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1. An analysis of anemia and pregnancy-related maternal mortality................................................................ 1

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An analysis of anemia and pregnancy-related maternal mortality

Author: Brabin, Bernard J; Hakimi, Mohammad; Pelletier, David ProQuest document link Abstract: The relationship of anemia as a risk factor for maternal mortality was analyzed by using crosssectional, longitudinal and case-control studies because randomized trials were not available for analysis. Full text: Headnote An Analysis of Anemia and Pregnancy-Related Maternal Mortality1,2 Headnote ABSTRACT The relationship of anemia as a risk factor for maternal mortality was analyzed by using crosssectional, longitudinal and case-control studies because randomized trials were not available for analysis. The following six methods of estimation of mortality risk were adopted: 1) the correlation of maternal mortality rates with maternal anemia prevalence derived from national statistics; 2) the proportion of maternal deaths attributable to anemia; 3) the proportion of anemic women who die; 4) population-attributable risk of maternal mortality due to anemia; 5) adolescence as a risk factor for anemia-related mortality; and 6) causes of anemia associated with maternal mortality. The average estimates for all-cause anemia attributable mortality (both direct and indirect) were 6.37, 7.26 and 3.0% for Africa, Asia and Latin America, respectively. Case fatality rates, mainly for hospital studies, varied from <1 % to >50%. The relative risk of mortality associated with moderate anemia (hemoglobin 40-80 g/L) was 1.35 [95% confidence interval (CI): 0.92-2.00] and for severe anemia (<47 g/L) was 3.51 (95% CI: 2.05-6.00). Population-attributable risk estimates can be defended on the basis of the strong association between severe anemia and maternal mortality but not for mild or moderate anemia. In holoendemic malarious areas with a 5% severe anemia prevalence (hemoglobin <70 g/L), it was estimated that in primigravidae, there would be 9 severe-malaria anemia-related deaths and 41 nonmalarial anemia-related deaths (mostly nutritional) per 100,000 live births. The iron deficiency component of these is unknown. J. Nutr. 131: 604S-615S, 2001. KEY WORDS: * pregnancy * anemia * mortality * malaria * iron deficiency Maternal mortality continues to be a major health problem in the developing world. Nearly 600,000 women die each year as a result of complications of pregnancy and childbirth; most of these deaths could be prevented with attainable resources and skills (WHO 1996). The worldwide maternal mortality ratio (annual number of deaths of women from pregnancyrelated 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 (Starts 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. 26 March 2014 Page 1 of 21 ProQuest

The relationship of anemia as a risk factor for mortality is derived mainly from cross-sectional studies and can be confounded for several reasons. Most studies report hospital data, often for moribund women, and there is limited attention to factors such as pregnancy hemodilution, hemoglobin rise in late pregnancy, concurrent infection, hemorrhage, prior treatment or poor maternal nutritional status. In young women living under endemic malaria conditions, especially in urban areas in which adults may have poor malaria immunity, severe malarial anemia and cerebral malaria may occur and can rapidly lead to death (Granje et al. 1998). 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. METHODS Identification of published studies. 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. 26 March 2014 Page 2 of 21 ProQuest

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)^sup 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.

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RESULTS Maternal mortality and anemia prevalence. 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?

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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. Considerable caution is required in interpreting the association shown in Figure 1 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 irondeficiency anemia. The WHO compilation separately lists a smaller number of studies that report serum iron concentrations and give values below the norm (<9 (mu)mol/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 26 March 2014 Page 5 of 21 ProQuest

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). Within-country variation is also considerable. In the WHO (1991) 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. The proportion of anemic women who die. 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 26 March 2014 Page 6 of 21 ProQuest

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 followup. 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). Figure 2 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 gIL. 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 26 March 2014 Page 7 of 21 ProQuest

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): 1.3-3.41. 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). Population-attributable risk of maternal mortality due to anemia. 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 (4080 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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Estimates of PAR derived from these data are shown in Table 9. 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. Adolescence as a risk factor for anemia-related mortality. Over half of the world's population is <25 y old and >80% of the world's youth live in developing countries. In the mid1990s, the global teenage population was estimated at 513 million. In this group of adolescents (10-19 y), the WHO has estimated that anemia prevalence 26 March 2014 Page 9 of 21 ProQuest

(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 (chi^sup 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.

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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

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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 at. 1985, Lawson and Listen 1964) not identified at the time of the earlier analysis. The goodness of fit shows a highly significant association for a quadratic model (R^sup 2^ = 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% Cl: 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). If 5-10% of severe anemias (Hb <70 g/L) in primigravidae are assumed to be due to sickle cell disease in subSaharan Africa and 18% due to malaria (from Table 10), 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: P X (PAR^sup m^) X (CFR) = maternal mortality from malaria anemia (1 - PAR^sup n^) X (CFR) = maternal mortality from nonmalarious anemia where P is the prevalence of severe anemia, PARm and (1-- PAR^sup m^) 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). Table 12 summarizes deaths attributable to iron-deficiency anemia (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 irondeficiency 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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These calculations suggest that nutritional deficiency is a major component of severe anemia deaths even in malarious areas. The calculations were based on primigravidae, but this conclusion should apply to multigravidae, who are less susceptible to malarial infection and may have a higher prevalence of nutritional deficits and iron-deficiency anemia than primigravidae (Isah et al. 1985). DISCUSSION AND CONCLUSIONS The more severe the anemia, the more likely it is to have multiple causes and not be related solely to iron deficiency. This creates difficulties in establishing attributable risk. Because several factors contribute to the prevalence and severity of anemia, it cannot be assumed that distinct epidemiological parameters predict the effect of anemia on maternal mortality. This is a difficulty in an analysis that aims to identify specific components of attributable risk. The specific nonmalarial components (mainly nutritional) of this attributable risk can be estimated, but the proportion of these related specifically to iron-deficiency anemia, while uncertain, could be substantial. 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 26 March 2014 Page 14 of 21 ProQuest

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. ACKNOWLEDGMENTS We thank James Bunn for finding the early report by Professor John Lawson and U. Lister (1953-1954), Jean Taylor for expert secretarial assistance and several colleagues for kindly helping with data sources and references. DISCUSSION Participants: Pelletier, Beard, Brabin, Allen, Rasmussen, Habicht, Tielsch, Premji, Oppenheimer, Stoltzfus, Horton 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 26 March 2014 Page 15 of 21 ProQuest

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-tomoderate range of anemia, what is it that hospitalbased 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 gfL 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. 26 March 2014 Page 16 of 21 ProQuest

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 malariaendemic 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-caredfor 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. Footnote 1 Presented at the Belmont Meeting on Iron Deficiency Anemia: Reexamining the Nature and Magnitude of the Public Health Problem, held May 21-24, 2000 in Belmont, MD. The proceedings of this conference are published as a supplement to The Journal of Nutrition. Supplement guest editors were John Beard, The Pennsylvania State University, University Park, PA and Rebecca Stoltzfus, Johns Hopkins School of Public Health, Baltimore, MD. 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. 3 To whom correspondence and reprint requests should be addressed. Email: l.j.taylor@liverpool.ac.uk. Footnote 4 Abbreviations: CI, confidence interval; Hb, hemoglobin; HIV, human immunodeficiency virus; PAR, populationattributable risk. References 26 March 2014 Page 17 of 21 ProQuest

LITERATURE CITED References Abouzahr, C. &Royston, E. (1991) Maternal mortality: a global factbook. World Health Organization, Geneva, Switzerland. Arkutu, A.A. (1979) Pregnancy and labour in Tanzanian primigravidae aged 15 years and under. Int. J. Gynaecol. Obstet. 16: 128-131. Bailey, L. B., ed. (1995) Folate in Health and Disease. Marcel Dekker, New York, NY. Barr, F., Brabin, L., Agbaje, S., Buseri, F., Ikimalo, J. &Briggs, N. (1998) Reducing iron deficiency anaemia due to heavy menstrual blood loss in Nigerian rural adolescents. Public Health Nutr. 1: 249-257. Beard, J. L. (1994) Iron deficiency: assessment during pregnancy and its importance in pregnant adolescents. Am. J. Clin. Nutr. 59 (suppl.): 50255105. Brabin, B. J. (1983) An analysis of malaria in pregnancy in Africa. Bull. WHO 61: 1005-1016. Brabin, B.J. (1985) Epidemiology of infection in pregnancy. Rev. Infect. Dis. 7: 579-603. References Brabin, B. J., Ginny, M., Sapau, J., Galme, K. &Paino, J. (1990) Consequences of maternal anaemia on outcome of pregnancy in a malaria endemic area of Papua New Guinea. Ann. Trop. Med. Parasitol. 84: 11-24. Brabin, B. J. &Rogerson, S. (2000) The epidemiology and outcome of maternal malaria. In: Malaria in Pregnancy: Deadly Parasite Susceptible Host (Duffy, P. &Fried, M., eds.). Harwood Academic Publishers, Newark, NJ (2001). Brabin, L., Verhoeff, F. H., Kazembe, P., Brabin, B. J., Chimsuku, L. &Broadhead, R. (1998) Improving antenatal care for pregnant adolescents in southern Malawi. Acta Obstet. Gynaecol. Scand. 77: 402-409. Brock, J.H. (1999) Iron and the immune system. In: Iron and Infection, 2nd ed. (Bullen, J. J. &Griffiths, E., eds.). John Wiley and Sons, New York, NY. Chanarin, I., Dacie, J. V. &Mollin, D.L. (1959) Folic acid deficiency in haemo lytic anaemia. Br. J. Haematol. 5: 245-256. Cheng-Chi, I., Agoestina, T. &Harbin, J. (1981) Maternal mortality at twelve teaching hospitals in Indonesia-an epidemiologic analysis. Int. J. Gynaecol. Obstet. 19: 259-266. DeMaeyer, E. &Adiels-Tegman, M. (1985) The prevalence of anaemia in the world. World Health Stat. Q. Rep. 38: 302-316. Diallo, M. S., Diallo, T. S., Diallo, F. B., Diallo, Y., Camara, A. Y. &Onivogui, G. (1995) An6mie et grossesse. Rev. Fr. Gynecol. Obstet. 90: 138-141. Elwood, P. C., Waters, W. E., Bentjamin, I. T. &Sweetnam, P. M. (1974) Mortality and anaemia in women. Lancet 1: 891-894. Fazio-Tirrozo, G., Brabin, L., Brabin, B., Agbaje, O., Harper, G. &Broadhead, R. (1998) A community based study of vitamin A and vitamin E status of adolescent girls living in the Shire Valley, Southern Malawi. Eur. J. Clin. Nutr. 52: 637-642. Fleming, A.F. (1970) Seasonal incidence of anaemia in pregnancy in Ibadan. Am. J. Clin. Nutr. 23: 224-230. Fleming, A.F. (1989a) The aetiology of severe anaemia in pregnancy in Ndola, Zambia. Ann. Trop. Med. Parasitol. 83: 37-49. Fleming, A.F. (1989b) Anaemia in pregnancy in tropical Africa. Trans. R. Soc. Trop. Med. Hyg. 83: 441-449. Fleming, A. F., Ghatoura, G.B.S., Harrison, K. A., Briggs, N. D. &Dunn, D. T. (1986) The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Ann. Trop. Med. Parasitol. 80: 211-233. Foord, F. A., Fox-Rushby, J. &Weaver, L. T. (1992) The effect of a midwifery outreach service on maternal anaemia and mortality in rural Gambia. Unpublished report, pp 1-20. Dunn Nutrition Group, MRC Laboratories, Gambia. Fullerton, W. T. &Turner, A. G. (1962) Exchange transfusion in treatment of severe anaemia in pregnancy. Lancet 282: 75-78. 26 March 2014 Page 18 of 21 ProQuest

Fullerton, W. T. &Watson-Williams, E.J. (1962) Haemoglobin SC disease and megaloblastic anaemia in pregnancy. J. Obstet. Gynaecol. 69: 729-735. Garner, P. &Brabin, B. J. (1994) A review of randomised controlled trials of routine antimalarial drug prophylaxis during pregnancy in endemic malarious areas. Bull. WHO 72: 89-99. Giglioli, G. (1972) Changes in the pattern of mortality following eradication of hyperendemic malaria from a highly susceptible community. Bull. WHO 46: 181-202. Gilles, H. M., Lawson, J. B., Sibelas, M., Voller, A. &Allan, N. (1969) Malaria, anaemia and pregnancy. Ann. Trop. Med. Parasitol. 63: 245-263. Granje, A. C., Machungo, F., Comes, A., Bergstrom, S. &Brabin, B. (1998) References Malaria related mortality in urban pregnant women in Mozambique. Ann. Trop. Med. Parasitol. 92: 257-263. Harrison, K. A. (1975) Maternal mortality in anaemia in pregnancy. West Afr. Med. (April): 27-31. Harrison,K.A. (1982) Anaemia, malaria and sickle cell disease. Clin. Obstet. Gynaecol. 9: 445-447. Harrison, K.A. (1989) Tropical obstetrics and gynaecology. 2. Maternal mortality. Trans. R. Soc. Trop. Med. Hyg. 83: 449-453. Harrison, K. A. &Rossiter, C. E. (1985) Maternal mortality. Br. J. Obstet. Gynaecol. 92 (suppl. 5): 100-115. Isah, H. S., Fleming, A. F., Ujah, LA.O. &Ekwempu, C. C. (1985) Anaemia and iron status of pregnant and nonpregnant women in the guinea savanna of Nigeria. Ann. Trop. Med. Parasitol. 79: 485-493. Johnson, J.W.C. &Ojo, O.A. (1967) Amniotic fluid oxygen tensions in severe maternal anemia. Am. J Obstet. Gynecol. 97: 499-506. Konar, M., Sikdar, K., Basak, S. &Lahiri, D. (1980) Maternal mortality. Ten years survey in Eden Hospital. J. Indian Med. Assoc. 75: 45-51. Lawson, J. B. (1962) Maternal mortality in West Africa. Ghana Med. J. (December): 31-36. Lawson, J. &Lister, U.G. (1954) Clinical Report of the Department of Obstetrics, University College, Ibadan, Nigeria. April 1st 1953-December 31 st, 1954. Vail and Company, Ltd., London, UK. Llewellyn-Jones, D. (1965) Severe anaemia in pregnancy as seen in Kuala Lumpur, Malaysia. Aust. N. Z. J. Obstet. Gynaecol. 5: 191-197. Macleod, J. &Rhode, R. (1998) Retrospective follow-up of maternal deaths and their associated risk factors in a rural district of Tanzania. Trop. Med. Int. Health 3: 130-137. McDermott, J., Slutsker, L., Steketee, R. W., Wirima, J. J., Breman, J. G. &Heymann, D. L. (1996) Prospective assessment of mortality among a cohort of pregnant women in rural Malawi. Am. J. Trop. Med. Hyg. 55:66-70. Murray, C.J.L. &Lopez, A. D. (1994) Global and regional causes of death patterns in 1990. In: Global Comparative Assessments in the Health Sector-- Disease Burden, Expenditures and Intervention Packages, pp. 21-54. WHO, Geneva, Switzerland. Oja,O.A. (1965) The pattern of anaemia in Western Nigeria. J. Trop. Med. Hyg. 68: 32-36. References Osbourne, G. K., Howat, R. C. &Jordan, M. M. (1981) The obstetric outcome of teenage pregnancy. Br. J. Obstet. Gynaecol. 88: 215-221. Pelletier, D., Frongillo, E. A. &Habicht, J.-P. (1993) Epidemiologic evidence for a potentiating effect of malnutrition on child mortality. Am. J. Public Health 83: 1130-1133. Rhode, J. E. (1995) Removing risk from safe motherhood. Int. J. Gynaecol. Obstet. 50 (suppl. 2): S3-S10. Ronsmans, C., Campbell, 0. &Collumbien, M. (1999) Slight modifications in definitions could alter interpretation of results. Br. Med. J. 319: 1201. Rush, D. (2000) Nutrition and maternal mortality in the developing world. Am. J. Clin. Nutr. (in press). Sarin, A. R. (1995) Severe anaemia of pregnancy, recent experience. Int. J. Gynecol. Obstet. 50 (suppl. 1): S45-549. 26 March 2014 Page 19 of 21 ProQuest

Shulman, C. E., Dorman, E. K., Cutts, F., Kawuondo, K., Bulmer, J. N., Peshu, N. &Marsh, K. (1999) Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebocontrolled trial. Lancet 353: 632-6;6. Starrs, A. (1987) Preventing the tragedy of maternal deaths. A report of the International Safe Motherhood Conference, Nairobi, Kenya. World Bank, Washington, DC. Tasker, P.W.G. (1958) Anaemia in pregnancy. A five year appraisal. Med. J. Malaya 8: 3-8. Thonneau, P., Toure, B., Cantrelle, P., Barry, T. M. &Papiemik, E. (1992) Risk factors for maternal mortality: results of a case-control study conducted in Conakry (Guinea). Int. J. Gynaecol. Obstet. 39: 87-92. United Nations Children's Fund (1999) State of the World's Children. United Nations Children's Fund, New York, NY Verhoeff, F. H., Brabin, B. J., Chimsuku, L., Kazembe, P. &Broadhead R. (1999) An analysis of the determinants of anaemia in pregnant women in rural Malawi-a basis for action. Ann. Trop. Med. Parasitol. 93: 119-133. West, K. P., Katz, J., Khatry, S. K., LeClerq, S. C., Pradhan, E. K., Shrestha, S., Connor, P., Dali, S., Christian, P., Pokhrel, R. &Sommer, A. (1999) Double blind, cluster randomised trial of low dose supplementation with vitamin A or p carotene on mortality related to pregnancy in Nepal. Br. Med. J. 318: 570-575. Wickramasuriya, G.A.W. (1937) Malaria and Ankylostomiasis in the Pregnant Woman. Their More Serious Complications and Sequelae. Oxford University Press, London, UK. World Bank (1993) World Development Report 1993: Investing in Health. World Bank, Washington, DC. World Health Organization (1991) Maternal Mortality-a Global Factbook. WHO, Geneva, Switzerland. World Health Organization (1992a) International Statistical Classification of Diseases and Relative Health Problems. loth rev. ed., vols. 1 and 2. WHO, Geneva, Switzerland. World Health Organization (1992b) The prevalence of anaemia in women: a tabulation of available information. Maternal Health and Safe Motherhood Programme, Geneva, Switzerland. World Health Organization (1996) Revised 1990 estimate of maternal mortality. A new approach by WHO and UNICEF. WHO, Geneva, Switzerland. References Zucker, J. R., Lackritz, E. M. &Ruebush, T. K. (1994) Anaemia, blood transfusion practices, HIV and mortality among women of reproductive age in Western Kenya. Trans. R. Soc. Trop. Med. Hyg. 88: 173-176. AuthorAffiliation Bernard J. Brabin,3 Mohammad Hakimi* and David Pelletier^ 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 Subject: Case studies; Pregnancy; Anemia; Mortality; Malaria; Iron; MeSH: Acute Disease, Adolescent, Adult, Africa -- epidemiology, Anemia -- epidemiology, Anemia, IronDeficiency -- mortality, Asia -- epidemiology, Cause of Death, Chronic Disease, Cross-Sectional Studies, Female, Folic Acid Deficiency -- mortality, Humans, Latin America -- epidemiology, Longitudinal Studies, Maternal Mortality, Pregnancy, Pregnancy Complications, Hematologic -- epidemiology, Pregnancy in Adolescence -- statistics & numerical data, Prevalence, Risk Assessment, Anemia -- mortality (major), Developing Countries -- statistics & numerical data (major), Pregnancy Complications, Hematologic -- mortality (major) Publication title: The Journal of Nutrition Volume: 131

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Issue: 2S Supplement: Iron-deficiency Anemia: Reexamining the Nature and... Pages: 604S-614S; discussion 614S-615S Number of pages: 12 Publication year: 2001 Publication date: Feb 2001 Year: 2001 Publisher: American Institute of Nutrition Place of publication: Bethesda Country of publication: United States Publication subject: Nutrition And Dietetics ISSN: 00223166 CODEN: JONUAI Source type: Scholarly Journals Language of publication: English Document type: Journal Article Accession number: 11160593 ProQuest document ID: 197424749 Document URL: http://search.proquest.com/docview/197424749?accountid=50268 Copyright: Copyright American Institute of Nutrition Feb 2001 Last updated: 2013-01-27 Database: ProQuest Agriculture Journals,ProQuest Nursing & Allied Health Source

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