The prevalence of iron-deficiency anemia in pregnancy is 35-75% in developing countries and 18% in industrialized countries. Anemia in pregnancy is associated with an increased risk for preterm delivery, low birth-weight and maternal mortality.

Chapter 2: Management of Iron-Deficiency Anemia in Pregnancy and the Postpartum

Introduction

Iron deficiency is the most common nutritional disorder in the world, affecting approximately 25% of the world's population. ¹ Pregnant women are particularly at high risk for iron deficiency and iron-deficiency anemia because of increased iron needs during pregnancy. The prevalence of iron-deficiency anemia in pregnant women is estimated to be between 35 and 75% (average 56%) in developing countries whereas in industrialized countries the average prevalence is 18%. ^{2, 3} Anemia during pregnancy has been shown to be associated with a two-fold risk for preterm delivery and a three-fold risk for low birth-weight ⁴ as well as maternal mortality. ^{5, 6} The World Health Organization (WHO) estimates that anemia contributed to approximately 20% of the 515,000 maternal deaths worldwide in 1995. ⁷ Moreover, iron-deficiency anemia is associated with impaired physical and work capacity as shown in non-pregnant women. ⁸ There are multiple causes of anemia during pregnancy, including inadequate diet (mostly inadequate iron supply but also folate and vitamin B12 deficiencies), impaired micronutrient absorption, blood loss resulting from hemorrhage, and helminth infestation. ^{Note ?} Non-nutritional causes include thalassemia, malaria and sickle cell disease. Repeated pregnancies, too, are a source of blood loss. However, it is generally estimated that half of the anemia cases in pregnancy are related to iron deficiency. ³

In the postpartum period, anemia is common and self-limiting, resolving itself within a week in many parturient patients. ⁹ In many other patients, it is a major cause of maternal morbidity and mortality. ¹⁰ The symptoms of postpartum anemia vary and may include breathlessness, fatigue, palpitations, dizziness, infection, lactation failure and prolonged hospital stay depending on the severity of blood loss and related anemia. ^11-13 Maternal iron-deficiency anemia has also been shown to be strongly associated with depression, stress and cognitive function in the postpartum period ¹⁴ and may result in difficulty for the mother to care for her baby, thereby influencing the emotional mother-infant bond. The prevalence of postpartum anemia varies from 4 to 27%. ^15-17 It appears to be higher in unfavorable socioeconomic conditions, reaching 48% among non-Hispanic black women in the US. ¹⁵ Anemia in this setting is often associated with markers of iron deficiency. In industrialized countries, iron stores are depleted in approximately one-third to one-half of parturients. ^18-20

1. Mechanism of Iron-Deficiency and Related Anemia During Pregnancy and the Postpartum

The prevalence of anemia is estimated to be 43% in non-pregnant women in developing countries and 12% in industrialized countries. 3 Statistics for iron deficiency are not available because of the technical and financial challenges of determining iron status in large populations. ¹⁶ The prevalence of iron deficiency is, however, logically far greater than that of anemia, ¹⁷ indicating that most women enter pregnancy with iron stores inadequate to meet the increased iron needs required for red blood cell mass expansion in the mother as well as for the development of the fetus and the placenta. Approximately 1000 mg of iron are needed during pregnancy, ^{18, 19} 500 mg are used to support the expanding maternal hemoglobin mass and 300 mg for the development of the fetus and placenta.

Almost all iron needs occur during the second half of pregnancy, ²⁰ when fetus organ formation occurs. Iron requirements are not as great in the first trimester because of the absence of menstruation and limited fetal needs. On average, daily iron needs are between 6 and 7 mg as opposed to 1 mg/day in normal physiologic conditions. During the last 6 to 8 weeks of pregnancy, the need increases to up to 10 mg/day. Although iron absorption is substantially increased during pregnancy and is adequate in healthy iron-replete women ^{Note ??} , it fails to meet the requirements in iron-deplete pregnant women. In women who enter pregnancy with low iron stores, iron supplements often fail to prevent iron deficiency. ¹⁷ Furthermore, conditions such as abnormal placenta implantation may induce chronic blood loss and increase iron requirements during pregnancy.

With regard to the postpartum period, an increase in plasma volume during pregnancy that is proportionally higher than the increase in the red blood cell mass results in physiological hemodilution. Consequently, the mother is protected from the loss of red blood cells during the bleeding associated with delivery. However, 5% of deliveries are accompanied by blood losses > 1 L, and symptomatic anemia, including cardiovascular symptoms, may develop in the parturients, thus exposing them to blood transfusions. ¹⁰ Pre-existing anemia even further exposes patients to more severe postpartum anemia and related complications, and increases the risk of peripartum transfusions. ²⁴

2. Diagnosis of Iron-Deficiency Anemia

Hemoglobin (Hb) concentration threshold values used to define anemia are obtained from statistical analysis of populations. Consequently, not all women will have clinical symptoms associated with anemia even when Hb values are below the recommended threshold. In non-pregnant women, anemia is defined by an Hb concentration < 12 g/dL. 16 However, because of physiological hemodilution, other Hb cut-off values have to be considered. The US Centers of Disease Control proposes an Hb of 11 g/dL as the lower normal limit in the first and last trimesters of pregnancy, with a recommended lower normal limit of 10.5 g/dL during the second trimester. ²⁵ Consequently, any Hb concentration < 10.5 g/dL indicates anemia during pregnancy.

Although iron deficiency is the major cause of anemia during pregnancy, other causes, such as infection, abnormal hemoglobin, kidney disease and parasites (malaria, helminthes), should be ruled out before the appropriate treatment is initiated. Complete blood count (CBC), including Hb concentration and red blood cell indices (mean corpuscular volume [MCV], mean corpuscular hemoglobin concentration [MCHC], and reticulocyte count), is, therefore, the first step for the positive and differential diagnosis of anemia in this setting as in others. ²⁶

The assessment of iron deficiency usually refers to serum ferritin (SF) concentration and transferrin saturation (TSAT). The gold standard for evaluating iron stores is bone marrow biopsy. In practice, though, this test cannot be used routinely. Therefore, because SF indirectly reflects iron stores, it is currently considered as the best available measurement for their evaluation.

It is also important to distinguish absolute iron deficiency from functional iron deficiency, particularly in patients receiving erythropoietin-stimulating agents (ESAs) such as rHuEPO [recombinant human erythropoietin]. In absolute iron deficiency, iron stores are depleted whereas in functional iron deficiency, iron stores are available but cannot be released rapidly enough to be used by erythropoiesis. Absolute iron deficiency is defined as SF values < 15 ?g/L. TSAT is commonly used to assess iron availability and functional iron deficiency; TSAT < 15% indicates functional iron deficiency if SF is within the normal range.

There are limitations to the use of SF and TSAT in appropriately evaluating body iron status. SF is an acute phase reactant and increased values are associated not only with conditions inducing systemic inflammation such as infection, but also with physiological responses to surgery or in the postpartum. ^32-37 As for TSAT, it varies daily. Moreover, transferrin concentration varies in parallel with serum albumin, which is influenced by nutrition28 as well as by cytokine production during acute and chronic inflammatory reactions. ²⁹ Therefore, other laboratory parameters have been suggested in order to obtain more accurate information on iron stores and iron availability, particularly in the presence of inflammation.

The percentage of hypochromic red cells (%HRC; normal < 2.5%) ³⁰ is assessed by automated red cell analyzers (Bayer H-1, H-2, H-3 or ADVIA? 120) that, unfortunately, are not available in all clinics. %HRC measures the proportion of red blood cells with suboptimal Hb concentration; it reflects not iron stores but iron availability for erythropoiesis and increases during functional iron deficiency. A recent study by Krafft et al. showed that %HRC values remain comparable in the pre- and early postpartum period (within 48 hours before and after delivery) and thus are not influenced by the inflammation associated with postpartum. ²⁷

Reticulocyte Hb content (CHr) is calculated by the simultaneous measurement of reticulocyte volume and Hb concentration by means of an automated analyzer (Bayer H3 or ADVIA? 120). This parameter reflects the level of effective erythropoiesis, ³¹ with values < 28 pg reported as the being the most accurate in detecting functional iron deficiency. ³² In the abovementioned study by Krafft et al., mean CHr was 27.1 ? 1.6 pg in the early postpartum period in 64 iron-deficient non-anemic (Hb ? 10 g/dL) women; interestingly, in this study, 67% of patients had CHr values < 28 pg while only 55% had SF < 15 ?g/L.

Another parameter used to assess iron deficiency is the serum soluble transferrin receptor (sTfR) concentration. sTfR essentially reflects the number of erythroblasts in the bone marrow and, therefore, total erythroid activity. The serum concentration of sTfR increases in response to erythropoietic stimulation by ESAs and in iron deficiency it is increasingly used to assess iron-restricted erythropoiesis. ³³ sTfR concentrations have been found to be unchanged in normal pregnancy ³⁴ and not influenced by inflammation, ³⁵ suggesting that this marker could be used to detect iron deficiency during pregnancy. STfR concentrations have been reported to decrease in the postpartum, probably reflecting suppressed erythropoiesis. This parameter has been proposed to differentiate iron deficiency and anemia attributable to inflammation when SF values alone are difficult to interpret. ²⁷

Erythrocyte protoporphyrin concentration increases in patients with iron deficiency and can be used to detect moderate iron deficiency without anemia. ³⁶ However, this parameter is influenced by inflammation, lead poisoning and hemolytic anemia-conditions that all induce a significant increase in its concentration.

Therefore, because of the inflammatory response in delivery, it is preferable to measure iron parameters prepartum rather than in the early postpartum. %HRC, CHr and sTfR measurements could provide additional information on functional iron deficiency and are less influenced by inflammation.

3. Treatment of Iron-Deficiency Anemia During Pregnancy

3.1. Oral Iron Therapy

Oral iron therapy has been shown to be effective in correcting iron-deficiency anemia in most cases. 37 Its efficacy may, however, be limited in many patients because of the dose-dependent side effects, lack of compliance and insufficient duodenal iron absorption. ^{17, 21} It should also be noted that while there is evidence supporting the correction of hematological and iron status parameters with oral iron supplementation, data on improving birth weight and decreasing preterm delivery are still lacking. ³⁸

In cases where oral iron is ineffective or associated with side effects, intravenous iron supplementation ^{Note ???} and rHuEPO are treatment options. These strategies can also be used when a more rapid correction of anemia is required.

3.2. Intravenous Iron Therapy

Although no data on toxicity of intravenous iron use during the first trimester of pregnancy are available, for safety reasons, intravenous preparations should be considered only after the second trimester. Intravenous iron dextran, iron gluconate and iron sucrose have been considered for the correction of iron-deficiency anemia during pregnancy, with most data relating to iron sucrose. Because of serious, unpredictable and life-threatening anaphylactic reactions associated with iron dextran in 0.6 to 2.3% of patients 39-41 and the availability of the two safer intravenous iron agents, ⁴² iron dextran is not commonly recommended in practice. Clinical data on intravenous iron therapy during pregnancy primarily deal with intravenous iron sucrose.

3.2.1. Intravenous Iron Therapy Versus Oral Iron

Two studies have compared intravenous iron sucrose and oral iron administration in the correction of iron-deficiency anemia during pregnancy. Al-Momen et al. 43 conducted a prospective, open-label, controlled trial in 111 pregnant women with severe iron-deficiency anemia (Hb < 9 g/dL, SF < 20 ?g/L). The patients were sequentially assigned to receive either intravenous iron sucrose (n = 52) or oral ferrous sulfate (n = 59). The total amount of iron to be given intravenously was calculated to correct the Hb deficit ^{Note ?} and administered as an infusion of single 200-mg doses in normal saline every 1 to 3 days. The controls received ferrous sulfate 300 mg (60 mg elemental iron) three times a day until the target Hb was reached, then once daily. The intravenous iron therapy resulted in higher levels of both Hb and SF, with the time to achieve maximal Hb concentration also significantly shorter in this group compared with controls (mean 6.9 vs. 14.9 weeks). No serious adverse events were noted with iron sucrose while 6% of patients could not tolerate oral ferrous sulfate and were excluded from the study; 30% of patients in the control group presented with disturbing gastrointestinal symptoms and 32% were non-compliant.

Another study conducted as a randomized controlled open trial compared intravenous iron sucrose with oral ferrous sulfate to correct iron-deficiency anemia (Hb 8 to 10 g/dL and SF < 50 ?g/L) in 50 pregnant women. ⁴⁴ The intravenous treatment group received a total amount of iron sucrose equivalent to the calculated total iron deficit ^{Note *} via six slow infusions. The group on oral iron therapy received ferrous sulfate 240 mg daily for 4 weeks. All patients received folic acid 15 mg daily. Although the difference in mean Hb concentration increase between the two groups was not statistically significant, only intravenous iron supplementation was able to restore iron stores in this patient population. In addition, even though the study was not powered to detect a difference in birth weight, mean birth weight was 250 g higher in the group that received intravenous iron sucrose (p > 0.05). Tolerance to intravenous iron sucrose was excellent whereas 30% of patients who received the oral iron had gastrointestinal disturbances.

One small, uncontrolled study ⁴⁵ examined the efficacy of intravenous iron gluconate in correcting iron-deficiency anemia in 21 pregnant patients (mean gestational age 28 weeks) with severe symptomatic anemia (Hb < 8.5 g/dL and anemia-related clinical symptoms) who previously had experienced severe side effects with oral iron, no improvement of anemia or had a history of gastrointestinal surgery. A mean total of 1,000 mg of iron (as iron gluconate 125 to 187.5 mg) was administered by daily intravenous injection. However, owing to the occurrence of dose-dependent side effects, the single-dose injection was subsequently limited to 62.5 mg. This treatment resulted in an increase in mean Hb and SF concentrations.

3.2.2. Intravenous Iron With or Without Recombinant Human Erythropoietin (rHuEPO) Therapy

In a prospective, randomized, open study, Breymann et al. 46 evaluated the efficacy and safety of intravenous iron sucrose with or without rHuEPO in correcting iron deficiency anemia (Hb < 10 g/dL and SF < 15 ?g/L) in pregnant patients (gestational age > 21 weeks) in whom the daily administration of oral ferrous sulfate 160 mg for at least two weeks failed to increase Hb concentration. Twenty (20) patients received either rHuEPO 300 IU/kg and iron sucrose 200 mg administered intravenously or iron sucrose 200 mg alone, twice weekly for 4 weeks or until the target Hb of 11 g/dL was reached. There was an immediate reticulocyte response and progressive increase in hematocrit (Hct) in both groups; however, a higher reticulocyte count and increase in Hct was observed in the group that received the combination therapy. Median duration of therapy was shorter in the combination therapy group (18 vs. 25 days) and more patients in this group reached the target Hb by 4 weeks (19 vs.15 patients). SF and TSAT increased progressively in both groups, with normal values reached in all patients. Functional iron deficiency, as assessed by %HRC, was present before treatment and persisted until the end of the study period. Interestingly, all women had prepartum Hb above 11 g/dL and none required blood transfusions during pregnancy or in the postpartum. There were no preterm deliveries or small-for-gestational-age infants in either group. No serious reactions to treatment were reported. Consequently, the authors concluded that intravenous iron therapy alone should be considered first in resistant iron-deficiency anemia during pregnancy. rHuEPO may be considered in severe anemia (Hb < 9 g/dL) cases requiring rapid correction of anemia or in patients who do not respond to intravenous iron therapy alone.

The same research team also reported on their experience from 1992 to 2000 with intravenous iron sucrose to manage iron-deficiency anemia (Hb < 10 g/dL and SF < 15 ?g/L) in 100 pregnant women (mean gestational age 31.5 weeks) resistant to treatment with ferrous sulfate 160 mg daily for at least 2 weeks. Patients received 200 mg of intravenous iron sucrose twice weekly (undiluted bolus or infusion in 200 mL normal saline over 30 minutes) for a maximum of 4 weeks or until a target Hb of 11 g/dL was attained. Mean treatment duration was 21 days (range: 8 to 29). Anemia was corrected in all patients-with a mean Hb increase of 1.9 g/dL-and associated with significant increases in mean corpuscular volume and mean corpuscular Hb. Mean SF concentration and TSAT, both in the abnormal range before treatment, improved significantly after two weeks and reached normal levels by the end of treatment.

Oral iron therapy should, therefore, be considered as first-line treatment in gestational iron-deficiency anemia in most cases. However, many patients will be refractory to anemia correction with this treatment. In such instances, intravenous iron therapy will correct the anemia in the majority of patients. Consistent data through controlled and randomized trials are available for iron sucrose while only limited published data are available on iron gluconate in this setting. As for intravenous iron dextran, it is not recommended given the possibility of rare, but life-threatening, anaphylactic reactions and the availability of safer iron preparations. ^{Note **} The impact of these interventions on clinical maternal and infant outcomes merits further studies.

4. Treatment of Postpartum Iron-Deficiency Anemia

The traditional approach to postpartum anemia has been to rely on oral iron supplementation or blood transfusions. However, both treatments involve serious disadvantages. Indeed, the efficacy of oral iron is limited owing to low duodenal absorption and lack of compliance 21; 48-49 while transfusions expose patients to risks inherent to blood products and should be considered only as a last resort in this young and otherwise healthy population. ¹⁰ Consequently, other strategies, including intravenous iron therapy and rHuEPO, have been considered.

4.1 Erythropoietin Therapy Plus Iron Versus Iron Therapy Alone

A recent Cochrane review on the treatment of women with postpartum iron-deficiency anemia 10 assessed the effects of oral and parenteral iron and folate supplementation, erythropoietin administration and blood transfusion. This work identifies six randomized controlled trials (RCTs) ^{11; 50-61} involving 411 women who received iron and/or erythropoietin as primary interventions. No RCTs that assessed treatment with blood transfusions were identified. Combination treatment with erythropoietin and iron therapy was not superior to iron therapy alone as regards the the need for transfusion. However, the studies may not have been powered enough to rule out such a difference. Surprisingly, Hb increase was higher when erythropoietin therapy was compared with iron alone or iron and folate as opposed to placebo.

Lebrecht et al. ⁵¹ conducted a randomized double-blind study to compare the efficacy and safety of intravenous iron sucrose alone or in association with rHuEPO in the correction of anemia (Hb < 9 g/dL) in 36 women 48 hours after delivery. Patients were randomized to receive either 20,000 IU of intravenous rHuEPO (n = 20) or placebo (n = 12) on a one-time basis; all received a single infusion of iron sucrose 400 mg in 500 mL normal saline over 1 hour on Day 2, followed by oral ferrous fumarate 200 mg and folic acid 1 mg for 4 weeks. Hb, Hct, SF and TSAT increased in both groups, but there were no significant differences in these values between the two groups at any time during the four-week study period. ^{Note ?}

In a randomized controlled trial, Breymann et al. ¹¹ examined the effect on hematological parameters of a single dose of intravenous iron sucrose alone (100 mg) versus combination therapy with a single dose of rHuEPO (300 IU/kg) administered either intravenously or subcutaneously in 90 patients with postpartum anemia (Hb < 10 g/dL, 48-72 hours after delivery). All patients received 160 mg elemental iron as oral ferrous sulfate and folic daily 0.7 mg for 6 weeks. Hb concentration increased in all three groups but significantly more in the group that received intravenous rHuEPO in conjunction with iron sucrose; however, the difference between the group that received intravenous iron sucrose alone was small and there was no difference between this last group and the one that received subcutaneous rHuEPO plus iron sucrose. Patients with baseline endogenous erythropoietin concentration < 145 mU/mL benefited more significantly from rHuEPO therapy. C-reactive protein (CRP) concentration was significantly higher in patients who underwent cesarean section compared with those who underwent vaginal operative or spontaneous delivery; there was no difference between CRP or SF values in patients with endogenous erythropoietin concentration < 145 mU/mL and the other patients. This study also suggested that a single dose of 100 mg of intravenous iron is not sufficient to prevent iron depletion during the recovery period of postpartum anemia because following an initial increase in SF, SF concentrations fell progressively and were below baseline levels six weeks after treatment. No patient required a blood transfusion in this study and there was no serious adverse reaction related to treatment.

In a randomized placebo-controlled study, ⁵² the same team compared intravenous iron sucrose and erythropoietin therapy with intravenous iron sucrose alone or oral ferrous sulfate in 60 patients with postpartum anemia (Hb < 10 g/dL, 24 to 72 hours after delivery). Placebo refers only to erythropoietin because placebo instead of iron would have been unethical in this setting. The treatment assignment was as follows: intravenous erythropoietin (300 IU/kg bolus dose) and iron sucrose (200 mg bolus dose); intravenous placebo and iron sucrose (200 mg bolus dose); or oral ferrous sulfate (80 mg elemental iron) plus folic acid (0.35 mg) (controls). Treatment was administered for 4 consecutive days and from Day 5 to Day 14 all patients received oral ferrous sulfate and folic acid at the same doses as the controls. Hct increased progressively in all three groups, particularly in patients who received rHuEPO and iron sucrose combination therapy. The reticulocyte response was higher in these patients compared with the others and higher in those who received intravenous iron sucrose alone versus controls. As for iron parameters, there was a significant increase in mean SF concentrations at the end of the study period in patients who received either iron sucrose plus rHuEPO or iron sucrose alone and a decrease in the controls (mean 80.6, 81.5 and 21.7 ?g/L, respectively, vs. 38.4, 30.5 and 28.6 ?g/L at baseline; p < 0.01 at the end of the study for both groups that received intravenous iron sucrose vs. controls). CRP was elevated in all patients 48 to 72 hours after delivery, but significantly higher in those who underwent cesarean section and normalized by Day 14. The post-hoc subgroup analysis showed that patients with cesarean section and those with elevated CRP concentrations, i.e., probably with blunted erythropoiesis, appeared to have benefited the most from rHuEPO therapy and had a significantly higher Hct response. No patient required a blood transfusion and there was no serious adverse event related to the study treatment.

Markrydimas et al. ⁵³ compared the effect of rHuEPO therapy (200 IU/kg/day subcutaneously) for 15 days in association with oral iron therapy (200 mg/day) and folic acid (5 mg/day) for 40 days versus oral iron and folic acid therapy alone (control group) at the same dose and duration in 40 women with postpartum anemia, i.e., Hb < 10 g/dL on Day 1 after delivery, in a randomized, single-center study. On Day 3, mean reticulocyte count was significantly higher in the women who received rHuEPO, as compared with the controls (p < 0.05). On Day 5, the mean Hb increase was > 2 g/dL in the group undergoing rHuEPO therapy as compared with 0.7 g/dL in the control group (p < 0.05). When compared with oral iron therapy alone, combination treatment with rHuEPO also increased the likelihood of lactation at discharge from hospital (RR [relative risk] 1.90; 95% confidence interval [CI] 1.21 to 2.9810). Furthermore, two women in the control group required blood transfusions while no transfusion was required in the rHuEPO group. A meta-analysis of this study involving 100 women shows a relative risk of 0.20 (95% CI 0.01 to 3.92) for blood transfusion requirement in patients receiving rHuEPO compared with those who received iron therapy only. ¹⁰ In this analysis, however, the limits of meta-analysis should be taken into account, as should the difference in anemia management approaches and transfusion policies of the two groups.

As for the impact of intravenous iron therapy on transfusion requirements in the postpartum, a retrospective analysis of 217 patients (5% of 4292 parturients) with postpartum anemia (Hb < 8 g/dL within 48 hours after delivery) who gave birth at a single institution examined the difference in terms of transfusion both before and after the availability of intravenous iron sucrose at the center. Intravenous iron sucrose was administered as single 100- to 200-mg doses once or twice a week for a total amount calculated by a formula. ?? Between April 2001 and March 2003, 15/103 patients (14.6%) received a blood transfusion and 88/103 received oral iron; between April 2002 and March 2003, 5/114 patients (4.4%) received a blood transfusion, 66 received oral iron, and 43 received intravenous iron. The mean increase in Hb over 7 days was higher in patients who received intravenous iron sucrose when compared with those who received oral iron exclusively (p = 3.9 x 10-8). Although a retrospective study, the findings show that there was a three-fold decrease in the proportion of transfused patients since the introduction of intravenous iron at the institution.

4.2 rHuEPO Alone Versus Placebo

In a randomized, double-blind, placebo-controlled multicenter study, Meyer et al. 54 compared treatment with a single intravenous dose of rHuEPO 10,000 IU versus an intravenous placebo administered 24 hours after delivery in 71 women with postpartum Hb < 10 g/dL. Five days after treatment, there was no significant difference in Hb or Hct; however, the Blues Questionnaire used to assess postpartum depression showed significant increases for the items "able to concentrate," "elated," "happy," "confident," and "calm" in the rHuEPO group compared with placebo (p < 0.001).

4.3 Subcutaneous Versus Intravenous rHuEPO Administration

The meta-analysis 10 of two studies ^{55, 56} suggests that there is no difference between the intravenous and the subcutaneous route of rHuEPO administration in terms of Hb or Hct increase. Interestingly, there was a significant heterogeneity when rHuEPO was given once, probably attributable to the fact that in one study ⁵⁷ all the women received intravenous iron sucrose whereas in the other ⁵⁶ patients received only oral iron supplementation.

Trials on the treatment of iron-deficiency anemia have principally considered hematological indices (Hb and Hct) and iron status parameters. The administration of intravenous iron is associated with significantly higher increases in Hb concentrations and improvement in iron status compared with oral iron. rHuEPO as adjunctive therapy seems to have an additional positive effect of particular benefit to a subset of patients with blunted erythropoiesis (e.g., those undergoing cesarean section). In one study, rHuEPO also increased the likelihood of lactation at discharge from hospital when compared with oral iron therapy alone. There is no apparent effect on transfusion requirements when rHuEPO is administered in association with iron versus iron therapy alone.


Notes

? Any blood loss results in a loss of 0.5 mg of iron per mL of total blood.

?? Iron absorbed from dietary sources, along with mobilized iron stores, is usually insufficient to meet iron requirements during pregnancy. Therefore, routine iron supplementation is required for all pregnant women, particularly in developing countries. 21 However, systematic iron supplementation during pregnancy, regardless of whether the woman is iron-deficient, has been the subject of debate in many developed countries. Moreover, prophylactic iron supplementation strategies to prevent iron deficiency during pregnancy differ among developing versus industrialized countries; WHO recommends routine oral supplementation of 60 mg elemental iron plus 400 ?g folic acid daily for 6 months during pregnancy in areas where the prevalence of anemia in pregnancy is < 40%. In areas where the prevalence of anemia in pregnancy is ? 40%, it recommends the same dosages for 6 months and continuing for 3 months postpartum. ²² In some developing countries, however, oral iron doses as high as 240 mg daily have been used ²³ while in many industrialized countries 30 mg elemental iron is recommended daily.

??? The intramuscular and subcutaneous routes for iron administration have been abandoned in many countries because of local side effects such as pain at the injection site or permanent skin staining and hematoma following intramuscular injection in the presence of coagulation abnormalities. However, iron preparations for intramuscular injection are available in some countries.

? Total iron deficit = body weight (kg) x (target Hb - initial Hb [g/L]) x 0.3 plus 10 mg/kg to replenish the exhausted iron reserves.

* Total iron deficit = body weight (kg) x (target Hb - initial Hb [g/L]) x 0.24 plus 500 mg, rounded up to the nearest multiple of 100 mg.

** A recent study using US Food and Drug Administration's Freedom of Information (FOI) surveillance database to compare the type 1 adverse event profiles for the three intravenous iron preparations available in the United States showed event reporting rates of 29.2, 10.5 and 4.2 reports/million 100 mg dose equivalents, while all-fatal-event reporting rates were 1.4, 0.6 and 0.0 reports/million 100 mg dose equivalents for iron dextran, iron gluconate and iron sucrose, respectively. 47

? Breyman et al. have never compared a blood conservation approach with a liberal transfusion policy because they considered this to be unethical. They consider that the correction of anemia is a valid endpoint per se, logically resulting in a reduction in transfusion requirements. Currently, in 2005, only 1% of parturients receive a transfusion in Dr. Breyman's institution.


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