Maternal Anemia and Maternal Mortality

The relationship between maternal anemia and the risk of mortality have been examined in two previous reviews [13, 14]. No randomized controlled trials to date provide data on the impact of iron supplementation on maternal mortality as the outcome. The likelihood of such trials being conducted in the future is low, mainly due to ethical and feasibility considerations. Observational studies conducted in Africa and Asia, primarily among pregnant women presenting at hospitals, provide evidence for the association between hemoglobin concentration upon admission at a hospital or clinic and maternal mortality. None of these studies provides information on iron deficiency per se or the proportion of anemia attributable to iron deficiency. Anemia, especially severe, can arise from multiple causes including malaria (mainly Plasmodium falciparum), hookworm, vitamin deficiencies, and chronic infections such as HIV. However, as shown by the review by Brabin et al. [14], P falciparum malaria as an etiology of anemia may be less important in leading to maternal death. In holoendemic malarious settings, an estimated 9 versus 41 deaths per 100,000 are due to malaria-related severe anemia compared with nonma-larial anemia deaths among primagravidae [14].

Previously, severe anemia alone was considered to be associated with an increased risk of maternal mortality [13, 14], and the population attributable risk was strong for severe but not moderate anemia (Table 21.1) [14]. Severe anemia (normally defined as hemoglobin [Hb] < 70 g/l) can result in circulatory decompensation and increased cardiac output at rest. The added stress of labor and blood loss, whether normal or excessive, can lead to circulatory shock and death. In most settings, however, the prevalence of mild-to-moderate anemia (70-110 g/l) tends to be much higher than that of severe anemia [15]. Recently data from nine studies were examined to determine the relationship between Hb concentration and case fatality (Figs. 21.1, 21.2) (R.J. Stoltzfus and L. Mullany, unpublished data) for estimating the global burden of disease linking iron deficiency to disability and death [16]. Hb data collected in these studies when plotted by the observed proportion of maternal

Table 21.1

Relative Risk and Population Attributable Ratio (PAR ) of Maternal Mortality for Moderate and Severe Maternal Anemia

Relative risk 95% CI PAR PAR

Population prevalence Moderate anemia (Hb 40-80 g/l) Severe anemia (Hb 27-47 g/l)

5% 20% 1.35 0.92, 2 0.017 0 3.51 2.05, 6 0.111 0.334

Malaysia (17)

Malaysia (17)

Severe Anemia Hemoglobin

0 50 100 150

Mid -Point Hemoglobin (g/L)

Fig. 21.1. Proportion of maternal deaths by hemoglobin concentration among pregnant women in nine studies

0 50 100 150

Mid -Point Hemoglobin (g/L)

Fig. 21.1. Proportion of maternal deaths by hemoglobin concentration among pregnant women in nine studies

Anemic Pregnant Female Pakistan
  • I— 60
  • I— 80

Mid -Point Hemoglobin (g/L)

Fig. 21.2. Proportion of maternal deaths by hemoglobin concentration ranging between 50 and 120 g/l among pregnant women in nine studies

  • I— 60
  • I— 80

Mid -Point Hemoglobin (g/L)

Fig. 21.2. Proportion of maternal deaths by hemoglobin concentration ranging between 50 and 120 g/l among pregnant women in nine studies deaths revealed a threshold relationship; case fatality increased dramatically at maternal Hb concentration below 50 g/l (Fig. 21.1). Using the same data but limiting the range of Hb concentration to between 50 and 120 g/l revealed the relationship to be a linear one in most countries, suggesting an inverse, continuous relationship between the two variables within the narrower range of Hb (Fig. 21.2). This newly defined association was used to model the decrease in proportion of maternal deaths with a unit increase in Hb concentration [16]. The WHO prevalence estimates for anemia were converted to mean Hb concentrations, assuming a normal distribution. These values were further adjusted to reflect a distribution of Hb for iron deficiency anemia assuming that iron deficiency contributes to 50% of anemia, globally [26]. Using relative risk estimates from published studies, an odds ratio estimate of 0.75 (95% confidence interval [CI]: 0.62, 0.89) was calculated, indicating a decrease of 25% in the odds of maternal death with every 10g/l increase in the population in mean Hb concentration [16]. Antenatal iron supplementation at dosages ranging between 60 and 120 mg/day and duration between 10 and 12 weeks has been shown to increase Hb concentrations by about 80-140 g/l [26]. Thus, antenatal iron supplementation would be an important strategy for combating the risk of anemia-related maternal mortality in the developing world. Also, it is noteworthy that the mortality risk increases precipitously at extremely low Hb concentrations (<50 g/l) (Fig. 21.1). However, because vast majorities of pregnant women are likely to be mildly-to-moderately and not severely anemic, the relationship that is observed between Hb concentrations between 50 and 120 g/l may be more meaningful in describing the risk at a population level. Furthermore, iron deficiency is unlikely to be the cause of such severe anemia. Rather, other etiologies such as malarial infection, hookworm, or chronic diseases may be responsible [13, 14]. A note of caution with respect to the anemia-maternal mortality relationship; confounding and bias cannot be overruled since data examining this relationship were derived solely from observational studies of women who may have presented to the hospital with multiple morbidities and whose Hb was assessed at the time of booking and not in early or even mid-pregnancy.

Recent studies that are not part of the previous reviews (as mentioned above) have also linked maternal anemia to the risk of maternal mortality and morbidity. In a small case-control study in Ghana, anemic women (defined as Hb <80 g/l) experienced more deaths (5/157) compared with age- and parity-matched controls (0/152) with Hb >109 g/l [27]. Anemic cases that were treated in this study (treatment unspecified) had an increase in median Hb from 65 to 95 g/l. In a second small study from India (n = 447 pregnancies), Hb was assessed as part of an antenatal exam (gestational age unspecified) [28]. While too small to examine mortality as an outcome, this study showed that subjects with Hb < 89 g/l had a four- to sixfold higher risk of prolonged labor compared with those with Hb >110 g/l. Similarly, the risk for caesarean section and "operative" vaginal delivery was higher by about the same magnitude. Both studies were observational with low sample sizes and failed to adjust for confounding variables. The lack of adjustment for confounding is problematic, as illustrated by a recent study of women with HIV in Tanzania [29]. Data in this study were analyzed linking anemia during pregnancy to female mortality (Table 21.2). While the relative hazards for both all-cause and AIDS-specific mortality increased with increasing severity of anemia, adjustment attenuated the magnitude of the risk and reduced the differential in the excess risk between moderate and severe anemia. Although these were not maternal deaths per se, and the median follow-up period represented in the analysis was 5.9 years (interquartile range: 3.8-6.7 years), this study showed an increased risk of mortality among HIV-infected women related to anemia. HIV infection is increasingly likely to contribute to the risk of anemia especially in the context of sub Saharan Africa.

Anemia and primary postpartum hemorrhage (PPH) together contribute to 40-43% of maternal deaths in Africa and Asia, where the burden of maternal mortality is the

Table 21.2

Anemia as a Predictor of Mortality among Women with HIV in Tanzania

Table 21.2

Anemia as a Predictor of Mortality among Women with HIV in Tanzania

All cause mortality

Relative Hazards (95% CI) AIDS-related mortality

Anemia

Unadjusted Adjusteda Unadjusted Adjusted,11

Moderate (Hb = 85-109 g/l) Severe (Hb < 85 g/l)

2.7 (2-3.6) 2.1 (1.5-2.8) 3 (2.1, 4.2) 2.2 (1.5-3.2) 6.2 (4.4-8.6) 3.2 (2.2-4.6) 7.2 (4.8, 10.7) 3.5 (2.2-5.3)

"Adjusted for CD4 count, WHO clinical stage, age, pregnancy, treatment arm in the study, and body mass index

"Adjusted for CD4 count, WHO clinical stage, age, pregnancy, treatment arm in the study, and body mass index highest [11]. While underlying anemia is considered to exacerbate the deleterious effect of PPH and death due to this cause, on its own it contributes to 9.1% of deaths in these two regions [11]. Although it is commonly stated that severe anemia can exacerbate the risk of death due to PPH, there are no empirical data to support this. In a series of 40 PPH deaths that occurred between April 1982 and April 2002 in rural India, hospital records indicated that 47.5% had severe anemia (Hb < 70 g/l) at the time of admission, and another 45% had Hb between 70 and 90 g/l [30]. However, without controls, it is hard to predict the mortality due to PPH among nonanemic women.

It has long been considered that anemia increases the risk of PPH [31, 32], although data supporting this are scant. The main causes of PPH include uterine atony, placental retention, trauma, and coagulopathy [33].

Few studies exist that have examined the risk of PPH itself by level of anemia. The few studies that have examined the risk, indicate a weak association (Table 21.3). Among emergency room patients admitted to a hospital in Auckland, New Zealand, between January and August of 1966, of 1,743 anemic women, 159 suffered from PPH compared with 15 out of 170 nonanemic women, suggesting no difference in the risk of PPH by anemia status [34]. More recently, Geelhoed et al. [18], using a cohort design in two subdistrict hospitals of Ghana, compared the risk of PPH among 157 severely anemic (Hb < 80 g/l) and 152 nonanemic pregnant women (Hb > 109 g/l) matched for age and parity and found no difference. On the other hand, Tsu [35] in a multivariate logistic regression analysis, after adjusting for other risk factors such as maternal age, parity, and antenatal hospitalization, reported that Zimbabwean women with PPH after normal vaginal deliveries were more likely to be anemic compared to those that did not experience PPH. In a study conducted in a hospital in Nigeria among 101 women who developed PPH and 107 controls, there was no difference in the prevalence of anemia measured during pregnancy [36]. Finally, in a hospital study, 374 cases of PPH were derived from 9,598 vaginal deliveries and matched to controls (ratio: 1:3) [37]. Cases had a significantly higher hematocrit (not lower) compared with controls at admission. There was no association between antenatal anemia and uterine atony, an important cause of PPH in a tertiary care hospital-based study in Pakistan [38].

In summary, study results are suggestive of neither (1) an increased risk of mortality due to PPH as a result of underlying anemia nor (2) an increased risk of PPH due to maternal anemia during pregnancy. However, as described previously, the association between maternal mortality and anemia remains consistent, albeit derived from observational studies. In addition, antenatal iron-folate supplementation is likely to affect

Table 21.3

Risk of Postpartum Hemorrhage and Maternal Anemia

Reference Population Risk of PPH: cohort studies

25a Auckland, New Zealand, booked emergency patients, 1,743 anemic vs. 170 nonanemic women 18b 157 severely anemic and

152 nonanemic Ghanaian women Risk of anemia: case-control studies

10.8

11.3

12.1

26c 151 cases of PPH and 299 controls 39.6 19 0.05

27d 1997 101 cases of PPH and 107 controls 5.9 4.7 NS

28 Hct, 374 cases and 1,122 controls 36.6±2.1 35.6±2.3 0.01

mean±SD

PPH postpartum hemorrhage, NS not significant, Hct hematocrit aAnemia defined as Hb<105 g/l and/or hematocrit <35 % or Hb > 105 g/l but blood film showing aniso-cytosis, microcytosis and hypochromia bAnemia defined as Hb <80 g/l and nonanemic women had Hb >109 g/l cHb < 120 g/l dAnemia was undefined other outcomes, reducing low birth weight and preterm delivery, and increasing infant iron stores. (These outcomes are discussed in Chap. 22, "Anemia and Iron Deficiency in Developing Countries".) There exists an international policy for iron-folate supplementation during pregnancy for women in the developing world [39]. This policy states that pregnant women should receive 60 mg iron and 400 mcg folic acid for 6 months during pregnancy in settings where the prevalence of anemia is <40%, and for 6 months during pregnancy through 3 months postpartum in settings where anemia prevalence is >40%. However, programs have failed to effectively reduce the prevalence of maternal anemia in many regions of the world. Anemia continues to affect 50-60% of women during pregnancy in countries in Asia and Africa. Data from Demographic and Health Surveys (DHS) reveal low rates of any antenatal iron use in developing countries, with the proportion of women taking at least 90 tablets, an amount recommended during pregnancy, being even lower in many countries (Fig. 21.3).

Iron supplementation, which usually is effective in halving anemia rates in developed countries is an insufficient strategy for combating the burden of this condition in the developing world. Malaria and hookworm control, reducing nutritional deficiencies in addition to iron and folic acid, and increasingly, treatment of HIV should be concurrent approaches for reducing maternal anemia in the developing world. The major barrier to effective supplementation programs is inadequate supply of iron tablets [41]. In a country such as Malawi, with one of the highest maternal mortality ratios (984/100,000 live births), women consider anemia to be a maternal health concern [42]. Similarly, perceptions of improvement in physical well-being and alleviation of symptoms of fatigue and poor appetite due to iron use would be helpful in efforts aimed at promoting antenatal iron supplementation in the developing world [41].

Percent

Sub-Saharan Africa Niger '98 Zimbabwe '99 Rwanda '00 Malawi '00 Gabon '00 Uganda '00-'01 Mali '01 Benin '01 Zambia '01-'02 Eritrea '02 Ghana '03 Burkina Faso '03 Madagascar '03-'04 Lesotho '04 Cameroon '04 Tanzania '04-'05

North Africa/West Asia/Europe Yemen '97 Turkey '98 Egypt '00 Armenia '00 Jordan '02

Central Asia Kazakhstan '99 Turkmenistan '00

South/Southeast Asia Nepal '96 Indonesia '97 Philippines '98 India '98-'99 Bangladesh '99-'00

Latin America/Caribbean Columbia '95 Dominican Republic '96 Haiti '00 Peru '00 Bolivia '03

Fig. 21.3. Percent of women who reported taking iron supplements [any (dark bars) and 90+ tablets (light bars)] during a previous pregnancy in the past 3-5 years. Data on prevalence of consumption of 90+ tablets were not available for many countries. (From Demographic and Health Surveys and [40])

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  • marta
    Why does anaemia increase risk of pph?
    6 years ago

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