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Articles |
1 From the School of Nutrition Science and Policy, Tufts University, Boston.
2 Presented at the meeting Iron and Maternal Mortality in the Developing World, held in Washington, DC, July 6–7, 1998.
3 Reprints not available. Address correspondence to D Rush, School of Nutrition Science and Policy, Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: rush{at}hnrc.tufts.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONHISTORICAL EPIDEMIOLOGY OF...ANEMIA AND MATERNAL MORTALITYANEMIA AND OBSTETRIC HEMORRHAGEMATERNAL NUTRITION AND...NUTRITION AND TOXEMIA OF...MATERNAL NUTRITION AND PUERPERAL...CONCLUSIONSREFERENCES |
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100-fold higher than rates in the industrialized countries. For 3 of the central causes of maternal mortality (ie, induced abortion, puerperal infection, and pregnancy-induced hypertension), knowledge of the contribution of nutrition is too scanty for programmatic application. Hemorrhage (including, for this discussion, anemia) and obstructed labor are different. The risk of death is greatly increased with severe anemia (Hb <70 or 80 g/L); there is little evidence of increased risk associated with mild or moderate anemia. Current programs of universal iron supplementation are unlikely to have much effect on severe anemia. There is an urgent need to reassess how to approach anemia control in pregnant women. Obstructed labor is far more common in short women. Unfortunately, nutritional strategies for increasing adult stature are nearly nonexistent: supplemental feeding appears to have little benefit after 3 y of age and could possibly be harmful at later ages, inducing accelerated growth before puberty, earlier menarche (and possible earlier marriage), and unchanged adult stature. Deprived girls without intervention typically have late menarche, extended periods of growth, and can achieve nearly complete catch-up growth. The need for operative delivery also increases with increased fetal size. Supplementary feeding could therefore increase the risk of obstructed labor. In the absence of accessible obstetric services, primiparous women <1.5 m in height should be excluded from supplementary feeding programs aimed at accelerating fetal growth. The knowledge base to model the risks and benefits of increased fetal size does not exist.
Key Words: Maternal mortality • pregnancy • developing world • nutrition • obstetric care • operative delivery • obstructed labor • toxemia of pregnancy • iron • anemia • nutrient requirements • supplementation • menarche • maternal height • fetal size • zinc • uterine rupture • maternal weight • maternal body mass index
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONHISTORICAL EPIDEMIOLOGY OF...ANEMIA AND MATERNAL MORTALITYANEMIA AND OBSTETRIC HEMORRHAGEMATERNAL NUTRITION AND...NUTRITION AND TOXEMIA OF...MATERNAL NUTRITION AND PUERPERAL...CONCLUSIONSREFERENCES |
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This review will relate the woman's lifetime nutritional status and dietary intake to pregnancy-related death, focusing on nutrition during pregnancy. One of its main concerns will be whether the associations between nutrition and maternal mortality may be causal and, if they are, whether amelioration is plausible.
The analysis will be concerned primarily with the developing, rather than the industrialized, world. There is no other public health statistic in which the discrepancy in risk between the industrialized and the developing worlds is greater than that for maternal mortality. In all likelihood, this discrepancy is often much higher than the usually quoted 100- to 200-fold increased risk (3). In the developing world, the dominant causes of maternal death are those that prevailed 2 centuries ago in Europe and the United States. Sadly, although ways to reverse most of the profound differences of risk between poor and affluent women are widely understood, they are often not available. The need for intensive and widespread improvements in obstetric services in the developing world is clear. What remains unclear is the extent to which improving the nutritional status of women, from early in their own lives through the reproductive years, is important or even essential as an adjunct to improved health services.
This review must, of necessity, make do with the data available now. It points, however, to a great need for more longitudinal, community-based studies of reproduction in the developing world, parallel to those conducted in developed countries in the past half century, such as the community studies in Aberdeen (4) or the US Collaborative Perinatal Study (5).
The paucity of comprehensive and accurate statistics makes it difficult to relate nutritional status directly to maternal death. This is a consequence of the relative infrequency and invisibility of maternal death, even at the tragically high rates prevalent in the developing world. Because of this, the review deals most often with relations between nutrition and those health conditions that are the proximal causes of maternal mortality.
Deaths during gestation do not usually result from malnutrition alone, but from conditions that may be exacerbated by poor nutrition. The 4 primary causes of maternal mortality are hemorrhage (in the intra- and postpartum periods), obstructed labor, pregnancy-induced hypertension (ie, the toxemias of pregnancy, preeclampsia, and eclampsia), and puerperal infection. This review will not address death after induced abortion, the fifth of the frequent causes of maternal death in the developing world. It is implausible that a strategy of nutritional improvement would reduce the danger from unsterile or technically inadequate abortion procedures.
A central tenet of this review is that nutrition and health services function interdependently. Setting priorities for nutrition programs, or allocating resources to support them, is illogical without interweaving these programs with health services; nutritional programs cannot confer anywhere near maximal benefits without effective health services. In fact, without such integration, they could even be dangerous. This danger could occur not only because of the diversion of resources away from essential health services, but from direct adverse effects of dietary supplementation, as will be explained below.
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HISTORICAL EPIDEMIOLOGY OF MATERNAL MORTALITY IN THE DEVELOPED WORLD |
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TOPABSTRACTINTRODUCTIONHISTORICAL EPIDEMIOLOGY OF...ANEMIA AND MATERNAL MORTALITYANEMIA AND OBSTETRIC HEMORRHAGEMATERNAL NUTRITION AND...NUTRITION AND TOXEMIA OF...MATERNAL NUTRITION AND PUERPERAL...CONCLUSIONSREFERENCES |
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Historical trends
The magnitude of the challenge faced by the developing world is almost unimaginably large: in the industrialized countries, it took 250 y to reach the current low maternal mortality rates from rates similar to those in developing countries today. Some approaches to reducing maternal mortality in developing countries might be drawn from the experience of the industrialized countries.
The precipitous decrease in maternal mortality in the West did not occur evenly or gradually. Instead, maternal mortality rates followed a pattern of abrupt declines followed by plateaus, even increases, and then further abrupt declines. This ebb and flow is illustrated in Figure 1
for Sweden from 1751 to 1980, during which time the initial ratio of maternal mortality was 
1000/100000 live births, and the most recent ratio was 4/100000 live births (6).
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are maternal and infant mortality ratios in the Netherlands from 1910 to 1960 (7). Infant mortality ratios fell regularly and steeply until the beginning of World War II, then rose sharply during the war, and declined after the war. In contrast, maternal mortality rates were static until the mid 1930s, when they began to fall sharply, but this decline was not affected by the war. The widespread deprivation associated with the German blockade late in the war had profound effects on infant mortality, but no obvious effect on maternal mortality. This is counterintuitive because antibiotics, the introduction of which from 1934 was concomitant with the beginning of the decline in puerperal infection, were likely to have been scarce to nonexistent during the blockade. Maternal and infant mortality rates during the 20th century until 1960 in England and Wales are shown in Figure 3 (8). As in the Netherlands, infant mortality rates fell sharply and continuously throughout the period, whereas maternal mortality was unchanged until the 1930s and only then began to fall precipitously. The underlying reasons for the decrease in maternal mortality clearly cannot be identical to those for infant mortality because they came into play at different times and under different conditions. How they differed, and to what extent, is explored in depth by Loudon (1).
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Social influences are strongly related to maternal mortality in the contemporary United States. The maternal mortality rate of the United States in 1995 was 7.1/100000 live births (11). However, the rate among black women was 22.1/100000, >5 times the rate of 4.2/100000 live births among white women. This disparity could have been due to different social conditions, provision of obstetric care, health-related behaviors, nutritional or health status, or a combination of these factors.
Antisepsis and maternal mortality
One unequivocal cause of the decline in maternal mortality in the industrialized world was the introduction of antiseptic techniques into hospital obstetric practice. Högberg et al (12) estimated that after the obligatory introduction of antisepsis into Swedish lying-in hospitals in 1880, hospital maternal mortality ratios from sepsis declined from 2701/100000 live births in the preceding 15 y to 96/100000 births in the subsequent 15 y, a decline of 96%. The introduction of sulfonamides in the mid 1930s also had a remarkable effect on maternal mortality. Shown in Figure 4 is the parallel, precipitous decline in death from erysipelas and maternal mortality due to puerperal fever in England and Wales that began in 1934 (1).
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), although not as steeply as the decrease in infection rates (1). These trends were universal throughout the industrialized world (Figure 6) and rates have continued to decrease (1).
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An attempt to distinguish the impact of health services from other factors on US women
Despite low maternal mortality ratios in the surrounding community, women who were members of a small religious sect were reported to have aberrantly high maternal mortality ratios. Spence et al (14) and Kaunitz et al (15) reported the perinatal and maternal mortality rates among Faith Assembly members during 1975–1982. The Faith Assembly became active in northeastern Indiana from 1973. One of its tenets was that members should not receive medical care in response to health problems. Pregnant women, therefore, received no prenatal care and gave birth at home without obstetric assistance. The group had 6 maternal deaths between 1975 and 1982, resulting in a maternal mortality ratio of 872/100000 live births, 100 times that in the surrounding community. (Four of the deaths were from hemorrhage and 2 were from infection.) This suggests that the risk of death during reproduction among women in modern America, who, apart from medical care, were presumably living in similar social and economic conditions others living in the same area was similar to that in contemporary developing countries or in the West during the 19th century. The nutritional status of the Faith Assembly women is unknown, and the experience, although dramatic, is not conclusive in identifying which factors might have been involved in their excess risk of mortality. Nevertheless, the causes of death suggest strongly that they could have been prevented with adequate obstetric care. The increase in the risk of death among women was much greater than that among infants: the perinatal mortality rate was 2.7-fold that of surrounding communities compared with the 100-fold increased risk of maternal mortality.
MATERNAL MORTALITY IN THE DEVELOPING WORLD
AbouZahr and Royston (13) published an encyclopedic description of the current state of knowledge of national maternal mortality in both the developing and developed world. In addition to data on national rates, they presented an invaluable compendium of smaller and presumably more intensive—and, therefore, more reliable—community and hospital-based studies. The authors estimate that 500000 maternal deaths occur each year, of which 494000 occur in developing countries. The worldwide maternal mortality ratio is estimated to be 390/100000 live births, 30/100000 in the developed world and 450/100000 in the developing countries. Within the developing world, regional rates are as high as 660–700/100000 live births in east, middle, and west Africa, and 650/100000 live births in south Asia. Even at these high levels, the reported rates for the developing world are probably underestimated.
Underestimates of maternal mortality
Much attention has been paid to the problem of accurately estimating maternal mortality in the developing world (3, 16). Despite the best intentions, these estimates are often no more than educated guesses, probably under- rather than overestimates because so many deaths are unattended and unregistered. In one area in India, only one-third of the maternal deaths were recorded in the health system (17). In another area of India, only 31% of maternal deaths had occurred in the hospital and 64% of cases had never been referred (18). In a southern district in Malawi, 56% of maternal deaths occurred outside a health facility (19). Similarly, 50% of maternal deaths were unreported in a regional study in Argentina (20). Clearly, the deaths of women who never reach a hospital are usually omitted from the health statistics system. Official national statistics are, therefore, unlikely to reflect the actual severity of the problem of maternal mortality.
A paradox exists in that some thoughtful students of maternal mortality have concluded that collecting accurate counts of death is a distraction. They argue that the problem of maternal mortality is severe, knowledge exists about what should be done to correct it, and resources should not be expended to collect data that in any case are highly suspect. Graham et al (21) concluded that maternal mortality is not a feasible outcome indicator of the success of interventions.
In contrast, Moodley et al (22) reported that structural changes in the health care system would only be possible with the establishment of a common information database and if confidential inquiries were held into all maternal deaths. This opinion probably reflects that these authors are attempting to lower a maternal mortality ratio in South Africa of 150/100000 live births, which is already much lower than ratios in most developing countries. Accurate counts and confidential enquiry may be the next appropriate steps in the South African context.
Clearly, there are conflicting views on the need for routine collection of data on maternal mortality. Nevertheless, it is not clear how programs can be refined and how scarce resources can be allocated without an accurate knowledge of both the extent of maternal mortality and the quantitative effect of interventions.
Reevaluation of the effect of antenatal care on maternal mortality
Some commentators have begun to question long cherished assumptions about the importance of antenatal care. Rooney (23), in a comprehensive assessment of the issue, concluded that little is known about the effectiveness of antenatal care. McDonagh (24) concluded that the evidence justifying antenatal care is weak. She cited the example of a prospective study in the Gambia that found no relation between antenatal care and maternal mortality. A subsequent publication, however, showed a more complex relation between the strengthening of primary health care and subsequent maternal mortality; maternal mortality rates did decline, but did so in both the villages with a primary health care intervention as well as in the control villages (in contrast, perinatal mortality rates decreased only in villages that received improved primary health care) (25). This suggests an effect from participating in the study, even as a control (ie, a Hawthorne effect), because of improved surveillance, heightened awareness, or better access to transport. A series of small studies reported the near disappearance of maternal death after the introduction of relatively uncomplicated health services. These include the experience of the MRC-Dunn Nutrition Unit in the Gambia (26) and a pilot program in the rural areas around the city of Fortaleza in northeastern Brazil (27). One of the best known intervention programs was the controlled trial in Bangladesh that introduced improved community-based midwifery services in the Matlab region (28). Maine et al (29), however, have disputed that the decline in maternal mortality rates in Matlab was due to improved primary care services and attribute the rates to improved access to hospital perinatal services.
The most remarkable localized effort to reduce maternal mortality was probably the Frontier Nursing Service in rural Kentucky, which began in 1925 (1). Only 9 maternal deaths from direct obstetric causes were recorded among >12000 deliveries between 1925 and 1965. In the early years of the Frontier Nursing Service, the mortality rates were 10 times lower than those in surrounding affluent communities. Which elements of the program were most important and whether they can be replicated remains uncertain, but this experience is a beacon for those who aspire to create good maternal health services under difficult conditions.
Maternal mortality and national social and environmental factors
Only one study was found on cross-national social indices and maternal mortality. Hertz et al (30) related national social and environmental indices, including several nutritional ones, to reported rates of maternal mortality, infant mortality, and life expectancy. Their tentative conclusions were that the indices differed among the 3 endpoints studied. The published regression model for maternal mortality included 3 nutritional variables that were significant; the model was apparently overdetermined, however, this was due to one variable in the regression model being mislabeled. The senior author has since clarified this error (JR Hebert, personal communication, 1999). The corrected final model showed that maternal mortality was positively and significantly related to the percentage of households with sanitation and total energy intakes, but negatively (and almost significantly, P = 0.07) associated with the residual of total fat intakes. This negative relation with energy derived from fat probably reflects that the latter was relatively expensive and thus may have been an index of affluence as much as of nutrition. National numbers of medical personnel, hospital beds, households with safe water, and literacy were not significantly related to maternal mortality.
Economic disparity, structural adjustment, and maternal health
Evans (31), reporting on a lecture by Professor Kelsey Harrison, indicated that the gulf between the richest and poorest countries' gross national product per capita increased from 8-fold in 1950 to nearly 30-fold in 1995. Although 24 countries were categorized as poor in 1950, in 1995 there were 47, of which 29 were in sub-Saharan Africa. The disparity in health between rich and poor countries was starkly reflected by the lifetime chance of a woman dying during pregnancy: 1 in 17000 in Italy compared with 1 in 7 in Mali. Harrison stated that the cost of an uncomplicated cesarean delivery in the area where he worked in Nigeria was $274. This was an average 9-mo salary, and those who needed the operation but could not afford to pay, died.
The conditions devised by the World Bank or the International Monetary Fund so that developing countries can receive loans typically require reduced government spending, usually leading to lower social expenditures, ie, health care expenditures, public education, and the education of women. This is likely to affect health adversely, both from reduced health services and from continued illiteracy; there is a close association between maternal literacy and health outcomes (32). Thus, these organizations, which represent the world community, although doing some well-motivated work to improve public health and nutrition, are also implementing other policies that are almost surely making population health and nutrition status worse, at least in the short run.
Effect of maternal death on surviving children
In their study of maternal mortality in Sweden in the 19th century, Högberg and Broström (33) found that 68% of infants born alive to dying mothers did not survive. Even more striking, siblings aged<1 y at the time of the mother's death had only a 3% chance of surviving to age 5 y. Similarly, siblings between ages 1 and 5 y had only a 13% chance of surviving to the same age. Although the effect in the contemporary developing world may not be this severe, the death of a mother is likely to be followed by the death of 50% of her children under the age of 5 y (34). Although some of these children may die of causes shared with their mothers (eg, starvation or AIDS), most will die directly or indirectly from the lack of maternal care.
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ANEMIA AND MATERNAL MORTALITY |
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TOPABSTRACTINTRODUCTIONHISTORICAL EPIDEMIOLOGY OF...ANEMIA AND MATERNAL MORTALITYANEMIA AND OBSTETRIC HEMORRHAGEMATERNAL NUTRITION AND...NUTRITION AND TOXEMIA OF...MATERNAL NUTRITION AND PUERPERAL...CONCLUSIONSREFERENCES |
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The assumption at the onset of this review was that the knowledge base underlying this apparent consensus would be confirmed and the paucity of examples of improved health following anemia treatment and prevention would be due primarily to the failure to carry out program protocols adequately. In other words, although the consequences and the prevention and cure of anemia would be straightforward, the implementation of programs to lower iron deficiency would be problematic. This has turned out not to be true. Upon careful review, the underlying basis for the consensus is clearly far from secure. The rest of this section explores why current policies to lower rates of anemia are unlikely to lower the risk of maternal mortality greatly, why there still might be appreciable benefit from more effective programs to deal with anemia, and why a great deal of further research—both basic and applied—is essential.
A series of linked assumptions underlie current thinking about the effect of maternal anemia on maternal mortality (listed below in the section "Responding to severe anemia during pregnancy"). None of the assumptions, however, is securely supported by the available evidence as presented below. This does not imply that increasing maternal survival by preventing and treating anemia, particularly severe anemia, may not be possible. Rather it reveals crucial gaps in knowledge about whether—and how—this might best be done.
Methodologic problems relating anemia to maternal mortality
The literature on anemia during pregnancy is extensive, but the available data on the association between anemia and maternal survival are limited. A few key studies are repeatedly referred to, usually in passing and uncritically, and discussion quickly moves onto other issues. It has been chastening to scrutinize the basic data on which the relation of anemia to maternal mortality is usually posited.
Ideally, to determine the relation between anemia and subsequent mortality, hemoglobin concentration and other hematologic and biochemical indexes of anemia should be measured prospectively before pregnancy. This would avoid confusion resulting from the hemodilution of pregnancy. Because anemia is defined by hemoglobin concentration, rates of anemia during pregnancy are much higher than those that occur during the nonpregnant state. Risk estimates calculated from hemoglobin concentrations measured before pregnancy would be better indicators of the need for prophylaxis or treatment (42). Measurements would be made in a representative population and women would be followed to the end of pregnancy. Pregnancy outcomes would be related to the rate and etiology of anemia, whether prophylaxis and treatment were received, and the extent to which anemia was corrected. Ideally, treatment would be double blinded (ie, assigned randomly with both recipients and observers unaware of treatment assignment). Unfortunately, no investigation has come close to such methodologic rigor.
Few studies even relate hemoglobin concentrations measured prospectively during pregnancy, usually at unspecified stages of gestation, to maternal mortality. Only one study reported clearly that hemoglobin concentration measurements had been recorded in early pregnancy (43), and all of the studies but one were in hospital populations. Although the hope that prepregnancy hematologic status can be related to subsequent risk during pregnancy may be utopian, the uncertainty of inference drawn from hemoglobin concentrations measured at the time of delivery cannot be overemphasized. Hemoglobin concentration measurements at delivery are confounded in at least 4 ways: by the hemodilution of pregnancy, the physiologic rise in hemoglobin concentration in the third-trimester, concurrent illness (especially hemorrhage or infections that may have been the reasons for coming to the hospital; the most important confounder), and the unrepresentativeness of the women (a flaw common to all studies on patients first encountered at confinement). Population rates of observed outcomes cannot be inferred from women enrolled at confinement because the referent population (those who are cared for in hospitals on an unbooked or emergency basis) can rarely be described or quantified.
The plea for representativeness in such studies may seem to be a methodologic nicety—epidemiologic prissiness—but it is a crucial issue. Women who arrive at a hospital only at the time of birth rarely do so because of disinterest or laziness. Quite the contrary: they typically go to the hospital because they are very sick and often do so after an arduous and unsettling journey. These sick women are at high risk of dying. It is difficult to justify comparing survivors with those who die among women who end up in the hospital and then imputing the results to the larger population from which they were drawn. Such comparisons are at best weak approximations and are probably very misleading. This is especially true because hemoglobin concentration at confinement is likely to be measured because of bleeding and may have been the reason for the transfer to the hospital in the first place. Most studies have correlated hemoglobin concentrations in moribund women entering the hospital with their subsequent death, which does not provide an adequate basis on which to decide how anemia affects maternal survival. Furthermore, no available studies have taken into account the effect of anemia prophylaxis or treatment, other than transfusion in the treatment of very severe anemia (<40 g/L) on the chance of dying. Fullerton and Turner (55), in Ibadan, Nigeria, reported that there were no cases of cardiac failure and no maternal deaths when hematocrit was >0.13. The death rate among severely anemic women (hematocrit <0.14) decreased from 20% to <3% by using exchange transfusion. Yet this patently inadequate set of studies is used as the basis for prophylaxis and treatment programs.
Drawing conclusions from the proportion of all deaths attributed to anemia rather than to the risk of death given anemia only adds to the confusion. Ross and Thomas (44), in their review of maternal anemia and mortality, used the proportion of all maternal deaths attributed to anemia as their central index. Their analyses were typically based on hospital series data. Such attribution can be highly subjective and is likely to vary widely. Moreover, estimating whether and to what extent the risk of death was increased in anemic women, using this approach, is not possible because the risk of death from anemia cannot be estimated by considering only those who died. With so many uncertainties, it is hardly surprising that the percentage of maternal deaths attributed to anemia, or in which anemia was considered a contributing factor, varied widely, from as low as 1.9% to as high as 18.6% [not nearly as high as the 20–40% conveyed by Viteri (39)]. Stokoe (45), in a review of 16 hospital-based studies of maternal mortality in the developing world, found that the median percentage of deaths attributed to anemia was zero (9 of 16 studies). Estimates in the other 7 studies cited ranged from 3.0% to 7.5%. These were not only lower rates, but were considerably less variable than those suggested by Ross and Thomas (44).
There are no universally accepted standards for attributing death to anemia; even if there were, they would be difficult to apply consistently from place to place and across time, especially when clinical information is incomplete, diagnostic criteria are not uniform, and data collection is not standardized. Not only is it difficult to specify the cause of death consistently and accurately, but bias in attributing cause of death is possible. A hospital could put itself in a better light by attributing death to anemia rather than to hemorrhage because the latter is more likely to be understood to reflect obstetric mismanagement.
A cohort approach is needed to estimate the risk of death from anemia: comparison of mortality rates between groups of pregnant women with and without anemia. If the same proportion of women who die have anemia with the same degree of severity as surviving women, anemia cannot logically be implicated as a contributory cause of death. (Even the few reports from which relative risk of death associated with anemia can be calculated, rarely, if ever, specify the causes of anemia or the effect of therapy.)
Studies relating anemia to maternal mortality
All studies relating anemia to maternal mortality from which relative risks could be calculated are presented in Table 1. Llewellyn-Jones (46) presented one of the rare reports that is probably entirely prospective, although he makes no explicit statement that all the hemoglobin concentration measurements were done before confinement. He described 73048 women delivered at the maternity hospital in Kuala Lumpur between 1953 and 1962, of whom 2250 (3.1%) had severe anemia, with initial hemoglobin concentrations <66 g/L. The maternal mortality ratio for those with severe anemia was 1556/100000 live births (n = 35) compared with 350/100000 live births (n = 248) for (presumably) all the other women, a relative risk of 4.4.
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Harrison (47) presented data suggesting that the percentage of anemia in 12262 mothers delivered in Zaria, Nigeria, was 6.1%, whereas that in mothers who died was 4.7%. The anemia criterion was not defined. Inferring from the author's data, it appears more likely that there were 36 deaths among the 760 anemic women, a ratio of 4.7%, and 142 deaths in the 11699 other women, or a ratio of 1.2% and a relative risk of 3.9.
In another publication from the same hospital, Harrison (48) presented the relation between hematocrit and maternal death for 5178 singleton births in 1976. Whether the hematocrit was measured before term was not specified. In this series, the maternal death rate was 20% (5/25) with a hematocrit <0.14, 3% (3/90) with hematocrit between 0.15 and 0.25, and zero (0/143) with hematocrit between 0.25 (equivalent, approximately, to a hemoglobin concentration of 80 g/L) and 0.29. Thus, maternal death was extremely common with very severe anemia and common with severe anemia, but nonexistent with moderate anemia. This is only 1 of 2 reports explicitly reporting the risk of maternal mortality associated with moderate anemia.
Harrison and Rossiter (49), also in Zaria, Nigeria, observed maternal mortality ratios of 370/100000 live births for patients registered for prenatal care (booked) and 2860/100000 live births for patients who presented at the hospital for the first time at delivery (unbooked). The 19 deaths among the booked patients were not arrayed by hematocrit. Only 22% of the unbooked survivors and 55% of those who died had hematocrit measured. Hematocrit values for the 219 unbooked women who died are compared with those of unbooked survivors in Table 2. Presumably, the women's hematocrits were not measured until they arrived at the hospital, and women with antepartum hemorrhage were not excluded. Although there was no clear relation between low hematocrit at delivery and either total mortality or mortality associated with antepartum or postpartum hemorrhage, high hematocrit was associated with high mortality. This does not, however, preclude the possibility that anemia might have been associated with high mortality; a relation could have been masked by the incompleteness of these data. The inference that can be drawn from these results is limited for 5 reasons: 1) The hematocrit of only a small number of women was measured, and these women were almost certainly, on average, sicker than women whose hematocrit was not measured. Because hematocrit was not measured universally, presumably measurement would have been far more likely when clinically indicated (ie, in the presence of anemia and when transfusion might be contemplated). 2) The at-risk population from which these women were drawn is unknown; inferring rates of anemia and estimating risks of death in the larger population is, therefore, very uncertain. 3) Hematocrit at hospital entry for delivery may have had a weak relation with hematocrit earlier in pregnancy. 4) The causes and duration of anemia in these women are unknown. 5) Iron deficiency was stated to be an unusual cause of anemia in this region.
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90 g/L at confinement. The death ratio among anemic urban women was 388/100000 live births compared with 184/100000 live births for the nonanemic women, a relative risk of 2.1. For rural women, the mortality ratios were 1348/100000 live births and 228/100000 live births, respectively, a relative risk of 5.9. All but 9 of the 108 deaths were emergency admissions and 40 were among women who were moribund at admission. Estimating population death rates is not only impossible, because the background populations from which these women were drawn are unknown, but the implications of hemoglobin measured at admission for women who were very sick and often in shock, are uncertain. Death ratios were not presented for women with hemoglobin concentrations between 90 and 110 g/L. The much higher risk of death associated with anemia for rural women is provocative and consistent with anemia being far more dangerous when access to obstetric care is limited; women who need obstetric services most are least likely to have access to them. These data strongly suggest the interdependence between nutritional status and health services in affecting pregnancy outcome. Thonneau et al (51) carried out a case-control study of 102 maternal deaths and 338 control women who delivered between July 1, 1989, and June 30, 1990, in Conakry, Guinea. The relative risk of death if anemia was present was 2.1 (95% CI: 1.1, 4.1). However, anemia was not defined, hemoglobin concentrations were not given, and is it not clear whether hemoglobin was measured prospectively.
In western Kenya, Zucker et al (56) observed 6 deaths among 73 severely anemic pregnant women with hemoglobin concentrations <60 g/L at admission, a death rate of 8.2%. The hospital apparently provided medical but not obstetric services. Of the 279 women in the reference group who were hospitalized but who did not have severe anemia, 177 of whom were pregnant, only 4 died. No results were presented for anemic pregnant women with hemoglobin concentrations >60 g/L, and these admissions were presumably a mix of both pregnant and nonpregnant women with either severe medical or obstetric problems. Neither death rates nor relative risks of death with severe anemia during pregnancy can be calculated because of the indeterminate reference population. Nevertheless, the very high death rate among the severely anemic is striking.
Diallo et al (52), in a prospective hospital study in Conakry, Guinea, observed a maternal mortality ratio of 852/100000 live births for the 10.7% of women who were anemic. Anemia was defined as <110 g/L hemoglobin. They stated in their summary that these 12 deaths represented 65% of all maternal deaths but, in the text, a value of 25% was given, which appears more plausible. If the latter value was correct, by comparing anemic with nonanemic women, the relative risk of death can be calculated as 2.8. From the data presented, it is not possible to estimate whether there were different death ratios for severe and moderate anemia. This population of hospitalized women served as an unrepresentative sample in which to study anemic women compared with nonanemic women, as reflected by the high frequency of severe anemia: 56% of all women with anemia had hemoglobin concentrations <80 g/L; only 44% had concentrations between 80 and 110 g/L, the reverse of what would be expected in the general population. Thus, this subset of women cared for in the hospital was skewed to the very sick.
Sarin (53) reported on maternal mortality in a hospital series (as well as a population survey of the prevalence of anemia during pregnancy) in Punjab State, India. The author related maternal mortality to hemoglobin concentrations measured at admission for delivery. For nonanemic women (n = 38), the maternal mortality ratio was 566/100000 live births, for mildly anemic women (n = 184) it was 927/100000, and for severely anemic women (n = 117) it was 1769/100000. These cross-sectional hospital-based data at delivery and those of Harrison (48) are the only data available that explicitly present the mortality risk associated with moderate anemia. The results of the 2 studies, however, are contradictory. Nevertheless, whether there was increased risk of mortality associated with moderate anemia, by far the highest risk of excess mortality was in the severely anemic.
The recent study of McDermott et al (54) in Malawi, which followed a cohort of 3740 pregnant women prospectively, is extremely important. Hematocrit concentrations and HIV antibodies were assessed. Of the 6.2% of women with hematocrit concentrations <0.25, the odds ratio for maternal death combined with death 3–10 mo after delivery was 5.9, and was 9.9 for later death alone. Among HIV-positive women, the odds ratios were 9.8 and 30.8, respectively, for the 2 time periods. The death rate for the 13.2% of women who had a hematocrit concentration between 0.25 and 0.29 was not reported and was, presumably, not raised significantly. In this population, severe anemia was profoundly related to maternal death, but mild-to-moderate anemia was probably unrelated. The role of nutrition was likely to be smaller than other factors, such as HIV infection, in the causation of both anemia and maternal death.
Conclusion
On the basis of the fragmentary evidence available, it seems reasonable to assume that the risk of maternal mortality is greatly increased with severe anemia. The data available only confirm an associative—not a causal—relationship. Nevertheless, the strength of this relationship makes it appropriate to presume that it is causal, all the while trying to collect more definitive data. From available evidence, it seems appropriate to take immediate action to correct severe anemia during pregnancy, with the understanding that there is a profound need to simultaneously examine key questions about the relationship between anemia and maternal mortality. The most urgent and most difficult of these questions is whether intervention during pregnancy can be shown to affect death rates.
The evidence of a relationship between maternal death and moderate anemia, however, is both scanty and contradictory. Until further data are available, it appears that moderate concentrations of anemia are probably best considered unrelated to excess maternal mortality, and correcting moderate anemia should be given lower priority than correcting severe anemia. There is an urgent need to clarify the relations between concentration of anemia and maternal survival and pregnancy outcome, and to estimate to what extent prophylaxis and treatment modify risk of morbidity and mortality.
Prevalence of anemia
Several extensive reviews of anemia prevalence during pregnancy have been published. A World Health Organization (42) report published in 1992 on anemia prevalence in women contains an exhaustive survey and is an update of the original summary compiled by Royston (43). The more recent report estimates that 58.27 million women worldwide are anemic during pregnancy, of whom 55.75 million live in developing countries and 2.52 million live in industrialized countries (Table 3). Anemia is less prevalent among nonpregnant women, but the absolute number of anemic nonpregnant women is much greater than that of anemic pregnant women. An estimated 400 million nonpregnant women are anemic worldwide, of whom >90% are in the developing world. The most severely affected area is south Asia, where 75% of women are anemic during pregnancy as are 58% of nonpregnant women. Anemia prevalence is also high in Southeast Asia, Africa (except southern Africa), and the Caribbean. The review by Sloan et al (57) summarizes all the reports on the rates of anemia from developing countries, published in refereed journals or national or regional reports between 1979 and the time of their review.
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Typically, even in the developing world, rates of severe anemia have been much lower than rates of mild and moderate anemia. In rural Zaire, Jackson et al (61) found that although 72% of women attending an antenatal clinic had anemia, only 3.7% had hemoglobin concentrations <70 g/L. Zucker et al (56) observed that 6% of pregnant women in western Kenya had hemoglobin concentrations <60 g/L. Gyssens and Meheus (62), in Niger, found that 46.7% of women at their first antenatal clinic attendance had hemoglobin concentrations <110 g/L, but only 1.9% of the women had concentrations <70 g/L. In Mozambique, Liljestrand et al (63) found that 58% of pregnant women had hemoglobin concentrations <110 g/L, but that only 10% of the women had values <90 g/L. Bergsjø et al (64) found that 74.5% of women in Moshi, Tanzania, had hemoglobin concentrations <110 g/L, but only 7% of the women had concentrations <70 g/L. Thus, although anemia is extremely common in poor, pregnant Third World women, the reported rates of severe anemia are, with exceptions such as these reports from rural south Asia or Papua New Guinea, no more than 10%.
Etiology, prevention, and treatment of anemia
Etiology of anemia
Anemia has multiple causes among Third World women, which are often concurrent, especially if the anemia is severe. In any one area there may be a mix of a deficiency of dietary iron (from low bioavailability and less often from low intakes; low iron bioavailability is usually caused by dietary phytate or other dietary iron absorption inhibitors, including tannins in tea, and malabsorption syndromes such as sprue); folate and vitamin B-12 deficiency; intestinal bleeding caused by hookworm or other parasites; vaginal bleeding; malaria, particularly in primigravid or young women; hemoglobinopathies such as sickle cell disease and thalassemia; and concurrent infections, especially HIV. For example, Harrison and Ibeziako (65) noted that in their area of Nigeria, red cell hemolysis that was indirectly due to Plasmodium falciparum infection was the main etiologic factor of anemia, but that folate deficiency and hemoglobinopathies were also found; iron deficiency was rare. Fleming (66) noted that among 248 consecutive admissions of anemia during pregnancy or the puerperium in Ibadan, Nigeria, only 2 patients were iron deficient and both had heavy hookworm infestation. In all the other patients, the anemia was due to P. falciparum, folate deficiency, hemorrhage, hemoglobinopathies, and various miscellaneous other causes. Ratten and Beischer (67) found that 34% of the 202 pregnant women with hemoglobin concentrations <82 g/L in Melbourne had ß-thalassemia. Melbourne has many immigrants from Mediterranean countries whose populations have high rates of the genetic trait for thalassemia.
Brabin et al (60) found that malaria prophylaxis was important for controlling anemia in Papua New Guinea. Atukorala et al (68) found in an observational study in pregnant tea plantation workers in Sri Lanka that among women supplemented with iron and folate, only those who also received anthelminthic treatment had increased hemoglobin and serum ferritin concentrations. Olukoya and Abidoye (69) found that hemoglobin concentrations in pregnant women in Lagos, Nigeria, were significantly lower if the women carried intestinal parasites. Other infections are also important causes of anemia, and HIV infection has become the most notorious problem in the developing world (54). Thus, the causes of anemia vary with dietary practices, infectious disease and parasite burdens, genetic factors, and socioeconomic status.
Interrelationships between iron and other nutrients
Grindulis et al (70) found a strong relation between iron and vitamin D nutrition for Asian toddlers in England. Mejia and Arroyave (71) found that vitamin A fortification in Guatemala was associated with increased transferrin saturation and serum ferritin concentrations. Suharno et al (72) found that although 68% of anemic pregnant Indonesian women responded to iron supplements alone, 97% responded to a combination of iron and vitamin A.
Prevention: effect of iron supplementation during pregnancy in community-based programs
Sloan et al (57), Yip (73), and Cook and Reddy (74) commented on the discrepancy between the results of clinical trials and population-based iron supplementation programs. They noted that clinical trials have repeatedly shown that iron supplementation increases iron stores and hemoglobin concentrations in pregnancy. In contrast, there is no convincing evidence that community-wide or population-based iron supplementation programs have had much, if any, demonstrable effect on either iron stores or, more importantly, other indexes of maternal or perinatal health. This failure of community programs to reduce the prevalence of anemia may be due to many factors, including low compliance, administrative inefficiency, or the use of iron to prevent or treat anemia that is only partially due to iron deficiency.
The Indian Council of Medical Research (75) evaluated the Indian national program of anemia prophylaxis with iron and folate supplements. This evaluation, whatever its limitations, is important because India has more severely anemic women than any other country. The report presents the distribution of hemoglobin concentrations by the number of iron tablets received by pregnant women and the results were interpreted as showing no significant effect of iron therapy on severe anemia (hemoglobin concentration <75 g/L). However, on reanalysis, the data show that there was a highly significant association between ingestion of iron supplements and the prevalence of severe anemia. The frequency of severe anemia was 22.7% in those women who received any tablets compared with 26.3% in those women who did not. The effect, however, was observed at an improbably low intake of as few as 15 tablets for the entire pregnancy. Only one-fifth of the women received tablets, which is a clear indication of program insufficiency. Although highly significant statistically, the small effect on the rates of anemia and the low rate of receipt of iron tablets are discouraging.
Sloan et al (57) did a meta-analysis on 24 randomized trials published between 1966 and 1989 that met their criteria for adequate study design. Nine of the 24 studies on the effects of iron supplementation during pregnancy were from developing countries. The findings are provocative. On average, the increase in hemoglobin concentration was only 2 g/L greater in subjects who received a traditional dose of 60 mg Fe/d than in control subjects who received a placebo. An appreciably greater effect was observed, however, with increasing doses of iron. The mean hemoglobin response was 16 g/L greater than that of the control subjects with a dose of 120 mg Fe/d (Table 4). These findings have 4 implications for anemia prevention programs: 1) The results appear to undermine the likelihood that less-than-daily supplementation will be optimal. Possibly those who were prescribed 120 mg Fe/d took less than that but still consumed enough to make a measurable difference in hemoglobin concentrations, whereas low compliance among those given 60 mg Fe/d could have led to negligible change. 2) Tolerance to oral iron decreases with increasing dose and, with the observed need for high doses, there is clearly a narrow therapeutic window between an effective and a tolerable dose. 3) There was a strong inverse association between the initial group mean hemoglobin concentration and the average response to therapy (Table 4). In the few developing country studies in which the initial mean hemoglobin concentration was relatively high (110–119 g/L), iron treatment led to an average increment of hemoglobin concentration of only 5 g/L compared with that of control subjects. This increase was one-half or less the effect of iron in studies in which the initial mean hemoglobin concentrations were lower. 4) When mean hemoglobin concentrations were lowest (<100 g/L), the effect of the intervention was less than that in the trials in which the initial mean hemoglobin concentrations were between 100 and 109 g/L (mean hemoglobin increase was 10 g/L compared with 13 g/L more than control values, respectively). This may have been a chance finding, but, without alternative data, it needs to be addressed with utmost seriousness. From what is known about the physiology of iron absorption, the opposite trend would be expected—with lower hemoglobin concentrations and presumably more severe iron deficiency, iron absorption should be increased. One explanation for this anomaly may be that in populations with lower hemoglobin concentrations, anemia was less often due to iron deficiency alone and, therefore, less responsive to iron or iron-folate therapy alone.
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Treatment: frequency of iron prophylaxis
Several reports state that weekly iron supplementation is as—or nearly as—effective in raising or maintaining hemoglobin concentrations during pregnancy as is daily supplementation. However, in their trial that showed 120 mg Fe/wk was as successful as 60 or 120 mg Fe/d in preventing third-trimester anemia, Liu et al (76) did not include women with initial hemoglobin concentrations <80 g/L for legitimate ethical reasons. The same research team showed that weekly doses of 60 mg/Fe for nonpregnant women without anemia were effective in preventing anemia (77). Ridwan et al (78) found that in anemic women (hemoglobin concentrations < 110 g/L), hemoglobin increased to approximately the same concentrations with weekly or daily iron supplementation. The increase in serum ferritin, however, was far greater with daily than with weekly supplementation. The authors did not report the results for severe anemia separately. Thus, the issue of weekly prophylaxis is not yet settled. The use of less-than-daily iron therapy for any level of anemia during pregnancy seems unlikely to become standard practice because of the results of the meta-analysis by Sloan et al (57). They found scant evidence of any effect on hemoglobin concentration even with traditional doses of 60 mg Fe/d.
The possibility of adverse pregnancy outcome with high or even normal hemoglobin concentrations or with iron supplementation
The scope of this paper precludes a comprehensive assessment of possible dangers of iron treatment other than during pregnancy. The association between high hemoglobin concentration and adverse maternal and infant outcomes, the possibility that oral iron ingestion can cause high hemoglobin concentration, and the direct evidence that iron-induced increases in hemoglobin concentration are associated with toxicity will be discussed and allusions will be made to the controversies about other possible toxicities of iron. Scrimshaw (79) has comprehensively reviewed the health effects of iron deficiency.
Iron, hemoglobin concentration, and fetal growth
Mahomed and Hytten (80) conducted a meta-analysis on the effect of routine iron, folate, or iron and folate administration during pregnancy. They concluded that supplemental iron prevents, or greatly reduces, the normal decrease in hemoglobin concentration during pregnancy, but that no clinical benefit is seen either in the pregnancy itself or in the infant, only a buildup of a woman's iron stores. On the other hand, there are hints that the reversal of the normal decrease of hemoglobin concentration and iron-induced macrocytosis may increase blood viscosity to a degree that could impair utero-placental blood flow. Compared with the concentration defined as signifying anemia, higher hemoglobin concentrations have consistently been associated with a worse prognosis for the mother and child. Harrison and Rossiter (49), in Zaria, observed that hematocrit concentrations of 0.45 were associated with a marked increase in maternal mortality (Table 2
), but the number of subjects was very small. Murphy et al (81) found a marked increase in the incidence of maternal hypertension, as well as increased perinatal mortality, low birth weight, and preterm birth associated with higher hemoglobin concentrations early in pregnancy. In the US Collaborative Perinatal Study, Garn et al (82, 83) found steeply increased fetal death rates in white women with a hematocrit concentration above 0.32 and black women with a hematocrit above 0.30. The associations were not as strong for increased premature delivery and low birth weight; they occurred in white women with hematocrit values >0.35 and in black women with hematocrit values above 0.32. Sagen et al (84), in Norway, observed markedly lower birth weights with maternal third-trimester hemoglobin concentrations >120 g/L, especially >130 g/L. Steer et al (85) found, in a large area-wide study in England, a J-shaped relation between midtrimester hemoglobin concentrations and both low birth weight and preterm delivery. The optimal hemoglobin concentrations were between 96 and 105 g/L, with moderately worse outcomes at lower and slightly higher hemoglobin concentrations, and much worse outcomes with hemoglobin concentrations >136 g/L.
There has not been much concern in the public health nutrition community about potential toxicity from iron treatment or prophylaxis during pregnancy, largely because as iron stores rise, the absorption of oral iron is usually depressed. For example, in their meta-analysis, Sloan et al (57) found that there was less response to oral iron supplementation when initial mean hemoglobin concentrations were highest. In developed countries, iron treatment induced an 8-g/L increase in hemoglobin when initial concentrations were 120 g/L, and a 10-g/L increase when initial concentrations were between 110 and 119 g/L. In developing countries, the mean increases were 5 and 13 g/L for initial hemoglobin concentrations of 110–119 and 100–109 g/L, respectively. Oral iron treatment of women with normal hemoglobin concentrations, however, has been shown to raise hemoglobin to concentrations associated with adverse pregnancy outcomes. Pritchard and Hunt (86) randomly gave either a placebo, 1000 mg intramuscular iron, or 104 mg oral iron/d to term to pregnant women near the end of their the second-trimester, including those with normal hemoglobin concentrations. They found that although only 8.2% of the subjects who received a placebo had hemoglobin concentrations 130 g/L at term, 39% of those who received intramuscular iron were at or above this concentration. Oral iron had an effect equivalent to parenteral iron: 40.5% had hemoglobin concentrations 130 g/L (Table 5). This study showed that women without overt anemia who were given either parenteral iron or oral iron supplements had hemoglobin concentrations that were raised to values associated with maternal and fetal toxicity. Hemminki and Rimpelä (87) reported essentially identical results, with routine iron administration having as great an effect on third-trimester hemoglobin concentrations in women with an initial hematocrit >0.41, as in women whose hematocrit was <0.36.
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120 g/L and 17% had concentrations of 130 g/L. Most studies and the reviews collating them, including the one conducted by WHO (42), do not typically report on the proportion of women with high hemoglobin concentrations. Sloan and Jordan (89) reviewed 43 prevalence studies of hemoglobin concentration during pregnancy of women living in developing countries. Of these, studies 3 (7%) reported mean initial concentrations of hemoglobin >130 g/L and another 17 (30%) reported mean concentrations between 120 and 130 g/L. Therefore, many women are potential candidates for adverse consequences from high hemoglobin concentrations if such effects can be induced by iron treatment. Knowing the differential response to routine iron supplementation in women with very low initial hemoglobin concentration is important. Knowing whether those women with normal or high hemoglobin concentrations could be tipped into possible high-risk status by receiving high doses of iron is also important. More important, however, is to know whether such risks are real. The practical significance of the observations on adverse outcomes associated with high maternal hemoglobin concentrations for both the mother and the infant is unclear for 2 reasons. The adverse outcomes associated with high hemoglobin concentrations may be due to relative macrocytosis, as suggested by Mahomed and Hytten (80), or due directly to placental perfusion problems because of high red blood cell concentration. They could also have little to do with iron or red cell mass because high hemoglobin concentrations, like low concentrations, reflect not only red cell mass, but also plasma volume expansion. A high hematocrit concentration may reflect inadequate plasma volume expansion and consequent poor vascular perfusion unrelated to red cell mass.
The studies of Hemminki et al (87, 90–93) are among the few to contribute to our understanding of whether iron supplementation can cause harm by increasing hemoglobin concentrations or by causing other toxicities (discussed below). In Hemminiki et al's studies, 2960 pregnant Finnish women were recruited and randomly assigned to receive either routine or selective iron supplementation during pregnancy. Third-trimester hematocrit values were much higher in the routine group than in the selective supplementation group. The authors found that iron supplementation increased hematocrit values but did not influence birth weight. The relation of high hematocrit values to poor fetal growth is thus probably caused by factors other than iron. The authors reported that their results were contrary to controlled trials in pregnant women and rats that consistently reported lower birth weight in groups receiving iron, yet also reported that prior studies had included fewer subjects and that in human studies, no such differences were significant. Thus, this large study suggests a dissociation between the effect of iron supplementation on hematocrit concentrations and on birth weight. Although more women in the routinely supplemented group reported adverse side-effects from the medication, the groups were similar in regard to most other outcomes, including the incidence of infection. There were several worse outcomes in the selective supplementation group, such as an increased likelihood of a cesarean delivery or blood transfusion, which the authors thought were due to the reactions of midwives and physicians to the low hematocrit values rather than to actual need for these procedures. At 7-y follow-up, the one difference in health outcome among the children, which was an important differentiation, was that the children of mothers who received routine iron supplementation during pregnancy had significantly higher rates of hospital admission for convulsions (93).
Iron and immune function
There are immunologic deficits associated with both iron deficiency and excess iron stores. Strauss (94) reviewed the literature on iron deficiency and immune function and concluded that, although the molecular defect had not been defined, an abnormality of immune function associated with anemia could be detected by several assays measuring cell-mediated immunity and that normal function was usually restored after iron repletion. Dallman (95) reviewed the relation between iron and immune function, including the possible toxic effect of supplemental iron. He concluded that the evidence that iron deficiency caused defects in cell-mediated immunity and bacterial killing was impressive, although there was little evidence of increased morbidity from infection. He also referred to several studies of toxicity from excess iron and concluded that avoiding both too little and too much iron is best.
Prema et al (96) found significantly lower proportions of T and B lymphocytes associated with hemoglobin concentrations <80 g/L but not with moderate anemia in third-trimester Indian women without overt infection. Concentrations of immunoglobulin (Ig) G were significantly higher in severely and moderately anemic women than they were in women without anemia. IgA concentrations were also higher in the severely anemic women than they were in the nonanemic women and, although the authors stated that Ig A concentrations were also significantly higher in moderate anemia, the tabulated data raise doubts about this. Kandoi et al (97) found that stimulation indexes of lymphocytes at 0 and 24 h were abnormally low in both maternal and cord blood of women whose hemoglobin was <80 g/L. Only the 24-h cord blood stimulation index, however, was significantly low when mothers were moderately anemic. Thus, there is some evidence that severe maternal anemia is associated with immunologic abnormality in pregnancy.
Although this is a review focused on pregnancy, the results of the study by Oppenheimer et al (98) raise some serious questions. They performed a randomized controlled trial of supplementing 478 newborn infants in Papua New Guinea with 150 mg intramuscular Fe and following them to
