Critical appraisal of the literature

1. 1. How should blood loss anemia be managed in otherwise healthy women?
   
   
   
   • Medline: iron deficiency anemia AND women AND review and a separate search for iron deficiency treatment AND oral iron preparations OR intravenous iron preparations
     
   • Hand‐searching reference lists were used to identify additional articles of interest.
     
   • Inclusion: References providing information relevant to the management of blood loss anemia published in the English language were included.

The first principle in the management of anemia due to iron deficiency resulting from blood loss is to identify the source of the bleeding with reasonable certainty. This may be determined simply by the history and physical examination and attributed to menstrual bleeding or blood loss associated with delivery in the case of menstruating women and those who are pregnant or postpartum. However, further diagnostic testing to unambiguously identify the source of bleeding is indicated in postmenopausal women, as otherwise there is a risk of missing sources of gastrointestinal blood loss, including colorectal malignancies.

Evidence indicates that in otherwise healthy women with a hemoglobin level below the normal range of 12–15.5 g dl⁻¹, a low serum ferritin level is the most reliable indicator of iron deficiency [2]. A low serum iron and elevated total iron binding capacity (TIBC) or serum transferrin level is also consistent with the diagnosis. Significant iron deficiency is associated with a hypochromic, microcytic anemia and decreased absolute reticulocyte count [3]. Additional tests that have been evaluated for the diagnosis of iron deficiency, such as the soluble transferrin receptor (sTf) or sTF/ferritin ratio, appear to contribute only modestly to the accurate diagnosis of iron deficiency [4].

Once iron deficiency or iron deficiency anemia is diagnosed, treatment with oral iron replacement is generally indicated. There are a variety of different iron salts available for oral use including ferrous sulfate, ferrous gluconate, ferrous fumarate, and ferrous carbonate. Although different preparations may have a different content of elemental iron and there are anecdotal claims that one preparation may be better tolerated than another, there is no clear benefit to the use of any one preparation in terms of safety or efficacy [5] (Table 32.1). For those women who cannot tolerate oral iron replacement therapy, and for those with symptomatic anemia, consideration can be given to the administration of intravenous iron. The potential benefits of this therapy, including more rapid resolution of anemia, must be balanced against the potential risks. Since a significant percentage of women (estimated at 15–25%) have difficulty tolerating oral iron, the availability of newer parenteral iron preparations with lower risk of anaphylaxis has provoked reevaluation of the potential benefits of parenteral iron [7]. As for oral iron preparations, there is little evidence in the literature to recommend use of one parenteral iron preparation over another, except that use of high molecular weight iron dextran, which has been associated with a relatively high number of anaphylactic reactions, has fallen out of favor. It has even been removed from the market in some countries. Low molecular weight dextran and other intravenous iron preparations associated with a lower incidence of this complication are preferred [6].

1. 2. What is the appropriate approach to identification and management of hemoglobin disorders that may be encountered during pregnancy, and what are the implications for the fetus?
   
   
   
   • Medline: hemoglobin disorders AND pregnancy and a separate search for sickle cell disease (SCD) OR thalassemia AND pregnancy AND transfusion.
     
   • Hand‐searching reference lists were used to identify additional articles of interest.
     
   • Inclusion: References providing information relevant to the management of hemoglobin disorders during pregnancy published in the English language were included.

Women with hemoglobin disorders, including thalassemia and SCD, require appropriate management during pregnancy in order to help ensure the most optimal maternal and fetal outcomes. In addition, clinicians need to be aware that some previously undiagnosed women with hemoglobin disorders such as hemoglobin SC‐sickle cell disease may first present during pregnancy with symptoms related to their underlying hemoglobinopathy [8]. Another important aspect relevant to overall management of women with hemoglobin disorders is providing appropriate genetic counseling, so that individuals can make informed choices before they become pregnant. The importance of appropriate genetic counseling prior to pregnancy is highlighted when there is a history of α‐thalassemia. Each human chromosome 16 has two genes encoding α‐globin. The form of α‐thalassemia trait that is most common in Asian populations involves deletion of both genes from one chromosome. If such women conceive with partners who also carry this same trait, a quarter of the pregnancies will result in fetuses affected by absence of any functional α‐globin genes, resulting in severe pre‐eclampsia, hydrops fetalis and fetal demise in the absence of intrauterine exchange transfusions. Thus, identification, proper counseling, and intervention, if indicated, in such individuals are important.

Pregnancy is considered to be relatively safe, and favorable outcomes have been reported in patients with β‐thalassemia major and β‐thalassemia intermedia. However, these women are at risk for a variety of different maternal complications during pregnancy, including cardiac failure and thrombosis [9] (Table 32.2). Because these individuals may receive regular transfusions, they may be on iron chelation therapy, which generally should be discontinued. Regular transfusion therapy during pregnancy for individuals with β‐thalassemia major, along with close monitoring is recommended.

Women with SCD, particularly those with sickle cell anemia (homozygous for hemoglobin S [HbS]), have an increased incidence of fetal loss, increased maternal mortality, and experience an increased number of complications, including vaso‐occlusive crises and thrombosis during and immediately following pregnancy [13] (Table 32.2). The use of prophylactic blood transfusion in patients with SCD remains controversial [14]. Though some studies have shown some evidence of benefit, most of these trials have been relatively small and have had potential methodological issues.

1. 3. What diagnostic evaluation should be performed in the evaluation of vaginal bleeding once gynecologic causes are investigated?
   
   
   
   • Medline: women AND bleeding disorder AND diagnostic evaluation
     
   • Hand‐searching reference lists were used to identify additional articles of interest.
     
   • Inclusion: References providing information relevant to the evaluation of hematologic causes of vaginal bleeding published in the English language were included.

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