Ensuring successful treatment of anemia in pregnancy

Anemia affects nearly 30% of reproductive-age women worldwide, and anemia in pregnancy has an estimated global prevalence of 37%, with iron-deficiency anemia being the most common cause.¹ Anemia in pregnancy is associated with increased maternal and fetal/neonatal morbidity. Maternal complications include increased risks of postpartum hemorrhage and postpartum depression, and increased need for blood transfusions.^2-4 Neonatal effects include a higher risk of low birthweight, preterm delivery, overall perinatal morbidity and mortality, and neurodevelopmental impact such as cognitive and behavioral disorders.^5-8 The diagnosis and treatment of anemia in pregnancy is important to help mitigate these maternal and neonatal risks.

Anemia is defined as a hemoglobin level or hematocrit value less than the fifth percentile in a healthy reference population based on gestational age.Table 1 breaks down cutoff amounts for anemia by trimester of pregnancy.⁹

Prevalence and risk factors

According to the 2021 World Health Organization report, the prevalence of anemia in pregnancy ranges from 12% in the US to nearly 60% in some African countries.¹⁰ Within the US, the prevalence of anemia in pregnancy is 2 times higher in non-Hispanic Black patients compared with non-Hispanic White patients.¹¹ Teenage patients had the highest prevalence of all age cohorts.¹¹ Iron deficiency is the most common cause of anemia in pregnancy and significantly increases in prevalence with each trimester, with up to 30% prevalence in the third trimester.¹²

Risk factors for developing anemia during pregnancy include multiparity, pregnancy with multiples, prepregnancy iron deficiency (commonly the result of heavy menstrual bleeding), and inadequate intake of iron during pregnancy (from a diet low in iron). Iron-rich diets include beef, turkey, beans, lentils, and seafood.13 Some breakfast cereals are fortified with supplemental iron. Certain foods can enhance iron absorption, including orange juice, grapefruit, strawberries, broccoli, and peppers.^13,14 On the other hand, some foods diminish iron absorption, including dairy, soy, spinach, coffee, and tea. Patients with malabsorption syndromes (such as those with a history of gastric bypass) or inflammatory conditions (such as inflammatory bowel disease) are also at risk for anemia.

Screening and workup of anemia in pregnancy

All pregnant patients should be screened for anemia with a complete blood count in the first trimester and again in the early third trimester.^9,14 Data from 2017 suggested that only 50% of pregnant patients were being screened at the start of prenatal care and even fewer with each trimester.¹⁵ Of note, even when performed, the complete blood count (CBC)-only screen fails to detect iron deficiency that may exist prior to the development of anemia, a missed opportunity for the early correction of iron deficiency.

The initial evaluation of a pregnant patient with anemia should include a thorough history and physical, as well as a complete blood count, red blood cell indices, and ferritin level.¹⁴ Hemoglobin electrophoresis is now universally recommended for all patients as of August 2022 by the American College of Obstetricians and Gynecologists (ACOG).¹⁶ Other laboratory tests to consider include serum iron studies and peripheral blood smears. For macrocytic anemia, folate and vitamin B12 levels could be considered as well.

If laboratory workup cannot be obtained, presumptive treatment for iron-deficiency anemia is an option. Increases in hemoglobin of more than 1 g/dL after iron treatment is also diagnostic for iron-deficiency anemia.⁹

Classification

There are 3 main ways of classifying types of anemia: inherited vs acquired, underlying causal mechanism, and red blood cell (RBC) morphology.¹⁴

Acquired vs inherited

Acquired causes of anemia include iron deficiency, nutritional deficiencies (vitamin B12 or folate), hemorrhagic anemia, anemia of chronic disease (also known as anemia of inflammation), acquired hemolytic anemia, and aplastic anemia.

Inherited causes of anemia include thalassemia, sickle cell anemia, other hemoglobinopathies, and inherited hemolytic anemias. The ACOG now recommends universal hemoglobinopathy screening because 1 in 66 people in the US have a hemoglobinopathy trait.¹⁶

Underlying causal mechanism

Anemias can be characterized by causal mechanisms, broadly separated into decreased RBC production vs increased RBC destruction.

Decreased production of RBCs can result from nutritional deficiencies, such as of iron, vitamin B12, or folate. Bleeding, malabsorption, or inadequate diet can all contribute to nutritional deficiencies. Other causes of decreased RBC production include bone marrow disorders or suppression, hormonal imbalances such as hypothyroidism, chronic diseases such as kidney disease characterized by low levels of erythropoietin, infection, and obesity.

Increased RBC destruction can be caused by inherited hemolytic anemias (eg, sickle cell anemia, thalassemia, hereditary spherocytosis), acquired hemolytic anemias (autoimmune, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, malaria), or hemorrhagic anemia.

RBC morphology

Classification of anemia by cell size or morphology entails stratifying by mean corpuscular volume (MCV; fL) [Figure 1]: microcytic (MCV less than 80 fL), normocytic (MCV 80-100 fL), and macrocytic (MCV > 100 fL).

Microcytic anemias include those caused by iron deficiency (the most common), thalassemias (second most common), chronic disease, sideroblastic anemia, copper deficiency, or lead poisoning. An MCV value less than 70 is more strongly associated with a thalassemia diagnosis.¹⁷

Normocytic anemias include those caused by acute blood loss (hemorrhagic), early iron deficiency, chronic disease, bone marrow suppression, chronic renal insufficiency (decreased erythropoietin production), endocrine dysfunction (hypothyroidism or hypopituitarism), autoimmune hemolytic anemia, hereditary spherocytosis, and hemolytic anemia with paroxysmal nocturnal hemoglobinuria.

Macrocytic anemias include those caused by nutritional deficiency (of folate, which is most common, or vitamin B12), drug-induced hemolytic anemia (eg, zidovudine), reticulocytosis, liver disease, ethanol abuse, and acute myelodysplastic syndrome. Anemia with an MCV value greater than 115 fL is almost exclusively seen in patients with folic acid or vitamin B12 deficiency.14 Other causes of macrocytic anemia include pernicious anemia, alcoholism, liver disease, myelodysplasia, aplastic anemia, and hypothyroidism.¹⁴

Physiologic causes of anemia in pregnancy

Physiologic changes that occur during pregnancy increase the risk of developing or worsening anemia. Plasma volume expands by 40% to 50% whereas erythrocyte mass increases less (by 15% to 25%), leading to a physiological drop in hemoglobin and hematocrit. Furthermore, even the 15% to 25% expansion of the erythrocyte mass increases iron requirements dramatically,¹⁸ and these are challenging to achieve without adequate iron stores and dietary iron supplementation.

During pregnancy, there is a coordinated increase in the mobilization of iron from stores and absorption of iron from the diet to allow for the increased maternal RBC production, growth of the fetus and placenta, and preparation for delivery.¹⁹ A healthy pregnancy requires 1 g of iron, with average prepregnancy iron stores in women only amounting to 300 mg.

Iron-deficiency anemia

Iron deficiency is the most common cause of anemia in pregnancy, affecting approximately 18% of pregnancies even in a high-resource setting.¹² Up to 25% of anemic pregnancies are complicated by severe iron-deficiency anemia.⁹

The majority of iron (70%) is functional iron (eg in the hemoglobin of RBCs and as a component of mitochondria and many enzymes in tissues), and the remainder is storage iron (tissue ferritin, primarily in the liver).¹⁸ Iron deficiency occurs when iron losses exceed iron intake. As iron deficiency develops, iron stores are initially depleted, and eventually the functional iron pool becomes affected, resulting in impaired erythropoiesis and tissue function.⁹

Of the multitude of laboratory results characteristic for iron-deficiency anemia, serum ferritin has the highest sensitivity (92%) and specificity (98%) for diagnosis of the condition.^20,21 A ferritin level less than 30 mcg/L confirms iron-deficiency anemia.22 Ferritin increase in response to treatment can be seen within 3 weeks after initiating oral iron supplementation (or faster with intravenous iron).²¹ However, ferritin is also an acute phase reactant and does not accurately reflect iron deficiency in the presence of inflammation.

A low MCV (<80 fL) is highly sensitive but not specific for iron-deficiency anemia.²³ In addition, a physiologic increase in MCV that occurs during pregnancy can mask iron-deficiency anemia. Transferrin is an iron transport protein in circulation, and a low transferrin saturation (TSAT) below 20% suggests iron deficiency, especially in the setting of low ferritin level.^22,23 Total iron-binding capacity (TIBC) reflects the amount of transferrin in the blood and increases physiologically in pregnancy, while chronic diseases (including kidney or liver disease) can lower TIBC, thus it has limited utility in pregnancy.^22,23 The soluble transferrin receptor (TfR) level can be used to distinguish true iron deficiency from inflammatory conditions associated with low serum iron and low TSAT.²² In the case of inflammation or iron-restricted erythropoiesis, TfR levels do not rise.

Treatment of iron-deficiency anemia in pregnancy

Oral supplementation

Recent studies have shown successful treatment of anemia in pregnancy can significantly reduce risk of preterm birth and preeclampsia.²⁴ The CDC has recommended universal iron supplementation in pregnancy except in the case of certain genetic disorders such as hemochromatosis.^9,25 Treatment maintains maternal iron stores, supports maternal erythropoiesis, and benefits neonatal iron stores (Figure 2). The daily recommended dietary iron intake in pregnancy is 27 mg and in lactation is 9 mg, while the average diet only provides 15 mg of iron.²⁵ The typical American diet is insufficient for iron requirements during pregnancy. However, the US Preventive Services Task Force noted there is insufficient evidence to evaluate the benefits and harms associated with routine supplementation among asymptomatic pregnant women.²⁶

Iron is included in most prenatal vitamins and is also available in a variety of preparations. Oral supplements include ferrous fumarate, ferrous sulfate, and ferrous gluconate. Intravenous preparations include iron dextran, ferric gluconate, and iron sucrose, and deliver a much larger bolus of iron.¹⁴ Formulations with respective dosages are shown in Table 2.¹⁴

Common adverse effects of oral iron are gastrointestinal, including nausea/vomiting, constipation, diarrhea, flatulence, and epigastric discomfort. Studies in recent years have shown intermittent oral supplementation has fewer adverse effects and at least equivalent benefits in improving iron-deficiency anemia.²⁷ Some have found that consecutive daily dosing of oral supplementation resulted in lower fractional iron absorption compared to alternate day dosing, and absorption was higher with 100 mg rather than 200 mg of iron supplementation.²⁸ The iron should be taken at least an hour prior to meals, and absorption can be limited by grains, coffee, and tea.

Parenteral iron supplementation

Intravenous iron should be considered for patients who cannot tolerate or lack appropriate response to oral iron supplementation, or who have malabsorption syndromes or severe iron deficiency anemia (hemoglobin less than 7 g/dL). It should also be considered for patients with mild or moderate anemia (hemoglobin less than 9 g/dL) in the third trimester of pregnancy in anticipation of delivery and its associated blood loss.

There are various ways of calculating the appropriate dose to administer, but a commonly used formula includes:²⁹ total iron deficit (mg) = weight (kg) times target hemoglobin (g/dL) less actual hemoglobin (g/dL) times 2.4 plusiron stores (mg).

IV iron preparations are largely safe, with serious adverse events occurring in less than 1 of 250,000 administrations.³⁰ Recent studies quote the overall rate of any adverse event at 3.9%.³¹ Contraindications to parenteral iron include prior hypersensitivity or anaphylaxis, or presence of iron overload, serious hepatic disease, or serious viral infections.

Premedication with antihistamines can increase the risk of adverse effects and are generally unnecessary.³¹ Patients who have severe asthma or multiple medication allergies can have increased risk of hypersensitivity. High-risk patients should be evaluated for premedication with intravenous corticosteroids such as methylprednisolone.³² The formulation ferric carboxymaltose can carry risk of hypophosphatemia.

Blood transfusion

Transfusion of red blood cells is mainly indicated for patients with ongoing blood loss at delivery, hypovolemia from blood loss, or trauma. It should also be considered in patients with coagulopathy or hemolytic anemia (eg, hemolysis, elevated liver enzymes, and low platelet countsyndrome).

Maternal hemoglobin levels less than 6 g/dL carry increased risk for low fetal oxygenation, resultant cerebral vasodilation, and increased risk of stillbirth.³³ Transfusion should be considered in these cases for fetal indications even in the absence of ongoing blood loss.

Conclusion

Anemia in pregnancy, especially iron-deficiency anemia, is highly prevalent even in resource-rich countries. The successful treatment of anemia in pregnancy has significant maternal and neonatal benefits. Universal screening, workup, and treatment with iron supplementation is recommended for pregnant patients with anemia.

References

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