Anemia and iron deficiency are significant global health issues affecting about one-third of the world’s population [1] . Iron deficiency anemia is more prevalent in women of reproductive age and preschool-age children compared to the general population, an observation independent of geographic factors or financial diversity [2] . Moreover, women in most age groups have a higher risk of anemia than men, regardless of geographic region [3] . The World Health Organization (WHO) reports that 30% of menopausal women have iron-deficiency anemia, and this prevalence may be higher among women undergoing gynecological surgeries [4] - [9] . Post-menopause, the primary cause of anemia is daily losses through bleeding from the gastrointestinal tract, uncompensated by the intestinal mucosa’s increased absorption of dietary iron [8] .

The occurrence of anemia in patients with indications for surgical treatment is higher than in the general population, reaching up to 75% in some populations undergoing major surgery [6] [10] . Preoperative anemia is associated with worse perioperative outcomes, including increased morbidity, mortality, blood transfusion, length of hospital stay, and increased complication rates [6] . Some surgical techniques can have a positive impact on preventing or improving perioperative anemia, such as minimally invasive techniques, which are associated with clinical benefits for the patient, such as reduced estimated blood loss (EBL), decreased blood transfusion requirements, shorter length of stay (LOS), reduced peri-operative pain and analgesic requirement [11] . Nonetheless, despite its preventability, many surgical patients experience hospital-acquired anemia, with an incidence ranging from 35% to 74% and reaching 100% in patients with an ICU stay > 7 days. Approximately 80% - 90% of patients will become anemic post-surgery [1] .

According to numerous guidelines, including the British Committee for Standards in Hematology, the Enhanced Recovery After Surgery (ERAS) program, the National Institute for Health and Care Excellence (NICE), the British Society for Haematology (BSH), the Society for the Advancement of Patient Blood Management (SABM), the European Association for Cardio-Thoracic Surgery (EACTS), the National Blood Authority Australia, the American College of Obstetricians and Gynecologists (ACOG) and the International Federation of Gynecology and Obstetrics (FIGO), tracking and treating anemia is crucial to minimize unfavorable events during the perioperative period [12] . Anemia has been associated with a higher rate of transfusion, increased risk of postoperative complications, prolonged hospital stays, delayed recovery, and reduced quality of life [8] . This can result in a four-fold increase in the risk of renal injury, three times the risk of mortality, double the risk of infection, and four times the need for transfusion [13] [14] . To optimize perioperative management, the ERAS program recommends preoperative treatment of anemia [15] .

Nonetheless, there remains a disparity in the implementation of “Patient Blood Management” (PBM) as a comprehensive approach to mitigating the risks associated with iron deficiency, anemia, blood loss, and coagulopathy [1] . PBM aims to improve patient outcomes by adopting evidence-based clinical and surgical practices to maintain hemoglobin (Hb) levels, maintain hemostasis, and reduce blood loss [16] .

Considering the high prevalence of iron-deficiency anemia in women undergoing gynecological surgeries, its association with worse postoperative results, the need to identify and treat preoperative anemia, and the need to encourage the implementation of PBM, we aimed to review preoperative iron-deficiency anemia in patients undergoing gynecological surgery. The proposed approach involves the treatment of anemia, emphasizing good medical practices based on PBM recommendations.

This study reviewed the literature on preoperative iron deficiency anemia in patients undergoing gynecological surgery. We identified references through searches in PubMed using relevant search terms (Anemia, Gynecological Surgery, Iron Supplementation, Iron Deficiency) and through the “snowball” method, used to identify references. We also considered some relevant pages found on the internet, such as data from the World Health Organization. The research was carried out using the English language. Articles unrelated to iron deficiency anemia were excluded and a total of 62 references were ultimately reviewed.

Iron plays a vital role in maintaining human homeostasis. It is involved in the synthesis of Hb and myoglobin and is a component of various enzymes involved in cellular respiration, including catalases and oxidases [4] . The average adult human body contains approximately 3 - 4 g of iron (45 mg/kg of body weight), with most (1.5 - 3 g) bound to Hb heme, which primarily oxygenates tissues. Normal adults absorb 1 - 2 mg of iron from their diet daily, with the amount absorbed from heme iron varying from 20% to 30% and the absorption of vegetable-derived iron 1% - 7% [17] .

Hepcidin, a hormone produced by the liver, plays a significant role in iron homeostasis. Its primary function is to inhibit iron release from enterocytes into the portal circulation and reticuloendothelial cells into the systemic circulation, ensuring controlled release of iron from storage sites to circulation and avoiding oxidative toxicity [18] . Hepcidin synthesis increases in inflammatory states, causing reticuloendothelial cells to have high intracellular iron stores. This leads to anemia secondary to chronic diseases such as chronic kidney disease and inflammatory bowel disease [4] [18] .

In non-pregnant adult women, anemia is defined as Hb < 12 g/dL. Anemia can be classified as mild (Hb > 10 g/dL), moderate (Hb 7 - 9.9 g/dL), or severe (Hb < 7 g/dL) [3] [19] . Preoperative anemia is considered Hb levels < 13 g/dL in surgeries with significant blood loss [20] . Women with borderline anemia are more likely to be transfused with more units of red blood cells and have a significantly longer hospital stay than non-anemic women [21] .

Iron deficiency remains prevalent among women during their fertile years and those with heavy menstrual bleeding (HMB) [5] . Chronic blood loss can result in iron deficiency prior to the onset of anemia if the continuous loss exceeds absorption [22] . In adult women, menstrual losses are the main factor associated with iron-deficiency anemia [4] [7] [23] .

Although iron deficiency anemia is the most common among all types of anemia, there are other types. Other substances interfere with hemoglobin synthesis and iron metabolism. Deficiencies of riboflavin (B2), pyridoxine (B6), cobalamin (B12) and folate are associated with anemia. Vitamin B12 and folate deficiencies can result in macrocytic anemia, affecting DNA synthesis and cell division in the bone marrow. Bioavailable forms of vitamin B12 are found primarily in animal-source foods and the origin of their deficiency commonly arises from inadequate dietary intake. However, deficiency can also occur due to malabsorption problems, particularly in the elderly, those with gastric atrophy, pernicious anemia, and bacterial or parasitic infections [3] .

Furthermore, numerous diseases such as aplastic anemia, hereditary bone marrow failure syndromes, chronic diseases, or autoimmune disorders contribute to anemia through various mechanisms, including impaired hemolysis or erythropoiesis and the impact of inflammation on iron metabolism. A low reticulocyte count may indicate conditions related to nutritional deficiencies, decreased erythropoietin levels, aplastic anemia, or hereditary bone marrow failure syndromes. Anemia associated with chronic diseases or autoimmune disorders usually presents as normocytic and with a low reticulocyte count. In autoimmune diseases, pro-inflammatory cytokines, notably IL-6, worsen the condition by altering iron metabolism [3] .

In addition, it is worth mentioning sickle cell disorders, the most prevalent genetic hemoglobin disorders. In sickle cell disease, abnormal sickle-shaped red blood cells result from defective β-globin chains. Thalassemias involve defects in the synthesis of globin chains, with α-thalassemia resulting from reduced or absent synthesis of the α-globin chain, while β-thalassemia results from reduced or absent synthesis of the β-globin chain. These autosomal recessive conditions manifest as chronic hemolytic anemia and impaired erythropoiesis, with severity ranging from asymptomatic carriers to severe cases, resulting in anemia, growth impairment, skeletal abnormalities, and potentially fatal outcomes in α or β thalassemia major [3] .

The preoperative diagnosis of iron deficiency anemia is crucial for identifying potential complications [7] [24] [25] . Table 1 shows the stages of iron deficiency and its laboratory findings [17] [22] .

A transferrin saturation below 20% and a ferritin level below 30 ng/mL indicate iron deficiency. However, ferritin is an acute-phase protein that increases during inflammation, and thus, evaluating C-reactive protein levels can help identify these situations [26] .

Iron deficiency anemia is typically hypochromic and microcytic. Differential diagnosis with traits of thalassemia, which also present with microcytic and hypochromic anemia, must be considered in populations where these traits are prevalent [26] . When there is a suspicion of an association between minor thalassemia and iron-deficiency anemia, it is recommended first to correct the iron deficiency and anemia, then quantify Hb A2. Another differential diagnosis is chronic disease anemia, which is associated with normochromic and normocytic anemia and is caused by inflammatory, infectious, or neoplastic diseases [17] .

PBM is a comprehensive care paradigm designed to control anemia, which is being utilized for various patient groups. PBM’s main objective is to improve patient outcomes while conserving health resources and reducing costs, dependence on blood transfusions, and associated risks and complications [27] . In 2010, PBM was endorsed by the World Health Assembly Resolution WHA63.12 [28] .

The core principle of PBM is using measures that preserve and protect a patient’s blood. The “three pillars of PBM” are the detection and treatment of anemia and iron deficiency, minimization of blood loss and optimization of coagulation, and optimization of the patient’s tolerance to anemia ( Figure 1 ) [29] . Other principles include patient education, shared decision-making, multi-professional protocols, and integration among primary care physicians, family physicians, specialists, and hospital health professionals [30] .

PBM leads to better outcomes for surgical patients, including lower morbidity and mortality, shorter hospital and ICU stays, and fewer complications [1] . For healthcare professionals, PBM results in better clinical outcomes, improved clinical performance, more satisfied patients, and reduced costs associated with transfusions [1] [27] .

Despite the scientific and economic evidence supporting PBM and its endorsement by the WHO, its adoption is still limited. Barriers to implementing PBM include a lack of awareness among patients and health professionals, a need for cultural and behavioral change, and structural adjustments in health services delivery. It is recommended that healthcare systems worldwide adopt PBM as a standard of care to improve patient outcomes and use health resources [1] .

The early detection and management of anemia is an essential strategy of PBM. However, preoperative anemia is often overlooked, with indiscriminate use of allogeneic transfusion as a “quick fix” [10] . Figure 2 shows a suggested algorithm for detecting and treating iron-deficiency anemia in the pre-surgical context.

Dietary modifications alone are insufficient to fully resolve iron-deficiency anemia. Iron supplementation, either oral or intravenous (IV), is crucial to correct the deficiency and is considered the first-line treatment [31] .

The preoperative approach should include strategies for correcting anemia and reducing perioperative blood loss. Among the possible interventions with this goal, gonadotropin-releasing hormone (GnRH) agonists (aGnRh) and antifibrinolytics stand out.

aGnRh’s are drugs similar to the hypothalamic GnRH, with a molecular structure similar to the endogenous hormone but with chemical alterations that prolong its half-life. The continuous presence of aGnRh in the pituitary initially leads to increased gonadotropin secretion, which can increase uterine bleeding. However, with constant stimulation, there is desensitization and downregulation of GnRH receptors, leading to a reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production and induction of a hypogonadotropic hypogonadal state, causing anovulation and amenorrhea [50] .

aGnRh is well established as a preoperative strategy for fibroids (myomectomies and hysterectomies), especially when there is a significant increase in uterine volume or iron-deficient anemia that is not responsive to iron treatment [50] . The reduction in uterine size occurs mainly in the first three months of treatment [51] . A Cochrane review showed that women with fibroids treated preoperatively with 3 - 4 months of aGnRh had significantly reduced uterine volume and size, improved preoperative hemoglobin, and reduced surgical and hospitalization times [52] . Furthermore, due to the volumetric reduction of fibroids, aGnRh may also increase the rate of patients who are eligible for a vaginal approach. Its use may be limited due to the short and medium-term adverse effects related to hypoestrogenism, such as vasomotor symptoms and urogenital syndrome [50] .

A study evaluating the use of aGnRh for preoperative treatment of patients with moderate to severe endometriosis showed a reduction in intraoperative blood volume [53] . Another study evaluating its use in preoperative hysteroscopic metroplasties found no evidence of benefits [54] . However, a recent randomized clinical trial comparing the use of aGnRh with ulipristal acetate in preoperative laparoscopic myomectomies showed that aGnRh use was more effective in terms of reducing fibroid volume, intraoperative blood loss, postoperative decrease in hemoglobin, time to suture the first fibroid, and various subjective parameters of surgical ease [55] . Antifibrinolytic agents are increasingly used to reduce bleeding, blood transfusions, and adverse clinical outcomes. Tranexamic acid (ATX) is the most widely studied and utilized in most countries [56] . ATX is a synthetic lysine analog antifibrinolytic. Its action is to reversibly bind to the plasminogen receptor site, reducing its conversion to plasmin and the consequent reduction in fibrin degradation. It is widely used in surgeries with a high potential for bleeding and, more recently, in severe trauma and postpartum hemorrhage due to its significant reduction in blood loss not associated with an increased risk of thromboembolic events [57] .

Despite concerns about the pro-thrombotic effect and potential toxicity, thrombosis has not proven to be a significant clinical concern, and adverse effects are rare [56] . In a systematic review assessing the occurrence of thrombotic events following spontaneous bleeding in individuals using ATX, the incidence rate for deep vein thrombosis or pulmonary embolism was found to be 1.9% [58] . The U.S. Food and Drug Administration and other authorities have approved oral ATX due to its remarkable safety track record in mitigating bleeding in women experiencing idiopathic HMB. This effectiveness may stem from its ability to inhibit heightened fibrinolytic action in the endometrium throughout the initial days of menstruation [56] .

Several clinical trials have demonstrated the efficacy of ATX in reducing intraoperative blood loss and transfusion rates, supporting its perioperative use in gynecological surgeries, such as hysterectomies, myomectomies, and oncological gynecological surgeries. Before surgery, intravenous administration is recommended in the immediate preoperative period or at the time of incision at a dose of 1000 mg or 10 - 20 mg/kg [57] .

The management of post-surgery anemia remains a subject of limited evidence and controversy [59] . To address this issue, an international consensus of experts convened to establish best practices and evidence-based statements on treating anemia and iron deficiency following surgery [60] . Patients with iron deficiency or significant drops in Hb levels after surgery should consider iron supplementation. However, there is currently no evidence to determine the best time to initiate iron supplementation in the postoperative period.

All patients undergoing major surgeries (surgeries with blood loss greater than 500 ml or a duration greater than 2 hours) who had preoperative anemia or moderate to severe blood loss during surgery should be screened for anemia post-surgery. If iron administration is necessary, early IV iron therapy is recommended after considering contraindications. Whenever possible, it should be administered using a single high-dose preparation for rapid infusion (15 - 60 min with doses of 1000 mg or more) for iron replenishment [61] [62] .

Blood transfusions should be performed in patients with severe anemia and clinical signs and symptoms. They should be considered in patients with active bleeding and severely anemic patients when bleeding has been stopped [61] .

The management of preoperative anemia is crucial for ensuring optimal outcomes for women undergoing gynecological surgeries. According to the PBM guidelines and the ERAS protocol, correction of preoperative anemia should be systematic. Iron supplementation therapy is preferred, as it is more effective and safer than transfusions. As there is generally not enough preoperative time to correct anemia with oral iron, administration of IV iron should be considered. In these cases, high-dose IV iron is preferred because it provides faster correction of anemia.

Despite rapidly increasing Hb levels, transfusions are associated with increased risks for patients, such as increased postoperative morbidity and mortality. Therefore, adopting a national policy for PBM with adequate resource distribution is essential to improve the population’s health status and individual patient outcomes.

In conclusion, addressing preoperative and post-operative anemia through systematic correction, following the guidelines of the ERAS protocol and PBM guidelines, is essential to improve perioperative outcomes in women undergoing gynecological surgeries. The adoption of a national PBM policy and the availability of resources will further enhance the benefits of this approach.