Gynecologic Conditions and Anemia: What Can We Do About Iron Deficiency Anemia in Women?

A 37-year-old woman with a history of heavy menstrual bleeding (HMB) and known uterine fibroids presented to an academic medical center with symptomatic anemia (hemoglobin, 5 g/dL) and pleuritic chest pain. Chest computed tomography (CT) scan showed bilateral pulmonary embolism (PE) with evidence of pulmonary infarcts. Pelvic sonogram revealed a large heterogenous fibroid measuring approximately 12.2 × 9.4 × 12.1 cm. Magnetic resonance venogram of the abdomen and pelvis showed complete collapse/occlusion of the inferior vena cava and bilateral common iliac veins as well as severe narrowing of the inferior abdominal aorta by the large fibroid. Lower extremity (LE) venous duplex ultrasound revealed a left femoral LE deep vein thrombosis (DVT). The patient was started on anticoagulation, which caused significant worsening of already heavy vaginal bleeding. Her iron studies showed severe deficiency, with an iron level of 27 µg/dL, unbound iron binding capacity of 432 µg/dL, transferrin saturation of 6 percent, and serum ferritin of 9.7 ng/mL. The hematology department was consulted for management of HMB, iron deficiency anemia, PE, and DVT. She received intravenous (IV) iron supplementation and was transfused one unit of packed red blood cells. Ultimately, she underwent a hysterectomy to relieve the pelvic and abdominal vessels of pressure from the large fibroid and to enable anticoagulation for the acute thrombosis.

Iron deficiency is a global health problem and is the most common cause of anemia. Pregnancies and menstruation render it highly prevalent in individuals of childbearing age, affecting at least one third of that population.¹  Symptoms can be numerous and nonspecific, including fatigue, decreased concentration, restless legs, pallor, heart palpitations, dyspnea, pica disorder (e.g., eating ice, clay, paper, or other inedible items), alopecia, and dry skin.^2,3 

HMB is underdiagnosed and is estimated to affect 18 to 38 percent of women of reproductive age, and may be higher in perimenopausal individuals.⁴  Causes include abnormalities of the genital tract such as fibroids, adenomyosis,⁵  malignancy, polycystic ovarian syndrome and trauma to the vaginal area,⁶  and inherited and acquired bleeding disorders such as von Willebrand disease, coagulation factor deficiencies, and anticoagulation use.⁷  Management strategies for HMB include combined hormonal contraceptives, progestin-only depot shots, oral gonadotropin-releasing hormone antagonists, hormonal intrauterine devices,^8,9  and hemostatic agents such as tranexamic acid.^4,6  More severe or persistent bleeding may require uterine artery embolization,¹⁰  endometrial ablation,⁹  myomectomy, and as a last resort, hysterectomy,⁵  as in this case.

Non-anemic iron depletion is common and underdiagnosed.¹¹  A study of 150 young women who presented with HMB revealed that 50.9 percent of them had a serum ferritin lower than 20 ng/mL, while only 41.4 percent (24 patients) were anemic.¹¹  Therefore, screening for iron deficiency in these patients is paramount to enable early oral or IV iron supplementation and prevent avoidable, inappropriate blood transfusion.^12,13 

In pregnancy, iron deficiency is even more common due to the increased iron requirements needed to support development of the placenta and fetus, and expansion of the maternal red cell mass.^14,15  Iron deficiency increases risk of maternal complications such as fatigue, postpartum depression, and postpartum hemorrhage¹⁵ ; adverse effects on the neonate have been reported.¹⁶ 

Guidelines from the United Kingdom emphasize the importance of starting oral iron supplements without delay in those identified with anemia, using empirical treatment as a diagnostic tool, and only investigating further if there is no improvement in hemoglobin level after two weeks. Only individuals with known hemoglobinopathy require a serum ferritin first. Consideration should also be given to the possibility of non-anemic iron depletion and where there are risk factors such as multiple pregnancy and multiparity, oral iron supplements should be given prophylactically.¹⁵ 

Dietary supplementation with iron-rich food sources may help to prevent iron deficiency but is inadequate for treatment of established disease⁴  where oral or parenteral iron supplementations are necessary.

Oral iron supplementation. Options for oral iron supplementation including ferrous sulfate, ferrous gluconate, and ferrous fumarate (Table), may be initiated as daily or alternate-day dosing regimens, with vitamin C to enhance absorption.¹⁷  Intolerance to oral iron is reduced by correct administration,¹⁸  taking it early in the morning when hepcidin levels are lowest, one hour before food, drink, or medications, which can interfere with absorption.

Parenteral iron supplementation. IV iron supplementations may be necessary for people with absolute intolerance to oral iron, who require rapid correction of iron stores, or who are very severely iron deficient such as in the case described earlier. Preparations include low molecular iron dextran, iron sucrose, ferumoxytol, ferric gluconate, ferric derisomaltose, and ferric carboxymaltose (Table). IV iron supplementation raises the hemoglobin level more quickly than oral iron and avoids gastrointestinal side effects. Severe adverse reactions to IV iron infusion are rare,¹⁹  but some may experience skin staining from extravasation, and hypophosphatemia can occur primarily with ferric carboxymaltose due to an increase in FGF23 concentration causing phosphaturia.²⁰  Some IV iron options are offered in small doses, while some formularies have larger doses with the benefit of iron repletion in just one or two sessions. Overall, IV iron supplementation is very safe but should be avoided in the first trimester of pregnancy and requires confirmation of the diagnosis by a low serum ferritin.

IV iron may be required if there is malabsorption such as with gastritis, history of bariatric surgery, celiac disease, or evidence of inflammation, such as in chronic kidney disease, where hepcidin levels are raised causing degradation of ferroportin and trapping of iron in intestinal cells, macrophages, and hepatocytes.

Correction of iron deficiency is also important preoperatively. Approximately 23 percent of patients preparing for hysterectomy to address HMB are reported to have anemia⁴ ; improving hemoglobin levels prior to surgery may improve surgical outcomes and reduce blood transfusion requirements.

Iron deficiency and iron deficiency anemia in female patients is very common but underdiagnosed. Severe HMB can result in extremely low hemoglobin levels and poor quality of life for patients. The case illustrates some of the complications that arise in these patients. Evaluating and/or treating for iron deficiency in at-risk patients early on improves wellbeing and avoids inappropriate blood transfusion. Oral and parenteral iron supplementation are effective for managing iron deficiency anemia. Parenteral iron is safe and often underutilized. A multidisciplinary team can be invaluable in the management of pregnant patients and for those with gynecological conditions that cause bleeding.

Dr. Akpan is a consultant for and has received fees for advisory boards for Pharmacosmos Therapeutics Inc. Dr. Pavord has received fees for educational talks and advisory boards from Pharmacosmos and Vifor Pharma.