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Departments of Nutrition, Biostatistics and Epidemiology, Harvard School of Public Health, Boston MA, 02115, and the * Departments of Community Health and Obstetrics and Gynecology, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania
2To whom correspondence and reprint requests should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • anemia • iron deficiency • HIV • pregnancy • Tanzania
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and
maternal morbidity and mortality in developing countries
(Koblinsky 1995
, Schwartz and Thurnau 1995
). Infection with human immunodeficiency virus
(HIV)3
during pregnancy may be associated with an increased risk of
anemia-related maternal death in developing country settings due to
increasing severity of anemia or to the combined effects of anemia and
other infections (McDermott et al. 1996
). Anemia also
has been associated with progression of HIV disease (Moore 1999
) and increased risk of preterm delivery (Murphy et al. 1986
, Scholl et al. 1992
). Preterm delivery
is a risk factor for vertical transmission (John and Kreiss 1996
, Minkoff et al. 1995
).
In Dar es Salaam, Tanzania, studies have consistently reported a
prevalence of anemia [hemoglobin (Hb) < 110 g/L] of ~60%
among women making arrangements for antenatal care (Massawe et al. 1996
and 1999a
). Anemia was noted as the immediate cause of
>20% of maternal deaths and was an important contributing cause to an
additional 18% of deaths to mothers who delivered at Muhimbili Medical
Center, the largest teaching and referral hospital in Dar es Salaam,
Tanzania (Justesen 1985
).
Recent studies in East Africa have reported associations between anemia
and HIV infection (Steketee et al. 1993
, Zucker et al. 1994
), but these data were not stratified by severity of
disease; thus, it is not clear whether an association exists between
anemia and asymptomatic HIV infection. Most studies from developed
countries show that the prevalence of HIV-associated anemia, due to
autoimmune reactions, drug reactions or impaired erythropoiesis,
increases as HIV disease progresses (Doweiko 1993
,
Zon et al. 1987
). In populations with a high risk of
exposure to infectious diseases, particularly malaria, the vicious
cycle of infection, impaired immunity and anemia may result in a
stronger association between HIV infection and anemia at earlier stages
of the disease. Thus, the epidemiology of anemia among HIV-infected
women in developing countries is likely to be quite different from that
in more developed countries. In these settings, anemia may be
associated with hastened progression of HIV infection. A recent review
of the literature showed no published studies on the epidemiology of
anemia and HIV infection among pregnant women. The objective of this
paper was to determine the prevalence of anemia among HIV-infected
pregnant women in their second trimester in Dar es Salaam, Tanzania,
and to identify risk factors that were associated with anemia.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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From April 1995 until July 1997, 1083 HIV-infected pregnant women
were enrolled in an ongoing randomized, controlled, double-blind
clinical trial designed to examine the effect of vitamin
supplementation on perinatal transmission of HIV infection and
progression of disease. Detailed methods are described elsewhere
(Fawzi et al. 1999
). In brief, HIV-positive pregnant
women were recruited at one of four district hospitals in Dar es
Salaam. After post-test counseling, consenting women who were <27
completed weeks of gestation (from last menstrual period) were
randomized and followed during pregnancy, delivery and at the Muhimbili
Medical Center in the city.
At the enrollment visit, specimens were collected to determine Hb, T-lymphocyte count (CD4, CD8, CD3 subsets), and infection with Plasmodium falciparum malaria, intestinal helminths (hookworm, Trichuris trichiura, Strongyloides stercoralis, Ascaris lumbricoides) or Schistosoma hematobium. Women were interviewed by trained (nurse) research assistants to obtain information about age, pregnancy history, socioeconomic status, morbidity during pregnancy and self-reported geophagia (pica) behavior, which was defined as eating clay soil during their pregnancy.
Laboratory methods.
Anemia was defined as Hb < 110 g/L and severe anemia was defined
as Hb < 85 g/L, according to the national cut-off point for
referral to the district level in Tanzania (Massawe et al. 1999a
). Venous blood was collected into EDTA vacutainers for
hematological investigations, thick and thin blood films for
parasitology, and T-lymphocyte counts. Stool samples were collected
from patients who were instructed to provide a stool without
contamination with water or urine. Designated senior laboratory
technicians within the Departments of Hematology and Parasitology of
the Central Pathology Laboratory of the Muhimbili Medical Center were
assigned to examine all specimens from this study. Laboratory supplies
and reagents were provided by the study when required.
During the early part of the study, hemoglobin was measured using a CBC5 Coulter Counter (Coulter Corporation, Miami, FL), but due to machine breakdown, measurement methods of hemoglobin were changed to the cyanmethaemoglobin method using a Colorimeter (Corning, Corning, NY). Erythrocyte sedimentation rate (ESR) was determined using the Westergren method.
To obtain an estimate of the proportion of women with characteristics
suggestive of iron deficiency, folate deficiency or other causes of
anemia, thin blood films with Leishman’s stain were prepared for red
blood cell morphology. Cell characteristics (i.e., anisocytosis,
poikilocytosis, hypochromasia, hyperchromasia, microcytosis,
macrocytosis, normochromic and normocytic) were classified into five
levels of severity coded as "absent," "+," "++," "+++"
and "++++." Each level corresponds to the proportion of cells
observed in a specified field that exhibit certain characteristics,
such as hypochromasis, microsytosis and macrocytosis. Thus, absent
means that no cells of a certain characteristic were seen in the field;
+ indicates that less than one fourth of the cells in the field are
abnormal; ++ indicates that one fourth to one half are abnormal; +++
indicates one half to three fourths of cells are abnormal; and ++++
indicates that more than three fourths are abnormal. A classification
system based on red cell morphology was used for describing the level
of suggested iron deficiency in this population. Iron deficiency was
defined broadly as any sign of hypochromasia, but was further
subdivided into three levels. The first level included only women with
severe ("++" or higher) hypochromasia and microcytosis; the second
level included women with less severe hypochromasia and microcytosis;
and the third level included women with hypochromasia but no
microcytosis. Women with normocytic and normochromic cells (with no
anisocytosis or hypochromisia) were classified as "normal"; the
remaining women with some abnormal cell characteristics were classified
into an "other" group (Dacie and Lewis 1991
).
Infection with P. falciparum malaria parasites was
identified and quantified using both thin and thick blood films with
Giemsa staining for each patient (virtually all malaria infection was
P. falciparum). Levels of parasite density per cubic
millimeter (mm3) were estimated from counting the number of
parasites in 300 white blood cells and assuming a leukocyte count of
8000/mm3 of blood (Molineaux et al. 1988
).
Stool specimens were first examined macroscopically for general characteristics (pus, mucus, blood) and worms. Stools were then prepared for microscopic examination using saline wet mount for detection of eggs, larvae protozoan trophozoites and cysts, followed by iodine wet mount for identification of cysts. The formalin-ether concentration technique was used for further identification of eggs, larvae and cysts. Helminth infection was classified as present or absent.
Absolute T-lymphocyte subset counting of CD4+, CD8+ and CD3 cells
was done using the FACScount system (Becton-Dickinson, San Jose, CA) by
trained technicians working in the Department of Microbiology of the
Muhimbili University College of Health Sciences. Serum retinol levels
were measured using HPLC (Bieri et al. 1979
) on plasma
samples, which were stored in -70°C freezers until shipment to
Harvard University for laboratory analysis.
Data management and statistical analysis.
A total of 1064 women had complete baseline hemoglobin measurement and
were included in this analysis. Data were summarized using frequency
tables and cross-tabulations between selected risk factors and the
presence of anemia. Univariate logistic regression models were used to
estimate the unadjusted odds ratios (OR) between risk factors and
anemia and to determine their statistical significance. The Wilcoxon
rank sum test was used to test for univariate associations between
continuous variables of interest and anemia. Variables with a
P-value 
0.20 were introduced into multivariate
logistic and linear regression models (SAS/STAT, Version 6.12, SAS
Institute, Cary, NC) to estimate the independent OR describing the
association of risk factors with severe anemia (Hb < 85 g/L) and
anemia (Hb <110 g/L). The method of hemoglobin measurement was
included in all models as a dichotomous adjustment variable equal to
method 1 (X1 = 1) or method 2
(X1 = 0). Confounding due to
gestational age was controlled by its inclusion in all models as a
continuous variable (days since last normal menstrual period). Adjusted
OR describing the association between anthropometric measurements
[body mass index (BMI), mid-upper arm circumference (MUAC) and
weight] and anemia were estimated in separate models to avoid problems
of colinearity. Variables were retained in the final adjusted
regression models if they had a P-value 0.10, or
if they affected the estimates of the other variables in the model.
Values are means ± SD or percentages.
Ethical clearance.
The data collected for this analysis were collected as part of a larger trial of vitamin supplementation conducted in Dar es Salaam as a collaboration between Muhimbili University College of Health Sciences (MUCHS) and Harvard University School of Public Health. The study protocol was approved by the Research and Publications Committee of MUCHS, the Ethical Committee of the National AIDS Control Program of the Tanzanian Ministry of Health and the Institutional Review Board of the Harvard School of Public Health.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.
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Descriptive characteristics of hematological indices, T-lymphocyte
counts, and serum retinol levels at baseline for the whole sample and
by levels of anemia defined by Hb are presented in Table 2
. Using WHO criteria, the overall prevalence of anemia during pregnancy,
defined as Hb < 110 g/L, was 83%, and 7% of the women had Hb
< 70 g/L. Twenty-eight percent of the women had Hb < 85
g/L. The mean Hb levels of women in the sample were 94.2 g/L
(SD = 16.8). Mean CD4+ cell count and serum retinol levels
were significantly correlated with Hb [Spearman correlation
(rs) = 0.10; P = 0.002 and rs = 0.20; P
= 0.0001, respectively], but CD8+ cell count was not associated
with hemoglobin (rs = 0.003;
P = 0.92; Table 2
).
|
).
|
. After adjusting for the effects of other variables in the model, the
only remaining background characteristics associated with severe anemia
were maternal age < 30 y, and having no education compared
with some education. Participants with a BMI < 19
kg/m2 were more than three times as likely to
have severe anemia compared with women whose BMI was 
24
kg/m2. Similar increased odds of severe anemia
were observed for other measures of anthropometric status (weight
< 50 kg; MUAC < 22 cm). Women who reported geophagous
behavior during the current pregnancy were more than twice as
likely to be severely anemic compared with women without such
behavior (Table 3)
.
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500/µL (Table 4)
. When the ESR was entered into the full model (as a categorical
variable), ESR rates > 16 mm/h were significantly and
progressively associated with severe anemia.
The only independent predictors of anemia defined as Hb < 110 g/L
were geophagia, hookworm infection, serum retinol levels < 0.70
µmol/L compared with women with serum retinol levels
> 1.05 µmol/L, and CD4+ cell count < 200/µL. The ESR was also strongly associated with anemia
in a separate model controlling for all other variables of interest. A
woman’s age, educational level, anthropometric status and level of
infection with malaria were not significantly associated with Hb
< 110 g/L in either the crude or adjusted analysis (Table 4)
.
A multiple linear regression model was used to determine the estimated magnitude of associations between selected exposure variables and hemoglobin levels (g/L). Lack of education was associated with hemoglobin levels > 6 g/L lower [95% confidence interval (CI): -10.64, 0.01]. Geophagia was associated with nearly 5 g/L lower hemoglobin levels (95% CI: -8.20, -2.44). Low serum retinol levels (<0.70 µmol/L) were associated with hemoglobin levels that were >7 g/L lower (95% CI: -10.84, -4.02), and serum retinol from 0.70 to 1.04 µmol/L was marginally associated with levels that were >3 g/L lower (95% CI: -5.97, 0.41). Malaria parasite density > 1000/mm3 was associated with hemoglobin levels that were >6 g/L lower compared with women with no parasites (95% CI: -10.97, 2.43). CD4+ cell counts < 200/µL were associated with a decrease in hemoglobin of >5 g/L (95%CI: -10.10, -1.24).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study of HIV-infected asymptomatic pregnant women, we found
that 7% of the sample had Hb levels < 70 g/L, and over one
fourth (28%) had hemoglobin levels < 85 g/L, the level at which
referral from peripheral health facilities to a district hospital is
indicated. Overall, 8 of 10 women were anemic (Hb < 110 g/L).
These prevalences were substantially higher than those reported in a
recent study of >2000 pregnant women in Dar es Salaam who were not
screened for HIV infection, i.e., 4% had Hb levels < 70 g/L and
18% had Hb levels < 85 g/L (Massawe et al. 1996
).
The effect of an increased burden of infection on erythropoiesis may
explain the higher level of severe and mild anemia in this population
compared with a general clinic population.
Most of the women with severe anemia had red blood cell characteristics
suggestive of iron deficiency anemia (hypochromasia, microcytosis),
although these data should be interpreted with caution in the absence
of more direct biochemical measures of folate, B-12 and iron status.
Nevertheless, when Nhonoli (1974)
measured serum
ferritin levels of pregnant women in Dar es Salaam 25 years ago, he
reported similar levels of iron deficiency anemia. Furthermore, our
findings are consistent with those of Massawe et al. (1999b)
who found that the majority of anemic women were iron
deficient according to serum ferritin and MCV levels. Peripheral blood
smears of women who were classified as iron deficient according to
standard criteria (e.g., serum ferritin) also showed cells with
hypochromasia and/or microcytosis. Although examination of the red
blood cell characteristics of iron deficiency may be specific, this
method is not very sensitive. Massawe et al. (1996b)
reported that the prevalence of iron deficiency was estimated to be
nearly 80% using serum ferritin, but only 40% using red blood cell
characteristics, and 50% according to MCV. Thus, our results based on
blood morphology may underestimate the prevalence of iron deficiency in
this population. Nevertheless, they are consistent with other studies
of pregnant women in Tanzania. It is noteworthy that the high
prevalence of iron-deficiency anemia has not been reduced over time
and remains the predominant cause of anemia even among HIV-infected
women.
In this population, we did not detect an association between prevalence of severe or moderate anemia or hemoglobin levels and clinical stage of HIV disease. However, women in later stages of HIV infection were underrepresented in this sample; thus, there was little power to detect an association by clinical stage of disease. As expected, there was an association between CD4+ cell counts < 200/µL and anemia. One explanation is that women with low CD4+ cell counts are suffering from chronic infections as a result of impaired immunity and HIV disease progression. Chronic inflammation and infections can lead to impaired erythropoiesis and lower hemoglobin. Alternatively, the morphological evidence pointing to the high level of underlying iron deficiency, likely resulting from poor nutritional status, may also have a causal effect on reducing immunity, as measured by CD4 cell counts.
The association between poor anthropometric status and anemia is not
surprising given the evidence from this and other studies that
iron-deficiency anemia is highly prevalent in this population. In
Tanzania, many people cannot afford foods rich in heme iron, and other
dietary factors or cooking methods may inhibit iron absorption. Low BMI
may also be a measure of wasting that is characteristic of more
advanced HIV disease. It may therefore indirectly reflect the burden of
infection due to HIV, but also poor nutritional intake due to
discomfort or disease, or loss of nutrients from diarrhea. Inadequate
levels of vitamin A, which may be correlated with overall poor
nutritional status and low BMI, may also be a factor that increases the
risk of anemia in this population. The hypothesized mechanism for the
association between anemia and vitamin A is that adequate levels of
vitamin A are required for normal erythropoiesis and sufficient iron
transport (Roodenburg et al. 1996
).
Although the data from this study are cross-sectional, the finding
that vitamin A levels < 0.70 µmol/L were
significantly related to severe anemia are consistent with results from
controlled trials. Suharno et al. (1993)
reported that
anemic pregnant women from a vitamin-deficient Indonesian
population responded better to iron supplementation with vitamin A
compared with iron without vitamin A. Notably, the proportion of women
who became nonanemic after 8 wk of supplementation with vitamin A but
without iron was twice that of the placebo group, with an estimated
independent effect size of vitamin A on hemoglobin reaching 4 g/L for
each unit (µmol/L) increase of vitamin A.
Another explanation, however, is that the observed association between
low serum retinol and anemia is confounded by other factors such as
infection or inflammation. We reported previously that multivitamin
supplementation during pregnancy was related to a 13 g/L increase in
hemoglobin during pregnancy, but that supplementation with vitamin A
alone was not associated with any significant change in hemoglobin
levels (Fawzi et al. 1998
). However, it has been shown
that reductions in serum retinol levels are correlated with elevated
acute-phase protein concentrations despite adequate liver stores of
vitamin A, and that intensity of infection with malaria may be one
particular illness that reduces serum retinol levels (Filteau et al. 1993
). Thus, the association between serum retinol levels
and anemia could be confounded by the presence of other chronic
infections that could not be controlled for in this analysis.
This interpretation is supported by the strong association we observed between the ESR and anemia, even after controlling for CD4 count, malaria infection, hookworm infection and serum retinol levels. The mean ESR in this sample was elevated; this is likely due to several factors unrelated to infected/inflammation that directly increase the ESR such as higher ambient temperature in the laboratory and pregnancy. In addition, a low ratio of red cells to plasma, as measured in the packed cell volume and indicative of many forms of anemia, also elevates the ESR by encouraging rouleaux formation, which accelerates sedimentation. Thus, the association that we observed between ESR and anemia was expected and is likely not to be entirely causal. Nevertheless, the usefulness of ESR as a clinical indicator of infection and inflammation makes the ESR an interesting variable to examine as a risk factor for anemia in this population.
Geophagia was related to a more than twofold increased risk of anemia,
and this association is consistent with the literature, which includes
many reports on the association between geophagia and anemia
(Danford 1982
, Geissler et al. 1998
,
Halsted 1968
). Whether this association is a cause or
consequence of anemia has been debated in the literature. Some have
hypothesized that ingestion of clay or soil actually impairs absorption
of iron or other nutrients, thus having a causal effect on iron
deficiency and anemia; however, studies on this mechanism provide
conflicting evidence (Minnich et al. 1968
,
Talkington et al. 1970
).
One report from Kenya on geophagia during pregnancy found that 56% of
an antenatal clinic population reported eating soil regularly, and that
the median daily intake of soil was estimated to be >40 g
(Geissler et al. 1998
). In Tanzania, a specific type of
hardened clay soil is commonly eaten, and in Dar es Salaam, the clay is
sold openly in the market for human consumption at affordable prices.
Recent discussions of pica, one form of which one is geophagia,
have concentrated on presenting a conceptual framework of pica that
focuses attention on the need to develop consistent definitions of
pica, conduct prevalence studies, identify risk factors for pica,
measure health outcomes associated with pica and formulate
recommendations for treatment and prevention (Lacey 1990
). There is very little research on geophagia in developing
countries, although there are likely to be important public health
implications given its high prevalence and the possible effects of
eating soil or sand on nutritional status or parasitic infection.
Infection with P. falciparum was strongly associated with
anemia, a result that was consistent with findings from other studies
of pregnant women (Bouvier et al. 1997
, Shulman et al. 1996
) and infants (Menendez et al. 1997
).
There is a well-documented association between primiparity and
increased susceptibility to malaria infection, and anemia as a
consequence (Fleming 1989
). In our population, although
the prevalence of malaria was higher among primigravida (23.0%)
compared with multigravida (16.4%), there was no significant
interactive effect between parity and malaria on anemia. It is possible
that we did not observe such an interaction because
pregnancy-specific immunity to malaria among multiparous women is
reduced due to HIV infection, as a study by Verhoeff et al. (1999)
recently suggested.
Tanzanian national policy continues to recommend the use of
chloroquine as the first line of treatment despite research showing
that chloroquine-resistant strains of P. falciparum are
prevalent in Tanzania (Hedman et al. 1986
, Premji et al. 1994
). Consequently, the policy of providing chloroquine
prophylaxis to all pregnant women is not likely to be
cost-effective given the low efficacy and potentially low
compliance with the regimen (Heymann et al. 1990
,
Massele et al. 1997
).
Shulman et al. 1999
showed recently in Kenya that
presumptive treatment of primiparous women for malaria infection with
sulfadoxine-pyrimethamine (SP) once or twice during pregnancy
significantly reduced rates of parasitemia at delivery and severe
anemia. However, similar trials in Malawi found that two doses of
presumptive treatment with SP had no effect on reducing parasitemia at
delivery (Verhoeff et al. 1999
), although two- and
three-dose regimes did improve fetal growth even among
HIV-infected women (Verhoeff et al. 1998
). Another
study in Kenya by Parise et al. (1998)
suggested that
monthly treatment with SP of primigravidae and secundigravidae may be
required among HIV-infected women to reduce the prevalence of
placental malaria at delivery to levels that may be achieved with only
a two-dose regimen among HIV-uninfected women. This compelling
evidence of the benefits of effective malaria control during pregnancy
should be translated into policies for Tanzania. Factors to consider
when developing such policies include the incidence of malaria
infection during pregnancy, prevalence of HIV infection and evidence
that multiparous women, particularly if HIV-infected, are also at
risk of adverse outcomes due to malaria infection.
Severe anemia in our study was not independently associated with
A. lumbricoides and S. stercoralis. In contrast
to other studies, we did not detect an independent association between
infection with hookworm and severe anemia (Stoltzfus et al. 1997
, Weigel et al. 1996
). This suggests that
most women with hookworm in this urban population probably have low
worm burdens and subsequently experience relatively low blood loss. It
is possible that an association with more severe anemia was not
detected because of our assessment of hookworm infection as present vs.
absent, thereby precluding classification of the intensity of
infection.
In conclusion, levels of anemia among pregnant women with HIV infection are very high in Dar es Salaam. In this study, the significant risk factors associated with anemia were anthropometric status, serum retinol levels, geophagia, malaria and CD4+ cell counts. Public health policies aimed at increasing hemoglobin levels should continue to support programs that provide iron supplementation. The risk of anemia secondary to malaria could be reduced through prompt and effective treatment during pregnancy to optimize the chances of an HIV-infected pregnant woman delivering a healthy infant. Further qualitative and quantitative research is required to elucidate the reasons why clay soil is consumed, and the potential risks associated with geophagia in Tanzania. If these cross-sectional correlates indeed turn out to be causal, it implies that factors associated with anemia are largely preventable, and the effects of anemia on maternal health and pregnancy outcomes among HIV-infected and uninfected women could be minimized with the use of cost-effective and technologically feasible public health interventions.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BMI, body mass index; CI, confidence interval; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; HIV, human immunodeficiency virus; MCV, mean cell volume; MUAC, mid-upper arm circumference; OR, odds ratio; SP, sulfadoxine-pyrimethamine.
Manuscript received November 15, 1999. Initial review completed January 6, 2000. Revision accepted March 24, 2000.
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