Hematologic Changes in Pregnancy

Physiologic Anemia of Pregnancy

Physiologic anemia of pregnancy, also termed dilutional anemia of pregnancy, occurs because the plasma volume increases to a greater proportion than the red blood cell (RBC) mass, resulting in dilution. Generally, hemoglobin levels decrease throughout pregnancy and may increase modestly during the last month of pregnancy. Total circulatory volume increases by approximately 50% during pregnancy. Erythropoietin levels increase throughout pregnancy in response, but increased erythropoiesis does not fully compensate for the expanded plasma volume. Hemoglobin as low as 10 g/dL can be credibly attributed to physiologic anemia of pregnancy. However, this is a diagnosis of exclusion, and other causes should be considered before this attribution is made. Plasma volume and RBC mass return to baseline within approximately 6 weeks postpartum.

Iron Deficiency Anemia

Iron deficiency anemia, which is the most common cause of anemia in pregnancy, is a risk factor for preterm delivery and low birthweight. Iron requirements increase during pregnancy because of maternal and fetal erythropoiesis. Anemia and low ferritin levels are considered diagnostic of iron deficiency (see Chapter 37 ). However, ferritin levels may increase in the last several weeks of pregnancy because ferritin is an acute-phase reactant. Consequently, concurrent determination of the transferrin saturation is important in women with an ambiguous picture. The clinical symptoms of iron deficiency are the same as in other contexts, including fatigue, pallor, pica, tachycardia, and poor exercise tolerance. The diagnosis and treatment of iron deficiency anemia is generally like those in nonpregnant patients, except for a greater emphasis on the use of intravenous iron given time constraints.

Iron supplementation is routinely provided during pregnancy because the typical diet in the United States provides only 50% of daily iron requirements for pregnant women and is due to the relatively high prevalence of iron deficiency in women of childbearing age. Typically, supplementation with 15 to 30 mg/day of elemental iron is administered to prevent adverse outcomes from iron deficiency anemia. Supplementation should begin at the start of gestation and continue until several months postpartum. The side effects associated with iron therapy include constipation, diarrhea, and nausea. Such side effects may be particularly troublesome because constipation and nausea are common symptoms of pregnancy.

Multiple studies have shown that routine iron supplementation in pregnancy decreases the incidence of iron deficiency anemia. In a randomized double-blind study in which 275 iron-replete pregnant women at no more than 20 weeks’ gestation received either a daily iron supplement or placebo from the time of enrollment to 28 weeks’ gestation, the incidence of both low-birthweight and preterm low-birthweight infants was lower among women who received daily iron. Research indicating that low fetal and infant iron stores predict worse cognitive function provides further support for normalizing maternal iron stores and optimizing transfer of iron to the fetus. In addition to justifying routine iron supplementation in prenatal vitamins, this is the primary motivation for increased use of intravenous iron.

There are limits to the effectiveness of routine iron supplementation. Patients may develop iron deficiency despite supplementation or be intolerant of oral supplementation. As mentioned, the side effect of constipation can be particularly troublesome with oral iron because constipation and hemorrhoids are common complaints during pregnancy. Active inquiry about these side effects may uncover nonadherence to oral iron when iron deficiency anemia persists.

Intravenous iron is appropriate in certain circumstances: intolerance of oral iron therapy has not improved iron stores and anemia, perhaps even severe iron deficiency anemia, persists. Due to lack of safety data, intravenous iron is generally avoided in the first trimester of pregnancy. All intravenous formulations of iron deficiency are effective and safe in pregnancy. For convenience and expediency, especially given the time constraint of pregnancy, formulations that can be administered in one or two visits are preferred.

Folate and Vitamin B ₁₂ Deficiencies

Folate and vitamin B ₁₂ (cobalamin) deficiency also occur more commonly during pregnancy (see Chapter 40 ). Vitamin B ₁₂ and folate are critical for fetal growth because they are used to produce tetrahydrofolate, which is essential for DNA synthesis.

Folate deficiency accounted for most cases of megaloblastic anemias in pregnancy prior to routine supplementation. The folic acid requirement for nonpregnant women is 50 to 100 μg/day, but this increases to 150 μg in pregnancy because of the increase in maternal RBC mass and fetal demands for folate because of rapid cell proliferation. With fortification of the food supply with folate and the routine use of folate-containing supplements during pregnancy, folate deficiency is an uncommon cause of anemia in pregnancy but should be considered, particularly in women not adherent to folate supplements.

The diagnosis of folate deficiency is best based on RBC folate levels, although many laboratories only offer serum folate assays. An elevated homocysteine level also helps confirm the diagnosis. Pregnant women should receive a minimum of 400 μg of folic acid per day. There are harms associated with excess supplementation because folate, which is a water-soluble vitamin, is readily excreted in the urine if ingestion exceeds requirements.

Vitamin B ₁₂ deficiency can also occur during pregnancy. Serum vitamin B ₁₂ levels may be less reliable during pregnancy due to altered protein binding. Diagnosis of vitamin B ₁₂ deficiency can be confirmed by elevated levels of homocysteine and methylmalonic acid. If a woman is found to be deficient in vitamin B ₁₂ during pregnancy, vitamin B ₁₂ injections are usually preferred over oral supplementation for initial therapy. A vitamin B ₁₂ dose of 1000 mcg intramuscularly is given weekly for 4 weeks and then monthly thereafter. Alternatively, after initial repletion with parenteral vitamins or if anemia and deficiency are mild, supplementation can be administered with vitamin B ₁₂ 1000 mcg by mouth daily. For ongoing therapy, oral dosing has been shown to be equivalent to parenteral administration, even in individuals with malabsorption of vitamin B ₁₂ .

Sickle Cell Disease

Every year, more than 300,000 children are born with either sickle cell disease or thalassemia (see Chapter 41, Chapter 42 ). Prenatal counseling is now routine in many countries. In the United States, all newborns are screened for sickle cell disease (see Chapter 42, Chapter 43 ). Management of pregnant patients with sickle cell disease requires coordination of care between the hematologist and obstetrician. Many women with sickle cell disease experience more frequent vaso-occlusive crises and other sickle cell–related complications during pregnancy. The increased frequency of vaso-occlusive crises, particularly during the latter half of pregnancy, results from heightened metabolic requirements in pregnancy, increased venous stasis, and the physiologic prothrombotic and inflammatory states associated with pregnancy. In addition, pathophysiologic changes in the renal and immune function of patients with sickle cell disease increase their susceptibility to urinary tract infections and pyelonephritis. By causing tissue hypoxia, sickling of RBCs within the placental vasculature may have deleterious effects on the fetus.

Additional complications in pregnant women with sickle cell disease and thalassemia include an increased risk of preeclampsia, thromboembolic events, placental abruption, intrauterine growth retardation, low birthweight, and postpartum infections. Studies have shown that women with sickle cell disease experience a higher incidence of stillbirths and perinatal mortality, as well as an increased risk of preterm labor and premature rupture of membranes. Consequently, women with sickle cell disease require close medical attention throughout the prenatal period, including counseling about intrauterine diagnosis of sickle cell disease, when appropriate. Pregnant women can undergo chorionic villi sampling as early as the 9th week of gestation or amniocentesis in the 15th to 16th weeks if fetal evaluation is desired (see Chapter 43 ). The reticulocyte count should be monitored to assess for bone marrow suppression or the development of nutritional deficiency. Urinalysis with urine culture is performed at least every trimester to monitor for asymptomatic bacteriuria, as this is more common in women with sickle cell disease than in those without and is treated, unlike in nonpregnant patients, because of its association with preterm birth and low birthweight infants. Finally, beginning at between 24 and 28 weeks’ gestation, patients should have weekly clinic visits and begin serial ultrasonography to monitor fetal growth.

Pregnant women with sickle cell disease should receive 5 mg/day of supplemental folic acid to address the extra demands of chronic hemolysis and pregnancy. Hydroxyurea can be continued in women with sickle cell disease who wish to become pregnant provided that they track their menstrual cycles and stop taking the drug as soon as a pregnancy test is positive. Hydroxyurea should be withheld during pregnancy but may be restarted in the late second or third trimester in women with serious symptoms. Use of hydroxyurea in pregnancy may be associated with low birthweight and prematurity, but it is difficult to ascertain if it is causal because women with severe sickle cell disease are already at risk of these complications. Ultimately, the risks associated with hydroxyurea must be weighed against the negative effect of poorly controlled sickle cell disease.

Studies examining the benefit of prophylactic blood transfusions have yielded mixed results; the only randomized trial revealed a reduction in vasoocclusive crises with transfusion but no improvements in fetal or other maternal outcomes. Given the risk of alloimmunization and iron overload, prophylactic simple or exchange transfusion is not appropriate for all pregnant women with sickle cell disease. However, individualized care is needed, and prophylactic transfusion may be appropriate for women with severe disease phenotypes.

Transfusion should be considered if the hemoglobin level falls below 6 g/dL if there are progressive complications related to sickle cell disease, or in the face of obstetrical complications. With these criteria, many women require transfusion during pregnancy, although at a lower volume than that needed for prophylactic transfusion. Women with a sickle cell crisis during pregnancy should receive analgesics, hydration, and oxygen while undergoing evaluation for infection or other precipitating causes.

At delivery, pregnant women with sickle cell disease are at risk of high-output heart failure. Supplemental oxygen and cautious hydration should be given to prevent sickling of RBCs and the associated complications. During the postpartum period, hemoglobin levels must be monitored, and VTE prophylaxis should be given unless there are contraindications to anticoagulation. VTE prophylaxis should be continued for 5 to 7 days after vaginal delivery and 2 to 6 weeks after a cesarean section (see Chapters 140 and 141 ).

Thalassemia

Pregnant women with thalassemia typically have β-thalassemia minor or α-thalassemia minor—conditions with relatively benign clinical phenotypes rather than β-thalassemia major, β-thalassemia intermedia, α-thalassemia major (also called hemoglobin Barts), or hemoglobin H disease (see Chapter 41 ). Pregnancy is a common setting for the diagnosis of thalassemia minor in previously asymptomatic women who are found to have anemia on routine laboratory evaluation. Dilutional anemia of pregnancy may be exacerbated in women with thalassemia minor, although this effect is variable and more common with β-thalassemia minor than α-thalassemia minor. Thalassemia minor does not adversely affect fetal development, fetal morbidity and mortality, or maternal morbidity and mortality.

Due to delayed pubertal growth or hypogonadism with associated anovulation, women with α- and β-thalassemia major have diminished fertility. Fertility is more variable with hemoglobin H and β-thalassemia intermedia. In the setting of widespread transfusion and iron chelation therapy, pregnancy has become more frequent in these women, and most have successful pregnancies without complication. However, there is an increased risk of maternal complications, especially heart failure. Women with β-thalassemia major and, to a lesser extent, those with β-thalassemia intermedia are at risk of intrauterine growth restriction (IUGR) and low-birthweight babies. Women with β-thalassemia intermedia and hemoglobin H disease often require transfusion during pregnancy.

Iron chelators carry a risk of teratogenicity and must be stopped at least during the first trimester of pregnancy; use in the third trimester—or, even more rarely, in the second trimester—is reserved for women in whom it is unsafe to withhold therapy throughout pregnancy. Therefore, cardiac status and the presence and extent of iron overload must be assessed when counseling women with thalassemia about the risks of pregnancy. Every effort should be made to optimize control of iron overload prior to conception to minimize the risk of decompensation during pregnancy and facilitate tolerance to discontinuation of iron chelation therapy during pregnancy.

Like those with sickle cell disease, women with thalassemia require vigilant follow-up throughout pregnancy. This includes interval monitoring of maternal vital signs and fetal heart-rate, maternal hemoglobin levels, and fetal growth as assessed by ultrasonography beginning between 24 and 28 weeks’ gestation. Prenatal genetic testing can be performed if desired, with results used for counseling and guidance of optimal care of the fetus. Women may choose to undergo testing after conception with the intention of terminating the pregnancy if the test is positive; in such cases, chorionic villus sampling may be indicated. Genetic testing is required for antepartum diagnosis of β-thalassemia because silencing of the beta globin gene until after birth results in a normal hemoglobin electrophoresis during pregnancy. Alpha thalassemia major can be diagnosed early by genetic testing, but it will also manifest as severe fetal anemia during the second trimester. When counseling about α- thalassemia major, it is important to note that intrauterine transfusion has rendered fetuses with this disorder viable, albeit still at high risk. Referral should be made to a maternal fetal medicine specialist trained in intrauterine transfusion if women with α-thalassemia major wish to continue their pregnancies.

Hereditary Spherocytosis

Hereditary spherocytosis is the most common inherited hemolytic anemia among people of northern European descent (see Chapter 46 ). Since some patients have low levels of hemolysis under normal conditions, the disease may not become clinically apparent until pregnancy. Pregnant women with hereditary spherocytosis are susceptible to pigment gallstones and folate deficiency related to the increased requirements of pregnancy superimposed on accelerated hemolysis. Pregnancy outcomes for women with hereditary spherocytosis are generally good, with better outcomes in those who have undergone splenectomy. Care is primarily supportive with folate (5 mg/day) and transfusion as needed. Splenectomy should not be undertaken during pregnancy. Accelerated hemolysis during pregnancy abates after delivery, and the need for splenectomy can be determined at that time.

Glucose 6-Phosphate Dehydrogenase Deficiency

Glucose 6-phosphate dehydrogenase (G6PD) deficiency leads to hemolytic anemia in the face of oxidative stress (see Chapter 45 ). The condition may increase the risk of spontaneous abortion, low-birthweight fetuses, and neonatal jaundice if oxidative stressors are not avoided. Women with G6PD deficiency should be instructed to avoid medications with oxidative potential. Complications after the ingestion of oxidative drugs have been reported in carriers of the G6PD deficiency gene if a male fetus has inherited the disease, particularly with medications that cross the placenta.

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder caused by somatic mutation in the membrane-anchoring protein PIGA (see Chapter 32 ). PIGA mutation leads to abnormal function of critical membrane proteins that in wild-type individuals are anchored by the gene product of PIGA . Features of the clinical phenotype include hemolysis, thrombosis, and bone marrow failure. Hemolysis results from deficiency in the membrane proteins CD55 and CD59, which renders affected individuals susceptible to complement-mediated intravascular hemolysis.

The clinical manifestations of PNH can have a devastating impact on pregnancy if left untreated. Prior to the availability of complement inhibitors, common complications included severe anemia, thrombocytopenia, thrombotic events, preterm delivery, low-birthweight infants, neonatal death, and maternal death, with a maternal mortality rate as high as 20%. As with treatment of PNH in other contexts, eculizumab, a C5 inhibitor, has significantly improved pregnancy outcomes. Accelerated clearance of eculizumab can occur during pregnancy. As such, patients should be monitored for breakthrough hemolysis and eculizumab dosed more frequently if this is noted. A structurally similar C5 inhibitor with a longer half-life, ravulizumab, is likely also appropriate for treatment during pregnancy, but there is less experience with the use of this agent. Pegcetacoplan is a C3 inhibitor with proven efficacy for PNH, but its use in pregnancy should be avoided because animal studies have shown potential for harm, and human data are not yet available.

For women not already on therapeutic anticoagulation, prophylactic dose anticoagulation with low molecular weight heparin should be initiated and continued for 6 to 12 weeks postpartum because of the high risk of thrombosis. Women on therapeutic anticoagulation should have this continued with therapeutic dosing of low molecular weight heparin (further discussed in the section on VTE).

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA; see Chapter 47 ) can occur de novo during pregnancy or be a flare of preexisting disease. Warm AIHA poses a greater risk than cold agglutinins because the relatively small size of immunoglobulin (Ig) G molecules allows them to cross the placenta and adversely affect the fetus. In contrast, the larger IgM antibodies in cold agglutinin disease do not cross the placenta. Patients with AIHA are treated with glucocorticoids and, less commonly, intravenous immunoglobulin (IVIg), both of which have an excellent safety record in pregnancy. Supportive transfusions can be administered when needed. For more severe cases, rituximab can be given during pregnancy and has not been clearly associated with birth defects. However, rituximab can cross the placenta and induce temporary B-cell lymphopenia in the neonate with a subsequent increased risk of infection. As such, rituximab administration during pregnancy is usually reserved for women with hemolysis that cannot be controlled with corticosteroids alone or who require a high dose of corticosteroids. For other women, rituximab is best deferred to the postpartum period. While rituximab is detectable in breastmilk, concentrations are low enough that this is unlikely to pose a risk of immunosuppression and should not be considered a contraindication while breastfeeding.

In rare instances, pregnancy can precipitate AIHA, likely due to the effect of pregnancy on immune regulation; management is the same as it is for flares of known disease or new onset disease.