Learning Objectives:After participating in this continuing education activity, the provider should be better able to:
1. Describe the importance of identifying anemia in advance of gynecologic surgery.
2. Identify the cause of anemia in surgical candidates.
3. Explain management options to correct anemia before gynecologic surgery.
A core part of the preoperative evaluation and preparation of a patient for gynecologic surgery is identification of risk factors for postoperative morbidity. These risk factors can then be addressed before surgical intervention, resulting in improved surgical outcomes and greater patient satisfaction.
Preoperative anemia has been associated with increased morbidity postoperatively including an increased likelihood of receiving perioperative blood transfusion and more postoperative complications including surgical site infection, delayed recovery, and greater length of hospital stay.1 Data from the World Health Organization (WHO) demonstrate that 30.2% of women worldwide and 17.8% of American women have anemia.2 Iron-deficiency anemia is the most common cause of anemia in the gynecologic population. Furthermore, the conditions that lead to the need for many gynecologic procedures are often associated with chronic blood loss that can lead to anemia.3 Forty-five percent of the nearly 430,000 women who undergo hysterectomies each year do so for abnormal uterine bleeding.4 Up to 22% of women who undergo hysterectomy are anemic.5 Thus, evaluation to identify preoperative anemia is especially pertinent in women undergoing gynecologic surgery. Although many women undergoing gynecologic surgery to correct abnormal bleeding may have already undergone unsuccessful medical therapy, the period before surgery can include optimization of hemoglobin levels. Use of allogeneic blood transfusions is associated with an increased risk of adverse clinical outcomes and increased health care costs. Therefore, optimization of anemia has shifted to preoperative medical management to reduce the need for allogeneic blood transfusion and improve perioperative outcomes.6
It is standard practice to obtain a complete blood count and thus obtain a hemoglobin level on a patient before surgery. Through this process, anemia is often identified preoperatively. However, the appropriate workup and optimal intervention to manage anemia is often not completed before surgery. Through this article, learners will better understand the scope of anemia in the patient population undergoing gynecologic surgery, how best to diagnose and evaluate anemia, and how to optimally manage these patients. Applying this increased understanding in clinical practice will result in improved surgical outcomes and patient satisfaction.
Preoperative Screening
Anemia is defined as a reduced number of circulating red blood cells (RBCs), which can be measured through the hemoglobin or hematocrit concentration in a complete blood count. The hemoglobin and hematocrit levels used to diagnose anemia vary based on age, sex, and pregnancy status. WHO developed cut-offs for mild, moderate, and severe anemia based on nutritional anemia studies. For the nonpregnant woman, mild anemia is defined as a hemoglobin level between 11.0 and 11.9 g/dL at sea level, moderate anemia between 8.0 and 10.9 g/dL, and severe anemia less than 8.0 g/dL.7 These ranges may not apply to certain populations, such as those living at high altitudes, smokers, African Americans, and patients with chronic disease. Symptoms of anemia may include fatigue, dyspnea, and palpitations; however, patients may be asymptomatic, especially if the anemia develops chronically.
Before surgery, all patients with a history of or suggesting anemia, and those undergoing a procedure where significant blood loss is expected, should have their baseline hemoglobin, blood type, and antibody screen measured. In current clinical practice, obtaining these laboratory studies is a part of routine preoperative testing. This testing should be performed at least 4 weeks before a scheduled procedure. It is imperative for patients with preoperative anemia to be identified and appropriately treated in a consistent and timely manner. If anemia goes unnoticed until the day of surgery, few options beyond an allogenic blood transfusion are currently available.8
Differential Diagnosis
The etiology of anemia (hemoglobin <12 g/dL, hematocrit <36%) should be identified before treatment is initiated. The most common cause of anemia before gynecologic surgery is chronic blood loss leading to iron deficiency,9 though a complete workup should be performed to rule out other causes of anemia. The first step in evaluation should, as always, include a complete medical history, including menstrual and obstetric history, history of gastrointestinal blood loss, use of nonsteroidal anti-inflammatory drugs or anticoagulants, and family history of bleeding or platelet disorders.
Testing for the most common form of anemia, iron deficiency, should be performed first. One should obtain blood for serum iron, total iron-binding capacity (TIBC), and ferritin. Findings consistent with iron-deficiency anemia include low serum iron (<75 [mu]g/dL for men and <60 [mu]g/dL for women), increased TIBC (>450 [mu]g/dL), and low ferritin (<15 ng/mL). One should note that ferritin may be normal in those with inflammatory conditions, as it is an acute-phase reactant in addition to an iron-storage protein.10 Additional findings consistent with iron-deficiency anemia include a low mean corpuscular volume (MCV, <80 fL/cell), and low reticulocyte count (<0.5%). In patients with an obvious cause of iron-deficiency anemia such as heavy uterine bleeding, a therapeutic trial of iron may be initiated in lieu of iron studies. The clinician should expect the anemia to begin to improve after 2 weeks of iron supplementation. A response to a trial of iron therapy can confirm the diagnosis of iron-deficiency anemia.
Anemia is typically categorized in several different classification systems; the most widely used is the morphologic classification (Table 1).11 To determine the etiology of anemia, one should first evaluate the MCV. If the MCV is consistent with microcytic anemia (MCV <80 fL), the next step should be to perform iron studies (Table 2). This will allow help the clinician to determine whether the patient has iron-deficiency anemia or one of the less common forms of microcytic anemia such as [alpha]- or [beta]-thalassemia, anemia of chronic disease, or sideroblastic anemia.12 Thalassemias are inherited hemoglobinopathies, in which the ratio of [alpha]- and [beta]-globin chains is disrupted. In addition to the findings of iron studies seen in Table 2, thalassemia patients may have a significant family history and may present with jaundice or splenomegaly. Peripheral smear may show target RBCs. Anemia of chronic disease is due to reduced RBC production by the bone marrow in patients with conditions such as chronic infection, inflammation, malignancy, chronic kidney disease, diabetes mellitus, or severe trauma. Sideroblastic anemia is caused by ineffective erythroblast maturation, increased ineffective erythropoiesis, and iron overload. The cause may be congenital or acquired from conditions such as myelodysplastic syndrome, chronic alcohol use, or copper deficiency. Ring sideroblasts, which stain positive for iron with Prussian blue, are found on bone marrow smear. These 4 main causes of microcytic anemia can usually be differentiated based on patient history and results of iron studies, as outlined in Table 2. Treatment of iron-deficiency anemia is outlined later. Treatment for anemia of chronic disease rests on treating the underlying cause, and there is no treatment for [alpha]- or [beta]-thalassemia aside from blood transfusions if indicated.
If the MCV is increased, the most common cause is megaloblastic anemia secondary to B12 or folate deficiency. If the patient is found to be deficient in B12 or folate, the clinician should first explore possible causes and then correct the condition with appropriate supplementation. Lastly, an MCV of 80 to 100 fL reflects normocytic anemia, and requires additional testing including a peripheral smear to look for abnormal RBCs, evaluation for hemolysis (elevated lactate dehydrogenase, indirect bilirubin, and decreased haptoglobin), presence of blood loss, and if indicated, evaluation for bone marrow suppression.
Surgical Optimization of Iron-Deficiency Anemia
Allogeneic RBC Transfusion
There is a significantly increased overall 30-day risk of mortality in patients with a hemoglobin level less than 6 g/dL who undergo noncardiac surgery.11 In the past, the American Society of Anesthesiology recommended transfusion until hemoglobin was greater than 10 g/dL and the hematocrit was above 30% before surgery. However, multiple observational studies and randomized clinical trials have demonstrated potentially serious risks to preoperative transfusion. Allogeneic RBC transfusion is associated with increased risk of perioperative infection including surgical site infection, thromboembolism, multiorgan dysfunction, acute respiratory distress syndrome, increased hospital length of stay, and morbidity and mortality (including increased 60-day mortality).6 Even when patient demographics, surgical complexity, and functional status before surgery were controlled for, there was still found to be a 29% increased odds of death and a 40% to 90% increased odds of sepsis, wound, or thromboembolic complications in patients who received 1 or 2 units of blood in the setting of noncardiac surgery.11 Based on this evidence found in The Transfusion Requirement in Critical Care and FOCUS trials, current guidelines including those by the American Society of Anesthesiology recommend blood transfusion when hemoglobin is less than 6 g/dL, and transfusion should be avoided when hemoglobin is greater than 10 g/dL. For hemoglobin levels between 6 and 10 g/dL, the decision to transfuse should be based on risk of or ongoing bleeding, intravascular volume status, and susceptibility to complications of inadequate oxygenation. It is rare for transfusion to be necessary when hemoglobin is greater than 10 g/dL. A cut-off of hemoglobin level greater or less than 7 g/dL can be used safely in most asymptomatic perioperative patients with no underlying ischemic heart disease.13 Although transfusion provides a rapid but transient increase in hemoglobin, it should be reserved for those with severe iron-deficiency anemia or acute symptoms requiring immediate correction. Only the minimum number of units to achieve clinical stability should be transfused.14
Preoperative transfusion of anemic patients should be avoided whenever possible. Therefore, it is important to understand the options for correct anemia other than allogeneic blood transfusion. Tyan et al15 recommend that surgeons consider the use of alternative treatments for preoperative anemia including oral or IV iron supplementation, preoperative hormone suppression, and erythropoiesis-stimulating agents.
Oral Iron Supplementation
One of the most common therapies for correction of anemia before surgery is iron supplementation. Oral iron supplementation was previously the mainstay of treatment for iron-deficiency anemia. In nonurgent surgical cases, oral iron can be of benefit. However, oral iron may be poorly absorbed, may take as long as 3 to 6 months to fully replete iron stores, and is known to cause constipation, thereby limiting patient compliance.16 Lower doses of <100 mg on alternate days may improve absorption and lessen unfavorable side effects. Patients with iron-deficiency anemia who do not respond adequately to oral iron therapy can be identified within 2 weeks of treatment initiation. A 1.0-g/dL hemoglobin increase after 2 weeks of oral iron therapy is an accurate predictor of subsequent hemoglobin responses at 6 to 8 weeks. Patients with a hemoglobin response <1.0 g/dL at week 2 of oral iron therapy should be considered for transition to IV iron supplementation.17
IV Iron Supplementation
Administration of parenteral (IV) iron sucrose was found to be more effective in correcting anemia due to menorrhagia when compared with oral iron treatment. There is also a higher success rate in achieving target hemoglobin levels before surgery when using IV iron sucrose as compared with oral iron supplementation.18 When administered before hysterectomy, IV iron supplementation alone has been demonstrated to increase hemoglobin levels by an average of 2.2 g in as little as 2 to 4 weeks before surgery.19 Preoperative treatment with IV iron has the additional benefit of reducing postoperative need for allogeneic blood transfusion.1
There are multiple parenteral iron preparations, and their safety has been well validated. Depending on the formulation, IV iron can typically be administered in 1 or 2 infusions, which last approximately 1 hour or less each. Different IV iron products include low-molecular-weight iron dextran, ferric carboxymaltose, ferric gluconate, ferumoxytol, and iron sucrose.20 Adverse events associated with all formulations of IV iron occur in fewer than 1% of patients and include allergic reactions, anaphylaxis, urticaria, palpitations, and dizziness. Low-molecular-weight iron dextran is often chosen because it can be administered in a single infusion and it is relatively inexpensive.21 Thus, parenteral iron is a safe, effective, and accessible management option to optimize anemia before gynecologic surgery.
Hormonal Contraception
Multiple types of hormonal contraceptives can be safe and effective methods to help correct anemia caused by abnormal uterine bleeding before surgery. Types of hormonal contraception include oral contraceptive pills, depo-medroxyprogesterone acetate, and the levonorgestrel intrauterine device (IUD). Combined oral contraceptives have been demonstrated to reduce menstrual blood loss by 35% to 69%. Due to the increased risk of venous thromboembolism associated with major gynecologic procedures, however, combined oral contraceptives should be discontinued 4 to 6 weeks before major surgery with anticipated prolonged immobilization. There is no indication to stop combined oral contraceptives if the patient is expected to ambulate postoperatively.22 Depot-medroxyprogesterone acetate injection has been demonstrated to decrease uterine bleeding by 49%. The levonorgestrel IUD is another highly effective method to treat heavy menstrual bleeding, and was demonstrated to reduce blood loss by 71% to 95% and increase hemoglobin levels by 7.5% from baseline after 6 months of use (eg, from 10 to 10.75 g/dL). Both depo-medroxyprogesterone and the levonorgestrel IUD are good options for patients with contraindications to estrogen use.23
GnRH Analogues
The growth of and amount of bleeding caused by uterine fibroids are among the most common causes of abnormal uterine bleeding. Fibroid growth and associated bleeding can be reduced through the use of gonadotropin-releasing hormone (GnRH) analogues such as leuprolide acetate.24 GnRH agonists initially increase gonadotropin release from the hypothalamus, but later lead to downregulation and decreased GnRH and subsequently decreased follicle-stimulating hormone, luteinizing hormone, and estrogen release. GnRH analogues thus induce a state of hypoestrogenism, which in turn leads to an approximately 50% reduction in uterine volume, reduced bleeding before and during surgery, and clinical improvement of anemia.23 Treatment with GnRH analogues before hysterectomy has been demonstrated to reduce the duration of surgery by an average of 10 minutes, the blood loss by 25 to 148 mL, the overall incidence of blood transfusion, and the rate of postoperative complicatons.25 The use of vertical incisions for laparotomies was also reduced by pretreatment with GnRH analogues. Side effects of GnRH analogues include of hot flashes, headaches, dizziness, and changes in breast size.26 In addition to the short-term side effects of GnRH analogues, their use for over 1 year may lead to significant loss of bone mineral density. Therefore, these agents are generally used for a limited duration, most commonly 3 to 6 months preoperatively. The peak effect of GnRH agonists is typically at 3 months.27
Ulipristal Acetate
Ulipristal acetate is an alternative medical preoperative therapy for women with uterine fibroids. Ulipristal acetate decreases both the size of uterine fibroids and uterine volume by selectively binding to and modulating progesterone receptors in the myometrium. When the efficacy of ulipristal acetate was compared with GnRH agonists for treatment of preoperative anemia, ulipristal acetate helped women achieve amenorrhea more rapidly than GnRH agonists, with median time to amenorrhea being 5 days for ulipristal versus 21 days for GnRH agonists. However, preoperative use of GnRH agonists led to a 47% reduction in uterine volume whereas use of ulipristal resulted in reduction in uterine volume by only 22%. Additionally, there are no differences between GnRH agonists and ulipristal acetate in regard to preoperative hemoglobin levels, blood transfusion rates, and reduction in bleeding. The most common adverse effects of ulipristal acetate therapy are headache and hot flashes, both of which were reported by 25.8% of patients taking ulipristal acetate. Serious adverse effects associated with ulipristal acetate are rare. No reports of venous thromboembolism were found in the PEARL I or II, the largest trials investigating ulipristal acetate.28 However, cases of liver toxicity have been reported in patients requiring multiple courses of ulipristal acetate before surgery, so patients should be screened for liver disease before beginning therapy and have their liver enzymes monitored while on ulipristal acetate.
Erythropoiesis-Stimulating Agents
Other options for medical management of preoperative anemia include erythropoiesis-stimulating agents, such as darbepoetin alfa and recombinant human erythropoietin (rHuEPO). The rHuEPO, also known as epoetin alfa (EPO), can be used before any surgical procedure where estimated blood loss exceeds 500 mL in patients with hemoglobin <12 g/dL who are not adequately responding to IV iron therapy alone. The onset of action of EPO is 4 to 6 days, and may take up to 2 weeks to achieve full effect. Therefore, it is recommended that EPO be started 3 to 4 weeks before surgery through a series of weekly injections, with the fourth and last dose given on the day of surgery. Most clinicians give rHuEPO along with IV iron supplementation during this preoperative period.29 In one study, it was found that treating anemic patients with rHuEPO and oral iron 4 weeks before hysterectomy led to significantly greater increases in mean hemoglobin compared with treatment with oral iron alone.30 It is important to coadminister erythropoiesis-stimulating agents and iron supplementation because the increase in RBC mass caused by EPO alone may lead to functional iron deficiency.31
Administration of rHuEPO is especially beneficial in elderly patients and those with kidney disease or myelodysplastic syndrome. Some potential risks to EPO therapy include thromboembolism and worsening blood pressure in those with uncontrolled hypertension. However, in patients with well-controlled hypertension, use of rHuEPO does not significantly increase blood pressure. Nonetheless, rHuEPO should be given with caution, as evidence has demonstrated a correlation between preoperative rHuEPO use and postoperative thrombosis.31 Although correction of anemia with rHuEPO has yet to be demonstrated to decrease the rate of allogeneic blood transfusion in gynecologic surgery,30 rHuEPO administration to correct anemia before cardiac and orthopedic procedures results in lower transfusion rates and fewer units of blood transfused.
Implementation
There are several methods that may be implemented for more effective identification and treatment of preoperative anemia. A standard protocol for the identification of preoperative anemia may improve outcomes.32 Additionally, electronic alert systems in the medical record have proven effective in alerting physicians of abnormal laboratory results and prompting physicians to act on those results.33 Automated alerts in the electronic medical record system could be created to alert a physician and/or nurse of a preoperative patient identified to have anemia on laboratory testing. Additionally, order sets have proven efficacious in aligning the physician's orders with evidence-based guidelines.34 To assist in the workup of anemia, a preoperative anemia order set could be created with prompts and appropriate workup depending on initial laboratory testing. A preoperative anemia order set could also be useful in ordering appropriate management options such as IV iron and corresponding clinic appointments for IV iron infusions. Additionally, close interdisciplinary collaboration has been demonstrated to improve patient outcomes and thus close collaboration with hematology would be beneficial when developing department and hospital protocols for preoperative treatment of anemia.35
Conclusion
Before gynecologic surgery, it is critical to identify and correct preoperative anemia, as it can lead to increased morbidity and mortality postoperatively. The most common cause of preoperative anemia is iron-deficiency anemia, but further testing to evaluate the etiology is warranted if a complete blood count and iron studies are not consistent with iron deficiency. When considering preoperative treatment for iron-deficiency anemia, the risks and benefits of allogeneic blood transfusion, iron supplementation, and other medical therapy should be considered. Although transfusion provides a rapid increase in hemoglobin, it is associated with increased postoperative morbidity and mortality. Thus, the optimization of anemia has shifted to preoperative medical management. IV iron supplementation is effective in increasing hemoglobin levels when given at least 1 to 2 weeks before surgery, has been proven to be more effective than oral iron, and has favorable postoperative morbidity outcomes. Medical therapies such as GnRH analogues and ulipristal acetate are especially beneficial for women with uterine fibroids. Lastly, erythropoiesis-stimulating agents may help increase hemoglobin levels in patients not responding to IV iron supplementation alone, especially patients with kidney disease or myelodysplastic syndrome.
Practice Pearls
* Identify anemia as early as possible before gynecologic surgery.
* In the gynecology patient population, the majority of anemia is caused by iron deficiency.
* Determine whether anemia is due to iron deficiency or a less common cause.
* Based on the clinical picture including the level of anemia, the etiology of the anemia, other relevant factors such as uterine fibroids, and the interval to surgery, determine the best management option.
* IV iron is more effective than oral iron and can improve anemia in a few weeks.
* GnRH analogues are helpful in decreasing abnormal uterine bleeding in a patient with a fibroid uterus and thus improving anemia before surgery and have an optimal effect at 3 months.
* EPO is an option to help correct preoperative anemia for patients who are not adequately responding to IV iron and should be started 3 to 4 weeks before surgery.
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