 45% of
non–iron-deficient women were anemic, suggesting that other causes of
anemia are present in this population. World Bank prevalence estimates
of iron deficiency in the general population were 69% for India but,
surprisingly, only 24% for Nepal (Levin et al. 1993
).
Our estimate of 81% in pregnant women suggests that the prevalence in
Nepal has been underestimated and is, at least in the terai region of
the country, comparable to that of other areas of South Asia.
Our findings are indicative of progressive iron depletion during pregnancy. Hemoglobin, EP and serum ferritin concentrations were indicative of poor iron status overall and were worst in the third trimester, suggesting that the high prevalence of anemia was caused by underlying iron deficiency. The extremely low serum ferritin concentrations observed in this study are evidence that rural Nepalese women enter pregnancy with depleted iron stores.
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Risk factors for anemia and iron deficiency |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONRisk factors for anemia...Implications for control of...REFERENCES |
|---|
We previously reported that hookworm infection is endemic among women
in the rural plains of Nepal (Navitsky et al. 1998
), and
the present results suggest that it is responsible for 54% of cases of
moderate to severe anemia during pregnancy. Hookworm infection was
associated with all three indicators of iron status in a
density-dependent manner. Mature hookworms cause intestinal
bleeding, leading to fecal blood loss proportional to the intestinal
worm burden (Roche and Layrisse 1966
). The intensity of
hookworm infection that causes iron deficiency anemia varies according
to the species and the iron status of the population. Hookworms in this
study sample were exclusively A. duodenale (Navitsky et al. 1998
), the hookworm species that causes the greatest
blood loss (Pawlowski et al. 1991
), and iron deficiency
was severe. Thus, hookworm infection exacerbated iron deficiency and
anemia in this setting.
Hookworm infection has been established as a strong predictor of iron
deficiency and anemia in other populations (Hopkins et al. 1997
, Layrisse and Roche 1964
, Roche and Layrisse 1966
, Stoltzfus et al. 1997
), but few
studies have examined these relationships in pregnant women. Hookworm
infection was associated with severe but not moderate anemia among
women receiving antenatal care at a hospital in Kathmandu, Nepal
(Bondevik et al. 2000
). A Kenyan study of anemia in
pregnancy reported that women with hookworm egg counts of 1000 eggs/g
feces had a lower hemoglobin concentration than women with <1000
eggs/g feces (Shulman et al. 1996
). A single course of
anthelminthic therapy in addition to iron-folate supplementation
significantly increased hemoglobin concentrations and improved iron
status (serum ferritin and EP) in pregnant Sri Lankan plantation
workers, suggesting that hookworm infection caused iron deficiency
anemia in that population (Atukorala et al. 1994
).
However, allocation to anthelminthic therapy was nonrandom and the
prevalence and intensity of hookworm infection were not assessed.
Malaria.
In Sarlahi, where the prevalence of malaria parasitemia was relatively
low (20%) and only P. vivax was identified, malaria
parasitemia more than doubled the odds of moderate to severe anemia
after control for other causes and was associated with anemia in both
nulliparous and parous women. This is one of the few
community-based studies to identify P. vivax malaria as
a contributor to pregnancy anemia. A clinic-based study in India
recently reported that pregnant women infected with P. vivax
malaria were significantly more anemic than noninfected pregnant
control subjects (Singh et al. 1999
). The hemoglobin
decrement reported among P. vivax--infected patients in that
study (-10 g/L) was larger than the decrement among infected women in
our study (-5 g/L, see Table 3
) and may be explained in part by
differences in disease severity. Malaria-infected women in the
Indian study were initially identified by clinical symptoms rather than
by screening all women, as was done in our cohort study, and therefore
represent only the most severe, symptomatic cases.
Studies of P. falciparum malaria have found it to be an even
stronger contributor to pregnancy anemia, particularly among
nulliparous women (Brabin et al. 1990
, Fleming 1989
, Matteelli et al. 1994
, McGregor 1984
, Shulman et al. 1996
), suggesting that the
epidemiology of malaria and anemia in pregnant women may differ by
species of malaria parasite. For example, P. vivax parasites
only infect reticulocytes (<2% of red blood cells) rather than
invading red blood cells of all ages, and their erythrocytic asexual
phase in the human host remains in peripheral circulation rather than
entering capillaries of internal organs. These differences result in
heavier parasitemia with P. falciparum associated with
serious complications and even death (Gilles and Warrell 1993
, Markell et al. 1992
). However, unlike
P. falciparum malaria, relapses of P. vivax
malaria can occur for years after an initial attack, leading to further
red cell destruction and worsening anemia (Gilles and Warrell 1993
, Markell et al. 1992
). South Indian men
infected with P. vivax malaria showed a progressive decrease
in hemoglobin concentration, packed cell volume and red blood cell
level with increasing number of malaria attacks, and this relationship
held across all levels of parasitemia (Selvam and Baskaran 1996
).
Vitamin A deficiency.
The prevalence of vitamin A deficiency in this sample was very high.
Twenty-one percent of women had a serum retinol concentration of
<0.70 µmol/L, and 54% had a serum retinol concentration of <1.05
µmol/L, virtually the same as previously reported in other concurrent
studies in the same population (Christian et al. 1998b
).
Women with a low serum retinol concentration were more than twice as
likely to be anemic compared with those with a higher serum retinol
concentration, suggesting that vitamin A deficiency decreases
hemoglobin synthesis. Numerous studies that examined the effect of
vitamin A deficiency on iron status have found an association between
serum retinol and hemoglobin concentrations in pregnant women
(Bondevik et al. 2000
, Suharno et al. 1992
), adolescent girls (Ahmed et al. 1996
) and
children (Mejía et al. 1977
, Mohanram et al. 1977
, Wolde-Gebriel et al. 1993
).
Suharno et al. (1992)
and Ahmed et al. (1996)
found 4- to 10-g/L increases in hemoglobin associated
with a 1-µmol/L increase in serum retinol concentration in
multivariate linear regression models adjusted for confounders. When we
adjusted for other risk factors, we found a relationship of similar
magnitude between serum retinol and hemoglobin (see Results).
Randomized trials to examine the effect of vitamin A supplementation on
iron status have reinforced the findings from observational studies. A
single, massive dose of vitamin A significantly increased hemoglobin
among vitamin A–deficient Thai children (Bloem et al. 1990
) and among Indonesian children who were both vitamin A
deficient and anemic (Semba et al. 1992
). In a
randomized, placebo-controlled trial among anemic Guatemalan
children, daily vitamin A supplements for 2 mo increased hemoglobin
concentration by 9 g/L compared with an increase of 3 g/L in the
placebo group (Mejía and Chew 1988
). The
consumption of vitamin A–fortified monosodium glutamate increased the
hemoglobin of Indonesian children by 10 g/L after 5 mo compared with no
change among control children (Muhilal et al. 1988
). A
randomized, placebo-controlled trial of vitamin A and iron
supplementation among pregnant Indonesian women found that 2 mo of
daily vitamin A supplementation significantly increased the hemoglobin
concentration and reduced the prevalence of anemia by 23%
(Suharno et al. 1992
). Among women who received both
vitamin A and iron, the positive effect on hemoglobin was even greater,
and anemia was almost completely eliminated.
We observed a significant interaction of serum retinol and P.
vivax malaria on hemoglobin and EP. These findings suggest a
synergistic negative effect of vitamin A deficiency and malaria
parasitemia on erythropoiesis. However, the mechanism of this
interaction is unclear. Vitamin A deficiency may inhibit erythropoiesis
directly (West and Roodenburg 1992
) or through
inhibition of iron mobilization or transport (Bloem et al. 1989
, Wolde-Gebriel et al. 1993
). Malaria
attacks hemolyze both infected and uninfected red cells, and the immune
response of the body to infection results in further red cell
destruction and progressive anemia due to phagocytosis (Markell et al. 1992
).
|
Implications for control of anemia and iron deficiency |
|---|
|
TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONRisk factors for anemia...Implications for control of...REFERENCES |
|---|
, World Health Organization, UNICEF and UNU 1998
) and possibly throughout the reproductive years to build
up the iron stores necessary to meet the high iron demands of pregnancy
and ubiquitous infections.
Anthelminthic therapy is inexpensive and is safe during pregnancy after
the first trimester (World Health Organization 1996
).
The World Health Organization recommends anthelminthic therapy for
women to control hookworm infection in areas in which the prevalence of
infection is >20–30% and anemia is prevalent (World Health Organization 1996
). The more severe anemia attributable to
malaria may also be reduced by antimalarial chemoprophylaxis during
pregnancy, as has been demonstrated among primigravidae in several
studies of P. falciparum malaria (Bouvier et al. 1997
, Fleming et al. 1986
, Gilles et al. 1969
, Greenwood et al. 1989
, Mutabingwa et al. 1993
, Nosten et al. 1994
). However,
chemoprophylaxis did not affect hemoglobin concentrations in trials
conducted in areas of lower malaria prevalence (Hamilton et al. 1972
, Jackson and Latham 1982
), and its impact
is not known when only P. vivax malaria is present.
Finally, improving the vitamin A status of vitamin A–deficient
pregnant women in addition to iron supplementation may reduce the risk
of mild anemia. Vitamin A supplementation of women before or during
pregnancy, or both, may be an effective intervention with multiple
benefits for the health and nutritional status of women
(Christian et al. 1998a
, West et al. 1999
). Our study was conducted as part of a randomized trial of
vitamin A and ß-carotene supplementation of women of childbearing
age, which will allow us to examine the treatment effect of
supplementation on anemia and iron deficiency. Efforts should be made
to prevent pregnancy anemia and its damaging consequences using an
appropriate mix of interventions that address the multiple causes of
anemia and iron deficiency in the population.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
3 Abbreviations used: MUAC, mid-upper arm circumference; AOR, adjusted odds ratio; CI, confidence interval; EP, erythrocyte protoporphyrin; LMP, last menstrual period.
Manuscript received February 14, 2000. Initial review completed April 28, 2000. Revision accepted June 27, 2000.
|
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K. M Rasmussen and R. J Stoltzfus New evidence that iron supplementation during pregnancy improves birth weight: new scientific questions Am. J. Clinical Nutrition, October 1, 2003; 78(4): 673 - 674. [Full Text] [PDF]
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R. W. Steketee Pregnancy, Nutrition and Parasitic Diseases J. Nutr., May 1, 2003; 133(5): 1661S - 1667. [Abstract] [Full Text] [PDF]
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M. W. Bloem, L. Kiess, and R. Moench-Pfanner Process Indicators for Monitoring and Evaluating Vitamin A Programs J. Nutr., September 1, 2002; 132(9): 2934S - 2939. [Abstract] [Full Text] [PDF]
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S. A. Tanumihardjo Vitamin A and Iron Status Are Improved by Vitamin A and Iron Supplementation in Pregnant Indonesian Women J. Nutr., July 1, 2002; 132(7): 1909 - 1912. [Abstract] [Full Text] [PDF]
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