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Liverpool School of Tropical Medicine, Liverpool, England and University of Amsterdam, Emma Kinderziekenhuis, Academic Medical Centre, Amsterdam, Netherlands;
*
Gadjah Mada University, Yogyakarta, Indonesia; and
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853
3To whom correspondence and reprint requests should be addressed. E-mail: l.j.taylor{at}liverpool.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSDISCUSSIONREFERENCES |
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KEY WORDS: • pregnancy • anemia • mortality • malaria • iron deficiency
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSDISCUSSIONREFERENCES |
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). The worldwide maternal mortality ratio (annual number of
deaths of women from pregnancy-related causes per 100,000 live
births) is estimated to be 390 per 100,00 live births (Abousahr
and Royston 1991
). Most of these occur in developing countries,
where women have a risk of dying in pregnancy and childbirth that is
50–100 times greater than that of women in the developed world
(Starrs 1987
). In the developing world, rates are as
high as 700 per 100,000 live births in many parts of Africa and in some
countries in south Asia. These large differences in risk are related
primarily to differences in available obstetric care for women living
in areas with inadequate antenatal and delivery care facilities.
Harrison (1989)
has championed the arguments for
developing improved pregnancy care to reduce maternal mortality in
developing countries. In reports from Nigeria, he has highlighted the
importance of maternal anemia as a contributory factor to maternal
death (Harrison 1975
, Harrison and Rossiter 1985
). In 1987, international agencies and leaders from 45
countries established the Safe Motherhood initiative with the goal of
reducing half of maternal deaths by the year 2000 (World Bank
1993
). A key component of Safe Motherhood is the eradication of
anemia during pregnancy. The WHO has produced estimates of the global
burden of deaths attributable to anemia (all forms) in women of
reproductive age (Murray and Lopez 1994
). These are
summarized in Table 1
. The total estimate is a minimum of 16,800 and maximum of 
28,000
annually with a greater risk of anemia-related death in younger
women.
|
). For these reasons, most
studies form an inadequate basis for determining how anemia relates
causally to maternal survival in communities, and extrapolation from
hospital delivery data must be considered an approximation that may be
misleading.
Intervention studies with maternal mortality as an outcome measure are
required to determine causality, but these are very difficult to
conduct for both ethical and logistic reasons. For example, there are
very few studies that did not use transfusion as an emergency procedure
in severely anemic women at term (Fullerton and Turner 1962
). If transfusions are taken into account, then
near-miss fatality could be an alternative outcome measured, but
the true risk in such cases remains uncertain. In view of these
difficulties, a number of alternative approaches that independently
assess this risk must be adopted. Consistency between analyses of
severe anemia and poor survival would add credence to the strength of a
causal relationship. Several issues are related to estimating
attributable risk for specific causes of anemia and in quantifying risk
for moderately anemic women because less anemia may still contribute to
death from other causes. Such information would be helpful for
intervention decisions.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSDISCUSSIONREFERENCES |
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Published studies on the relationship between anemia (defined by severity) and maternal mortality were identified using Medline, references in published papers, Cochrane Review issues and personal communications. Unpublished data from Nigeria available in a detailed hospital report by Lawson and Lister were reanalyzed and included in a separate summary of Nigerian data. Studies that included postnatal deaths up to 40 d were included, although in practice few studies reported follow-up data beyond delivery.
Selection of studies for inclusion in the analyses.
Studies included in the review were limited to cross-sectional, longitudinal and case-control studies because no randomized controlled trials were available for analysis. Attention was given to the assessment of possible biases in studies of mixed validity. Studies identified were reviewed with regard to the following factors: maternal age, parity, anemia severity, clinical presentation, gestational age, use of blood transfusion, length of follow-up, etiological diagnosis, laboratory estimation of hemoglobin (Hb)4 or hematocrit, and analytical methods. Hematocrit was converted to a Hb value by dividing by 3 and multiplying by 10. Studies that listed anemia as a direct cause of death were of particular value, permitting the estimate of the total number of maternal deaths attributed to anemia. Data from the WHO compilation of maternal mortality was reviewed and categorized by source (hospital or community), direct or indirect cause of anemia, region and number of studies available. Hemoglobin midpoint values were calculated when the range was available. For other studies, anemia cut-off points were used below which proportional groups of women with anemia were defined.
Analyses.
The definition of maternal death used in this review was based on the
10th revision of the International Classification of Diseases, which
defines a maternal death as the death of a woman while pregnant or
within 42 d of termination of pregnancy, regardless of the
duration and site of the pregnancy, from any cause related to or
aggravated by the pregnancy or its management but not from accidental
or incidental causes (WHO 1992a
).
Maternal deaths were also divided into two groups as follows: 1) direct obstetric deaths, resulting from obstetric complications of the pregnant state (pregnancy, labor and the puerperium), interventions, omissions or incorrect treatment, or a chain of events resulting from any of the above; and 2) indirect obstetric deaths, resulting from previously existing disease or disease that developed during pregnancy and was not due to direct obstetric causes but was aggravated by the physiological effects of pregnancy.
For each of the studies selected, estimates of the relative risks and
their 95% confidence intervals were calculated using established
methods. These were used with prevalence estimates to obtain
population-attributable risk (PAR) of anemia-related maternal
mortality. Several case fatality studies could not be used in the risk
analysis because they did not present mortality data for the
less-anemic subjects in their study population. The formula for PAR
is as follows:
 |
where Prev is the prevalence of anemia of a given severity and RR is the ratio of mortality in the anemic to mortality in the less anemic (referent group).
Methods of estimation.
The following six methods of estimation were adopted: 1) The correlation of maternal mortality rates with maternal anemia prevalence derived from national statistics in the WHO compilation on anemia in the world. 2) The proportion of maternal deaths attributable to anemia. 3) The proportion of anemic women who die (i.e., case fatality estimates) and how this risk varies with anemia severity. 4) PAR of maternal mortality due to anemia. 5) Adolescence as a risk factor for anemia related mortality. 6) Causes of anemia associated with maternal mortality.
Definitions.
Mild anemia was defined as Hb <110 g/L, moderate anemia as <70 g/L and severe anemia as <50 g/L. The 110 g/L cut-off value is based on international convention, whereas the other two cut-off values are commonly used in the literature. The 50 g/L cut-off value is related in part to functional consequences associated with cardiac decompensation.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSDISCUSSIONREFERENCES |
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A detailed compilation of anemia prevalence in women published by WHO
includes estimates of maternal mortality from anemia for nine selected
countries (WHO 1992b
). These estimates range from 27 per
100,000 live births in India to 194 per 100,000 live births in a
hospital-based study in Pakistan to 42 of 44 maternal deaths in
Somalian refugee camps. The cut-off values for defining anemia vary
for these studies as does anemia prevalence in the communities in which
these women live (WHO 1992b
). The WHO tabulation adopts
the international definition for anemia for pregnant women of <110
g/L. The percentage below this value identifies the anemic population,
although no single value will separate all anemic from all nonanemic
women. What is the relationship between these population prevalence
estimates for all-cause anemia and maternal mortality ratios, and
how does this differ between areas with high and low maternal
mortality?
The graph shown in Figure 1
uses data on anemia prevalence from the WHO tabulation of available
information on nutritional anemia in women (WHO 1992b
),
and maternal mortality ratios reported by United Nations
Children’s Fund (1999)
for the years 1990–1997. Anemia
prevalence values for individual countries were selected by using the
following criteria: national data if available, altitude < 2000 m, not a refugee population, survey completed after 1980,
largest available sample size and actual (not estimated) prevalence
available (Table 2
). Anemia refers to Hb values <110 g/L. The correlation between these
two variables is highly significant (Pearson correlation coefficient
0.561, P < 0.001). For evaluations of the goodness of
fit for three models, i.e., linear, quadratic and exponential, the
coefficients of determination were 0.315, 0.424 and 0.411 with
F-values 19.3, 15., and 29.3, respectively, indicating that
the exponential (logarithmic) model fits the data well.
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because confounding and correlates that are based on
country-level information may not necessarily reflect the
relationship at an individual level. There is a strong possibility that
the association may be driven by a large number of data points in one
quadrant of the scatterplot from one region (sub-Saharan Africa) that
has high rates of maternal mortality, anemia and malaria, poor
obstetric care and other confounders. Nevertheless the association is
of interest; it has not been described previously and may provide
insight at national levels for programs designed to reduced maternal
mortality. The prevalence values are related to all-cause anemia and no conclusions can be inferred in relation to iron-deficiency anemia. The WHO compilation separately lists a smaller number of studies that report serum iron concentrations and give values below the norm (<9 µmol/L). Applying the same criteria for selection as for the anemia surveys, 17 studies were available for analysis along with the maternal mortality ratio. A positive correlation was observed that was not significant (Pearson correlation 0.415, P > 0.098).
Few community studies are available that report anemia prevalence in
women and the maternal mortality ratio for large samples from the same
cohort of women. A prospective rural community study in Malawi, in a
malarious area, estimated the maternal mortality ratio as 398 (per
100,000 live births) and found an anemia prevalence (hematocrit <0.25)
in pregnancy of 6.2% for the same cohort (McDermott et al. 1996
).
The proportion of maternal deaths attributable to anemia.
A detailed compilation of reports on the causes of maternal deaths
attributable to anemia is published by WHO (1991)
. This
lists 62 reports from 33 countries for which a proportion is provided
for maternal deaths attributable to anemia. Anemia is listed as a
direct cause of death in 26% of these reports and as an indirect cause
in the remainder. The definitions of anemia vary substantially between
studies and many are based on clinical assessment alone; most (88.5%)
are hospital based, with a high proportion of complicated deliveries.
Anemia was given as a direct cause of between 1 and 46% (mean 10.0%) of maternal deaths in 23 studies. Many reports did not include anemia as a cause of death; most were from Latin America, but 52 studies were from Africa and 45 from Asia. No study lists anemia both as a direct cause for severe cases and indirect cause for others, suggesting that the criteria for attribution depend on the obstetrician’s perception of the relative importance of anemia, with many listing anemia only as an indirect cause. There is little documentation for the criteria used in these clinical judgments.
The average estimates for all-cause anemia-attributable mortality
(i.e., both direct and indirect) from these reports are 6.37, 7.26 and
3.00% for Africa, Asia, and Latin America, respectively. These
regional estimates average considerable variation among countries. They
correspond reasonably well with three community-based studies from
Africa (mean 7.3%) and four community-based studies from Asia
(mean 9.4%) (WHO 1991
). Crude maternal mortality ratios
from anemia can be calculated by using these values and regional
estimates for the maternal mortality ratio. These estimates are given
in Table 3
, which shows the maternal mortality ratio from all-cause anemia and
the days of life lost from maternal anemia. In Africa, this mortality
is fivefold higher than for Latin America. Within these regions,
maternal mortality from anemia varies greatly among countries. For
example, in community studies in Asia, values vary (per 100,000 live
births) from 27 in India and 54 in Bangladesh to 194 in Pakistan and in
Africa from 35 in Senegal to 82 in Kenya (WHO 1991
).
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Global Factbook, only three countries
worldwide listed three or more studies giving values for maternal
deaths attributable to anemia. These are Nigeria, Tanzania and India.
Table 4
shows the summary of data for these countries and illustrates the
widely inconsistent estimates of anemia-attributable mortality
among studies in these selected countries. There are a number of
reasons for this. First, only two of the Indian, one of the Tanzanian
and none of the Nigerian studies were community based. Second,
estimates will vary according to whether maternal deaths reflect
differences in outcome between large tertiary referral hospitals and
smaller district hospitals. Third, risk of death will alter depending
on the prevalence of hemoglobinopathies, malaria and nutritional
deficiency among populations within a country. Four of the Nigerian
studies, for example, selectively reported on maternal deaths
attributed mainly to hemoglobinopathies.
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The relationship of anemia and its correlates can best be examined in
individuals. Acute onset of anemia during pregnancy will greatly
increase the risk of death because this can lead to rapid cardiac
decompensation. When the Hb concentration is < 80 g/L,
compensatory mechanisms fail, lactic acid accumulates and patients
become breathless at rest. Cardiac failure may occur when Hb is < 40 g/L, especially with twin pregnancies or splenomegaly
(Fleming 1989b
), and when anemia is not the primary
cause of death, it may frequently be a contributory factor. The
distinction between anemia as a primary or contributory factor for
death is related to its acute and chronic pattern of onset. Severe
acute anemia can be a primary and rapid cause of death, (e.g., in
Nigeria) related to the acute hemolysis of sickle cell disease
(Lawson 1962
), whereas chronic anemias are considered to
be frequent contributory factors, especially to the consequences of
hemorrhage and infection. Iron-deficiency anemias may contribute to
increased morbidity and mortality by increasing maternal susceptibility
to infection (Brock 1999
). Because there is good
documentation that pregnant women are more susceptible to several
infections (Brabin 1985
), further information is
required to determine how increased susceptibility to injection is
related to nutritional anemia. Increased infection risk could provide a
plausible biological mechanism for increased mortality risk in
moderately anemic women.
How can acute and chronic influences on mortality risk in anemic women
be distinguished, and is there a threshold effect for anemia severity
at which maternal mortality greatly increases? Tables 5
and 6
summarize available data on case fatality in relation to pregnancy
hematocrit or Hb values. Nearly all of these studies are hospital based
and report women dying mainly in the perinatal period. Several provide
no information on exclusions or duration of postpartum follow-up.
The proportion of women treated by transfusion is unclear except for
five studies (Cheng-Chi et al. 1981
, Fullerton and Turner 1962
, Harrison 1975
, Harrison and Rossiter 1985
, Isah et al. 1985
).
Differences in available obstetric care and blood transfusion greatly
influence mortality risk in severely anemic women, and disparity among
findings for individual countries could primarily reflect these
differences. In this context, it is of value that there are seven
studies for comparison from Nigeria alone, three of which are reports
by Harrison and his colleagues (Harrison 1975
and 1982
,
Harrison and Rossiter 1985
). Case fatality fell with
transfusion from 27.3 to 1.7% in women with hematocrit values <0.14.
The Nigerian studies are especially valuable because they allow assumed
midpoints to be calculated for each hematocrit category, and the
results represent findings from large teaching hospitals that are
tertiary referral centers in which adequate obstetric care facilities
should be available. Also at the time these were undertaken, maternal
human immunodeficiency virus (HIV) infection was not a confounder. A
single report from India from a tertiary facility also presents data
that allow a midpoint to be calculated (Table 6)
(Sarin 1995
). The data listed in Table 6
for the non-Nigerian
studies mostly do not allow estimation of Hb midpoints nor provide case
fatality estimates for very severe anemia (Hb <50 g/L).
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|
shows the plot of maternal case fatality against Hb level for studies
from Tables 5
and 6
for which Hb midpoints were available (Hb equals
hematocrit divided by 3 and multiplied by 100). Case fatality ranges
from <1% to >50% and mortality increases with extremely low Hb
levels (<30 g/L). This result is driven by four data points from
Ibadan, Nigeria, in mid-century, with Hb levels <25 g/L. If these
four points are excluded, there is no apparent relationship between Hb
levels and case fatality rates among the remaining data points. For the
studies listed in Tables 5
and 6
, few details are provided on the
etiology of anemia, the relative contribution of acute or chronic
disease, coexisting conditions, exclusions, percentage transfused and
other aspects of obstetric care. These factors can create both positive
and negative confounding. No details on iron-deficiency anemia are
provided, although Llewellyn-Jones (1965)
stated that
aggressive parenteral iron was their main form of therapy.
Fullerton and Turner (1962)
in Nigeria mention the
importance of hookworm coinfection and Wickramasuriya (1937)
in Ceylon stratified case fatality by the presence or
absence of hookworm infection and showed significantly higher risk of
death in infected women who presumably had chronic iron-deficiency
anemia, [relative risk 2.1; 95% confidence interval (CI): 1.3–3.4].
Most reports were from malarious areas, and malaria is an important
contributor to pregnancy anemia, especially in primigravidae
(Brabin 1983
). However, in a recent study in Malawi, the
attributable risk of anemia in pregnancy was greater for iron
deficiency than malaria (Verhoeff et al. 1999
).
|
Attributable risk can be a useful summary statistic for describing the
effect of a risk factor on mortality at the population level. However,
the more severe anemia becomes, the more likely it is to have multiple
causes and not be due to iron or nutritional deficiency alone. This
creates difficulties in establishing attributable risk, particularly
across populations whose epidemiological background and disease
exposure may be very different. This problem was addressed by
Pelletier and colleagues (1993)
in discussing the
epidemiological evidence for a potentiating effect of malnutrition on
child mortality.
Causality should be inferred only in the light of the consistency of
the epidemiological evidence, and in the present discussion, terms such
as PAR are meant to refer only to statistical associations. Rush (2000)
estimated relative risks for anemia-attributable
maternal mortality and discussed in detail the limitations of several
of the studies cited in Tables 5
and 6
. On the basis of evidence
available, he considered it a reasonable working assumption that
maternal mortality is greatly increased with severe anemia, and the
strength of the relationship made it appropriate to assume a causal
association with severe anemia but that the association with moderate
anemia was less clear.
By way of deriving the most reliable estimates of the effects of
moderate anemia, the relative risks from five of the studies that had
adequate data were calculated using only internal reference values and
mutually exclusive categories of Hb concentrations. These estimates are
shown in Tables 7
and
8
. For the moderate Hb range (40–80 g/L), there is no consistency in the
relative risk estimates among the five studies although all are from
one country (Nigeria). The table also highlights the small sample size
for most of these analyses, suggesting caution in drawing inferences
from these individual values. When the data from all five studies are
pooled, the relative risk of mortality associated with moderate anemia
was estimated to be 1.35 (95% CI: 0.92–2.00). The lack of a
significant association arises in part because mortality risk in the
referent groups was not low and none of these groups were nonanemic.
The relative risk of maternal mortality for severe anemia (<47 g/L)
for the same five studies was significantly increased at 3.51 (95% CI:
2.05–6.00) (Table 8)
.
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|
. The PAR value of 31% reported by Zucker et al. (1994)
for a group of women with a 6% severe anemia prevalence (Hb <60 g/L)
is higher than the estimated value for severe anemia at this prevalence
from Table 9
(13%). A best estimate of the actual prevalence of
severe anemia in many developing countries is likely to be 
5%.
Pending further studies, the only PAR estimates that could be defended
would be based on the strong association between severe anemia and
maternal mortality.
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Over half of the world’s population is <25 y old and >80% of the
world’s youth live in developing countries. In the mid-1990s, the
global teenage population was estimated at 513 million. In this group
of adolescents (10–19 y), the WHO has estimated that anemia prevalence
(Hb <110 g/L) is 16% in less-developed countries but 45% in
Africa (DeMaeyer and Adiels-Tegman 1985
). The risk
of anemia is high in teenage primigravidae in developing (Arkutu 1979
, Barr et al. 1998
, Fazio-Tirrozo et al. 1998
) and developed countries (Beard 1994
,
Osbourne et al. 1981
). Maternal deaths in a community
study using verbal autopsy in Tanzania showed no association with
maternal age (Macleod and Rhode 1998
). These authors did
not examine whether maternal deaths related to anemia were more common
in adolescents. In a large hospital-based study in Northern
Nigeria, a higher maternal mortality from severe anemia (43%) was
compared in very young (<15 y) adolescent, older adolescent and
nonadolescent pregnant women (<10%) (Harrison 1989
).
Lawson and Lister (1954)
in an early Nigerian study of
188 moderately anemic women (Hb <70 g/L) observed a case fatality of
1.89% in adolescent pregnancies compared with 8.89% in nonadolescent
women (
2 = 2.9, P < 0.1).
Only 3 of the 53 adolescents were <16 y old.
In an early study from Guyana of the pattern of mortality after the
eradication of hyperendemic malaria (Giglioli 1972
), 100
deaths were recorded for pregnant women in 1937–1966. Of these women,
24% were <20 y old and none was >40 y old. There was a marked
reduction in the incidence of such deaths in successive periods of
improved malaria control. Anemia related to hookworm infection was
given as the primary cause in 4 of these deaths. No information was
provided on the incidence of severe malarial anemia.
There is a scarcity of data on adolescent mortality and severity of
anemia in developing countries. Presumably, onset of nutritional anemia
at an early age results in chronic anemia that perpetuates any risk of
anemia-related mortality through subsequent pregnancies. Effective
antenatal care may reduce these risks because more frequent antenatal
care visits for pregnant adolescents in Malawi correlated with a
significant reduction in the prevalence of severe anemia (Brabin et al. 1998
).
Causes of anemia associated with maternal mortality.
Anemia in pregnancy in women in developing countries is multifactorial
in etiology. Iron- and folate-deficiency anemias are common. The
former are related to nutritional deficiency and intestinal helminthic
infections and the latter to poor intake and chronic hemolytic states.
Hemolytic anemia, to a greater or lesser degree, is commonly seen
during pregnancy in malarious areas of developing countries. The
observation that severe anemia is greatly reduced in patients who have
received regular malaria prophylaxis during pregnancy (Fleming et al. 1986
, Garner and Brabin 1994
,
Shulman et al. 1999
) indicates that it is related to
chronic infection with Plasmodium falciparum malaria. It is
therefore not surprising to find that the number of patients admitted
with severe anemia is highest during the months after the rainy season
(Fleming 1970
, Verhoeff et al. 1999
).
Hemolysis as a factor in the development of megaloblastosis in
folate-deficiency anemia has been demonstrated by Chanarin et al. (1959)
and P. falciparum infection is an
important cause in holoendemic malarious areas (Fleming et al. 1986
). A further group of patients who contribute to these
severe hemolytic anemias are those with sickle cell disease. This group
accounted for <10% of all cases in Ibadan, Nigeria (Fullerton and Watson-Williams 1962
). What proportion of the remainder
of severe anemias can be attributed to either malaria or iron
deficiency or both?
One approach to estimating the malaria-attributable anemia
component is to calculate this anemia excess in primigravidae compared
with multigravidae and attribute this excess to their greater exposure
to malaria. This assumption is reasonable because in areas of high
transmission, a large number of studies have confirmed that P.
falciparum malaria and anemia are more frequent in primigravidae
(Brabin 1983
). Figure 3
shows the relative risk for anemia in first compared with later
pregnancies at different Hb cut-off values using data derived from
studies in malarious areas of Africa and Papua New Guinea. The figure
is derived from a previous estimate of this excess risk (Brabin
and Rogerson 2001) but includes additional studies (Isah et al. 1985
, Lawson and Lister 1964) not
identified at the time of the earlier analysis. The goodness of fit
shows a highly significant association for a quadratic model
(R2 = 0.996; P = 0.0041). This model indicates that, in malarious areas, there is only a
small excess of mild anemia in primigravidae compared with
multigravidae. A larger excess is observed with moderate and severe
anemia (Hb <80 g/L: relative risk, 1.55, 95% CI: 1.4–1.7; Hb <7:
relative risk 1.86, 95% CI: 1.6–2.1). The PAR values of anemia due to
malaria in primigravidae derived from this method are given in
Table 10
, which shows that 1 in 6 cases of severe anemia (Hb <70 g/L) and 1
in 25 cases of mild anemia (<110 g/L) can be attributed to malaria in
primigravidae. Table 10
also shows PAR values derived using a second
method based on the presence or absence of P. falciparum
parasitemia. There is reasonable agreement between PAR calculations
using these two different methods. These are consistent with results
from a randomized controlled trial of antimalarial drugs in Kenya
(Shulman et al. 1999
).
|
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), then the remaining 75% of cases would be
attributable mainly to iron, folate, vitamin A and vitamin B-12
deficiencies or HIV infection. In the Nigerian studies summarized in
Table 5
, HIV was not a contributing factor because all of these surveys
were completed before 1962. Nutrient deficiencies were therefore the
major contributors.
Cause-specific mortality in primigravidae related to severity of anemia
can be calculated using the following formulas:
 |
 |
where P is the prevalence of severe anemia,
PARm and (1-PARm) are the
PAR estimates, respectively, for malarial and nonmalarial severe anemia
in primigravidae, and CFR is the case fatality rate (taken as 1.0%
from Fig. 2
). Through the use of this formula, then, in a holoendemic
malarious area with a 5% severe anemic prevalence (Hb <70 g/L), there
would be 9 severe malaria anemia-related deaths per 100,000 live
births to primigravidae and 41 nonmalarial anemia-related deaths
(Table 11
).
|
summarizes deaths attributable to
iron-deficiencyanemia (all forms) in women 15–44 y old and published by WHO (1993) as part of their Global Burden of Disease
Statistical Reports. The mortality rates per 100,000 attributable
to iron-deficiency anemia were < 2.8 per 100,000 population
for the regional estimates in 1990, and projected deaths were lower for
the year 2000. The estimate for sub-Saharan Africa (2.2 per 100,000
population) is much lower than the value derived above for nonmalarial
pregnancy-related anemia mortality (41 per 100,000 live births).
The difference is influenced by the method of calculation, which, for
the global burden of disease estimate, includes the total number of
pregnant and nonpregnant women in the denominator population, whereas
the estimate in this analysis is per 100,000 live births in
primigravidae. The difference between these estimates highlights the
fact that the risks for anemia-related mortality are greater for
the pregnant population and include several nutritional factors other
than iron deficiency.
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DISCUSSION AND CONCLUSIONS |
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|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSDISCUSSIONREFERENCES |
|---|
Because moderate anemias are common and less strongly associated with
malaria, nutritional deficiency anemias would comprise the larger
component of anemia-attributable maternal mortality. This result
highlights the need to determine mechanisms by which nutritional
deficiency anemia, especially iron deficiency, could increase maternal
mortality. Nutritional deficiency may impair immune responsiveness, and
in nonpregnant women, iron-deficiency anemia has been associated
with increased risk of death from circulatory disease (Elwood et al. 1974
). Iron deficiency is likely to be a major contributory
cause, although vitamin A deficiency could also be important. Routine
supplementation with vitamin A in a large trial in Nepal reduced
maternal mortality, but the mechanisms were poorly defined and not
obviously attributable to anemia reduction (West et al. 1999
). Folate deficiency may also be important (Baily
1995
). HIV infection, which is common in some pregnant
populations in Africa and in some studies has been associated with
lower Hb levels, could enhance the effect of nutritional deficits on
mortality risk.
Figure 2
showed that high Hb values (>130 g/L) were associated with
slightly increased mortality risk. This result was obtained through the
inclusion of the data of Harrison and Rossiter (1985)
,
which showed a marked increase in mortality risk in women with
hematocrits >0.45. The explanation for this is not known but could be
related in part to dehydration and hemoconcentration in emergencies.
Mortality in nonpregnant Caucasian women with high hematocrits was
attributed to higher cholesterol and blood viscosities in such subjects
and was related in part to cardiovascular disease (Elwood et al. 1974
). Similar mechanisms may apply in women from developing
countries, but some caution is required in interpreting this
observation because the result is from a single study.
There is almost no evidence that the treatment of anemia other than
with exchange transfusion (Fullerton and Turner 1962
) or
judicious use of blood transfusion (Lawson and Lister 1954
), or treatment of acute severe malarial anemia
(Gilles et al. 1969
) lowers risk of maternal mortality.
A controlled intervention trial would be a stronger approach, but this
would require a very large sample size and may not be ethically
acceptable. Thus, indirect methods of analysis are of particular
relevance in demonstrating the strength of associations of anemia with
maternal mortality. There are several limitations to this approach that
have been mentioned previously, not least that the methods of Hb
measurement vary (methods include Sahli, Talquist, hematocrit, hemacue,
Coulter counter techniques and use of optical spectrophotometers).
However, this analysis has identified a large number of reports and the
strength of statistical associations can be adequately tested.
Estimates of PAR can be defended on the basis of the strong association
between severe anemia and maternal mortality, but not for mild or
moderate anemia. The policy implications of this are, first, that some
reduction in maternal mortality should be achievable in developing
countries through reduction in severe maternal anemia, with the
greatest effect resulting from reductions in both malaria and
nutritional anemias. This conclusion contrasts with the situation in
Western countries, where neither historical review nor review of
obstetric literature identified a plausible contribution of nutritional
factors to the decline in maternal mortality (Ronsmans et al. 1999
). The size of this effect is likely to be small unless
there is a very high prevalence of severe anemia in the population.
However, the evidence is insufficient for or against treatment of
iron-deficiency anemia as a preventive measure for maternal
mortality. Second, with good antenatal and obstetric care, most
anemia-related deaths are preventable, and policies to reduce
anemia prevalence should not be divorced from efforts to provide
adequate antenatal and delivery facilities for women in developing
countries. Putting into operation nutrition interventions as the magic
pill approach will have to compete with budgets allocated for essential
obstetric care. Finally, iron deficiency and malarial anemia should be
treated differently from other categories of risk in maternal health
such as height, weight, age, parity, previous history and use of
antenatal care services. Iron-deficiency anemia, like malarial
anemia, is in fact a complication, a medical condition that requires
treatment. The broad use of terminology, which clusters together such
unrelated criteria, could be detrimental to effective health care
strategies (Rhode 1995
).
John Lawson, in his classic annual report in 1954, concluded that it was hoped that maternal (and fetal) loss from anemia would show a steady decline in the future. In his view, the declining level of Hb in some patients meant that they reached a point of no return and would die however they were treated. Fifty years later, maternal and fetal losses are still unacceptably high, although today we have better ways of preventing women from reaching that point of no return.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSION AND CONCLUSIONSDISCUSSIONREFERENCES |
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Dr. Pelletier: Several comments on the Nigerian studies, which report the lowest hemoglobin values. They are all from around 1960, all from one country, and all with a certain level and type of obstetric care and they are clearly pulling the risk curve up. So, if you fit various models to that, it turns out the best fit is exponential. I am trying to zero in on the mild and moderate range, independent of any sort of very powerful data points that are pulling it up. There does not seem to be any relationship if you exclude those four studies. So, if we want to look for a dose-response relationship, we really have to see evidence of it over the entire distribution and be wary of influential data points, especially because those seem exceptional.
Dr. Beard: Do we have any documentation of the kind or type of obstetric care that was given then relative to what is available in that part of the world now?
Dr. Brabin: I think the obstetrics has improved greatly. I do not think we can ignore those four points. These old Nigerian studies document the situation with relatively little interference, where women have desperately low hemoglobin and are dying. These are the only data that exist in the world.
Dr. Pelletier: I am not suggesting we ignore them. It would be, probably, the causal effect of severe anemia.
Dr. Beard: Are you willing to allow those four studies to stay in the analysis?
Dr. Pelletier: Yes, for the purposes of making inferences about severe anemia, but if we start fitting curves they will begin to have a distorting influence on our judgment. Imagine that it was absolutely horizontal and then it goes up with severe anemia. If you fit an exponential curve to that, it is going to fit very nicely.
Participant: Are there other sub-Saharan Africa studies of the mid-1960s in your pile of 28 studies? I am just trying to figure out what the situation would be if you took them all out.
Dr. Pelletier: Actually, I am looking at that curve again and Brabin is right. It is not just those four. It turns out that eight data points are up there. Seven of the eight are from Nigeria. One is from Guinea. So, they are all from sub-Saharan Africa. Some of the less extreme points are also from Africa.
Dr. Allen: Were they all the same investigators?
Dr. Brabin: No. There were three different groups of investigators.
Dr. Beard: One of the things that generally concerns me about hospital-based data in resource-poor environments is what gets you admitted to a hospital. What gets you admitted to a hospital if you show up with a hemoglobin of 30 or 40 g/L is going to be very different from what gets you admitted if you show up with a hemoglobin of 60 or 80 g/L. Right? So, it seems to me that the people who are showing up with hemoglobins of 60 or 80 g/L are being admitted primarily for completely other reasons.
Participant: That would tend to diminish the relationship.
Dr. Beard: That would tend to inflate the mortality risk among the moderately anemic because they are selected for a higher risk profile. I think the question is in the mild-to-moderate range of anemia, what is it that hospital-based data can tell us in this kind of environment, and how much is selection bias influencing our assessment of the relationship.
Dr. Habicht: At least down to 60 g/L or so, I do not see any admissions because of hemoglobin. They are all there for other reasons. Now, is there any reason to believe that those other reasons would be different across the hemoglobin range? Probably not.
Dr. Brabin: Any woman who comes to the hospital whatever her hemoglobin is admitted so that she can deliver her baby.
Dr. Habicht: I think we need to divide the conversation into different parts. First, do we believe that that excess risk below 50 g/L is really there? It seems to me that everybody believes that. So, the second question is whether there is any excess risk above 50 g/L? From these data, if you just took the fitted lines away so you were not being prejudiced, you would not see a relationship above 50 g/L. This is an underestimate of the true relationship. If it is a flat line, it is an underestimate because those people are being selected into the hospital sample because they are likely to die.
Dr. Tielsch: So, you think the comorbidity profile of women with hemoglobin 60 g/L at admission for birth is the same as for women who have 100 g/L at admission. I suggest that is not probably true, in fact, because we know that anemia is related to poverty and poor health. So that women who get admitted—who are coming to the hospital to deliver—and have got an admission hemoglobin of 100 g/L are likely to be healthier.
Dr. Habicht: Then your conclusion is very clear. Taking that into account—rather than this apparent flat relationship between hemoglobin and mortality—you then have a positive relationship between hemoglobin and case fatality above 60 g/L, going up to the right-hand side.
Dr. Tielsch: I cannot figure out what the true relationship is.
Dr. Premji: I wanted to ask Brabin whether he has any clue about the association between malaria and mortality.
Dr. Brabin: I cannot enlighten you. We have done a retrospective analysis of a very large data set from the north coast of Papua New Guinea and an equally large data set from the highlands of New Guinea. In the malaria-endemic north coast, for the same level of hemoglobin in the mother at delivery there was a significantly increased risk of postpartum hemorrhage. This is just a hint that malaria is in some way related to the risk, because postpartum hemorrhage is associated with mortality. I do not know the mechanism.
Dr. Tielsch: This is outside primagravida—independent of that?
Dr. Brabin: Independent.
Dr. Oppenheimer: I remember seeing a review about maternal mortality in Nigeria in the 1960s and they had a real problem with anemia and heart failure because they did not have effective rapid-acting diuretics. If they were transfused, their heart failure got worse. In fact, they were trying to use exchange transfusion to cope with this problem. So, there was a particular problem of management of severe anemia and heart failure.
Dr. Brabin: The Nigerian studies do give clinical reasons for death, and heart failure is mentioned as one cause of death. It has been shown in Nigeria that exchange transfusion dramatically reduced the risk of death in these severely anemic women.
Dr. Beard: Some of us may recall Henry J. Whipple, who won the Nobel Prize in Medicine for looking at the effects of severe anemia on cardiovascular adaptation and cardiac failure. So, this question of severe anemia, oxygen transport and cardiovascular adaptation has been around for a really, really long time.
Dr. Stoltzfus: It is remarkable that this hemoglobin mortality risk curve is flat across the wide hemoglobin range about 60 g/L, given all we expect from other anemia survival curves in nonpregnant adults. I think that reverse causality is part of all these anemia-survival associations, but the fact is that they are there, even in well-cared-for populations, even in surgical patients, who are not necessarily suffering from an infectious disease that is causing their surgery. The fact that this occurs in British data makes it astounding to me that that is absent in African data. I do not know what to conclude from that.
Dr. Pelletier: Bear in mind that these data points are assembled from 12 different studies. So, the picture is a bit deceiving. We are used to having a reference group and several groups of increasing severity, and then you would expect to see something like that. However, this is a meta-analysis. There is lots of stuff going on between these data points besides different degrees of anemia.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 This article was commissioned by the World
Health Organization (WHO). The views expressed are those of the authors
alone and do not necessarily reflect those of WHO.
4 Abbreviations: CI, confidence interval; Hb,
hemoglobin; HIV, human immunodeficiency virus; PAR,
population-attributable risk.
|
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