Chapter 28: The Management of a Sickle Cell Crisis in Pregnancy

Hemoglobinopathies are inherited disorders that result in abnormal hemoglobins. Broadly speaking, the disorders can be classified as disorders of the quantity of hemoglobin such as thalassemia or structural disorders such as sickle cell anemia. Hemoglobinopathies are relatively common and affect 5% to 7% of the world’s population. Sickle cell trait occurs in 8% of African Americans while sickle cell anemia occurs in one of every 600 African Americans. It is estimated that 30 million people worldwide carry at least one copy of the gene for hemoglobin S. Approximately, 1500 children with sickle cell anemia are born annually in the United States.

Pregnancies complicated by sickle cell anemia are marked by an increase in maternal and fetal complications. The maternal complications relate to the effects of chronic hemolysis, increased susceptibility to infection, intermittent crises, underlying multiorgan involvement, and an increased risk of preeclampsia. There is an increase in maternal mortality. The fetal effects include increased rates of intrauterine growth restriction (IUGR), low birth weight, and preterm birth in addition to the potential for the fetus to be either a homozygote or heterozygote for the sickle cell gene.

Hemoglobin is the iron-containing transport protein responsible for oxygen delivery from the lungs to the cells. Adult hemoglobin normally contains 4 globin chains. The most common adult hemoglobin is hemoglobin A₁ which consists of 2 α and 2 β chains (α₂β₂). Adults have a small amount of hemoglobin A₂ which consists of 2 chains of α and 2 δ chains (α₂δ₂). The predominate fetal hemoglobin, hemoglobin F, consists of 2 α and 2 γ chains (α₂γ₂). After birth, the γ chain is replaced by the β chain. However, hundreds of variations of α, β, γ, and δ chains have been described.

In sickle cell anemia, there is a point mutation in the β chain in which valine is substituted for glutamic acid. This results in the formation of hemoglobin S which distorts the red cell membrane such that the normal shape and deformability of the red cell are lost. The crescent-shaped red blood cells have a diminished capacity for oxygen transport and their abnormal shape and easy fragmentation causes obstruction to flow, particularly in small vessels. Sickle cells are more adherent to endothelium, further contributing to a viscous cycle of vascular occlusion, thrombosis, and tissue damage. The cells are more easily dehydrated which shortens their life span from the normal 120 days to less than 20. This results in a chronic state of intravascular and extravascular hemolysis.

The tendency of a red cell to sickle depends upon the amount of hemoglobin S and the level of oxygen. The more the hemoglobin S or the lower the oxygen level, the higher the risk. Patients who are homozygous have 80% to 100% of their hemoglobin in S form and will sickle at normal oxygen levels. Patients who are heterozygotes, the so-called sickle cell trait, have only 25% to 40% of their hemoglobin in the S form and generally do not form sickle cells unless there are extreme conditions.

The disease is characterized by a chronic hemolytic anemia, increased release of bilirubin, a predilection to infection, and vascular congestion with thrombosis. Table 28-1 lists the common infectious complications. Patients should be considered immunocompromised and are at high risk from infection from encapsulated organisms due to asplenism. The anemia and stasis lead to widespread hypoxic damage but particularly affect the liver, kidneys, subcutaneous tissues, spleen, and heart. Lower extremity ulcers of the skin and subcutaneous tissue are common. Damage and thrombosis in retinal vessels lead to vision loss. Some patients develop cor pulmonale and/or pulmonary hypertension and are at increased risk of stroke. The marrow becomes hypercellular. Extramedullary hematopoiesis initially occurs in the liver and spleen but by adulthood most patients are functionally asplenic. The liver is enlarged. The chronic hemolysis causes hemosiderosis and cholelithiasis. The kidney is particularly susceptible to injury because the low oxygen content in the medullary increases sickling. Renal papillary necrosis and infarcts affect 30% to 40% of patients. Proteinuria, hematuria, and an inability to concentrate urine are common. It is easier for patients to become dehydrated. Patients with sickle cell disease and sickle cell trait have higher rates of renal medullary carcinoma. Table 28-2 lists the renal complications seen in sickle cell anemia.

There is cardiomegaly due to the chronic anemia. The left atrium and both ventricles are enlarged. The precordium is hyperdynamic and grade II to III systolic murmurs are common even outside of pregnancy. Patients may have diastolic dysfunction and usually have a marked reduction in exercise tolerance. The cardiac output is elevated at rest and there is a very limited capacity to increased cardiac output in times of stress. Myocardial infarctions have been reported even in children affected with sickle cell. Sudden death is not uncommon.

The lungs are damaged by repeated episodes of infection and infarction. The functional pulmonary vascular tree is reduced. Pulmonary hypertension is increasingly being recognized as a major problem in patients with sickle cell anemia.

The diagnosis of sickle cell anemia is suspected on the basis of a microcytic hypochromic hemolytic anemia in a patient of African American descent. However, sickle cell anemia also occurs in patients who are from the Caribbean, the Middle East, India, the Mediterranean, and South and Central America. Although most patients have a hemoglobin in the range of 6 to 9 dL, some patients may have a hemoglobin that is higher and closer to normal, particularly if they are compound heterozygotes.

The diagnosis of sickle cell anemia can be made by showing a high concentration of hemoglobin S using techniques such as DNA analysis, high-performance liquid chromatography, isoelectric focusing, or cellular acetate electrophoresis. A hemoglobin electrophoresis passes electric current through hemoglobin. Different hemoglobins have different electric charges and will separate based on their charge. Normally, about 95% or more of an adult’s hemoglobin should be A₁ (α₂β₂), with about 3% to 5% A₂ (α₂δ₂), and less than 1% F (α₂γ₂). There should not be any hemoglobin C, S, E, or H. A patient with sickle cell anemia will have 80% to 100% hemoglobin S while a patient with sickle cell trait will have less than 45% hemoglobin S. Patients can also be compound heterozygotes by virtue of coinheriting another abnormal hemoglobin, usually hemoglobin C or hemoglobin β thalassemia. However, multiple other types of abnormal hemoglobins have been reported. Patients with hemoglobin SC disease usually have about 60% hemoglobin C and about 40% hemoglobin S. Compound heterozygotes tend to have less severe disease.

The physiologic changes that occur in pregnancy place enormous demands on patients with sickle cell anemia. Physiologic anemia is common in pregnancy and there is increased demand for folate. Patients with sickle cell anemia are already anemic and folate deficient. Pregnancy significantly increases the work of the heart and many patients with sickle cell anemia have underlying pulmonary hypertension and reduced exercise tolerance and are already at maximum cardiac output. Pregnancy increases the risk of thromboembolism, another common complication in sickle cell anemia (Table 28-3).

Patients with sickle cell disease have a variety of pregnancy complications. They are more prone to infections, gallstones, preeclampsia, eclampsia, thromboembolism and pulmonary embolism, IUGR, and preterm birth. The infectious morbidity includes an increased risk of urinary tract infections, pneumonia, postpartum infections, and sepsis. The increase in sepsis and preeclampsia combined with preexisting renal dysfunction increases the risk of acute renal failure. They may have antibodies to various red cell antigens as a result of past transfusions. Many are dependent upon narcotics for control of painful vaso-occlusive crises. They are more likely to be delivered by cesarean section and to have a low-birth-weight or preterm infant. The chronic hypoxia and placental thrombosis increase the risk of IUGR.

Pulmonary hypertension is common. Since the maternal mortality of a pregnancy complicated by pulmonary hypertension has been reported to be 25% to 50%, patients should be carefully evaluated for this complication. Some authors have suggested that a tricuspid regurgitant jet velocity greater than 2.5 ms on echocardiography is a useful screening test for pulmonary hypertension. Because of the increased cardiac flow in pregnancy, it is not uncommon to have an impression of pulmonary hypertension on ECHO and patients may need a cardiac catheterization to confirm the diagnosis.

Patients with sickle cell trait have an increased risk of preeclampsia and urinary tract infections as well as an increased risk of medullary renal carcinoma. Some authors have advocated antibiotic prophylaxis while others have suggested obtaining urine cultures at least every trimester. Although there are no randomized data to guide therapy, it may be helpful to treat patients with sickle cell anemia with low-dose aspirin to reduce the risk of preeclampsia particularly in those patients with abnormal uterine artery Doppler in the first trimester. The differential diagnosis of eclampsia in a patient with sickle cell includes a cerebrovascular accident which is not an uncommon complication. There should be very liberal indications for the use of imaging techniques in any patient with a seizure to exclude a stroke.

Many patients with sickle cell anemia are treated with hydroxyurea, a cytotoxic drug. Hydroxyurea destroys the more rapidly produced cells containing hemoglobin S thereby inducing the production of hemoglobin F. It may also reduce the adhesiveness of the sickle cell to endothelium. If a patient becomes pregnant the hydroxyurea needs to be discontinued as it is teratogenic in animals. Although there have not been reports of fetal anomalies due to hydroxyurea, the data are very limited. Hydroxyurea should not be taken by mothers who are breast-feeding.

There is some controversy about the role of prophylactic transfusions during pregnancy to reduce the frequency of a crisis and to improve pregnancy outcome. Both prophylactic transfusions and partial exchange transfusions have been studied and most authors do not think there is a role for their routine use. Transfusions increase the risk of alloimmunization and/or transfusion reactions. Transfusions have been shown to be helpful for acute chest syndrome associated with hypoxia, symptomatic anemia, preoperatively before major surgery, in extreme fatigue, or if there is evidence of heart failure.

As with many conditions, the course of sickle cell anemia and the number and types of crises that pregnant patients experience closely parallels their course outside of pregnancy with the exception that some pregnant women experience an increase in vaso-occlusive crises. Patients may be particularly vulnerable to a vaso-occlusive crisis in the immediate postpartum period due to the large hemodynamic changes that occur at that time. The management of a crisis does not differ substantially in pregnancy or the postpartum period from that recommended outside of pregnancy.

There are several types of sickle cell crises (Table 28-4). The most common crisis is a vaso-occlusive crisis in which the patient experiences severe pain, typically in the long bones or joints and probably as the result of the low oxygen environment of the marrow. The most common sites are the humerus, tibia, and femur. About 60% of patients with sickle cell anemia have at least one vaso-occlusive crisis a year. A crisis may last from several days to weeks and is precipitated by many factors including infection, infarction, dehydration, acidosis, stress, drug or alcohol use, exposure to cold, and pregnancy. As many as a third of crises are due to infection. However, most crises occur without a clear precipitating event. Although bone pain is most commonly due to a vaso-occlusive crisis, it can also be a presentation of osteomyelitis. Both will have pain, increased warmth, swelling, and a leukocytosis. The distinction can usually be made based on the temperature and white blood cell count. Generally both are much higher in osteomyelitis. Other orthopedic complications are common (Table 28-5).

Although the pain of a vaso-occlusive crisis occurs most often in long bones it can also occur in the chest, abdomen, and back. Pain may be localized or migratory. It is common to have pain in several sites simultaneously. The pain of a vaso-occlusive crisis has been described as constant or throbbing as well as sharp, dull, pounding, and cutting. Many patients describe a prodromal period of 1 to 2 days prior to a full-blown crisis in which they feel parenthesis, numbness, or a dull ache in areas which subsequently become much more painful. Up to 20% of patients have had a recent hospitalization for a crisis. Recovery from a crisis predisposes patients to a high risk of thromboembolic disorders as the patients have increased erythropoiesis, elevated levels of fibrinogen, and increased plasma viscosity. It can be difficult to distinguish the pain of a vaso-occlusive crisis from that of other abdominal etiologies such as cholelithiasis or appendicitis. One must be careful to consider all etiologies and not simply attribute abdominal pain to a sickle cell crisis. Generally, patients in a vaso-occlusive crisis who have abdominal pain still have bowel sounds. The absence of bowel sounds should prompt consideration of another cause of the abdominal pain such as appendicitis or cholecystitis.

In addition to the vaso-occlusive pain, many patients have chronic pain as a result of leg ulcers, bone conditions, or neuropathies. Some patients will never be entirely pain free.

The acute chest syndrome (ACS) is a type of crisis in which the patient presents with fever, chest pain, tachypnea, an increase white blood cell count, and infiltrates on chest x-ray. This common complication is due to infection or infarction of lung tissue and is seen more often in patients who are asthmatic. The most common organisms are Chlamydia, Mycoplasma, Parvovirus B19, and various respiratory viruses. It can also be due to Staphylococcus and Streptococcus pneumoniae. ACS can also occur because of an underlying rib infarction as patients hypoventilate and develop atelectasis due to the pain of respiration. It can be difficult to distinguish ACS from pneumonia or a pulmonary embolism.

A megaloblastic crisis occurs in the setting of folate depletion when insufficient folate levels leads to a cessation of erythropoiesis. Folate deficiency is common in sickle cell anemia due to the rapid turnover of cells. A megaloblastic crisis can occur with poor oral intake, alcoholism, or with increased demands for folate such as that which occurs in pregnancy.

Several types of crisis are more commonly seen in children. These are splenic sequestration crisis, an aplastic crisis, and a hyperhemolytic crisis. By adulthood most patients are functionally asplenic so splenic sequestration is not typically seen in pregnancy. Many aplastic crises have been reported in association with a Parvovirus B19 infection. A hyperhemolytic crisis is defined by a 2-g drop in hemoglobin associated with an enlarged spleen. As with a splenic sequestration crisis, a hyperhemolytic crisis is generally confined to childhood as adults are functionally asplenic. A hyperhemolytic crisis can occur in conjunction with mycoplasma infections, hereditary spherocytosis, and medications, especially in patients with glucose-6-phosphate deficiency (G6PD). However, since G6PD is an X-linked disorder, this is rarely seen in females.

A patient in crisis should be admitted, preferably to an intensive care setting. Since most crises are vaso-occlusive the priorities are hydration, pain relief, and evaluation for a precipitating cause, most commonly infection (Fig. 28-1). Since at least a third of vaso-occlusive crisis are caused by an infection, the patient should be carefully evaluated especially for the most common type of infections which are urinary tract infections, cholecystitis, pneumonia, and osteomyelitis. Urinary tract infections should be treated at least for 10 days. Patients with sickle cell disease have a reduced capacity to concentrate their urine and can easily become dehydrated. In addition, they may have ongoing fever or gastrointestinal losses. If possible the patient should be orally rehydrated with a minimum intake of 60 cc/kg/d. If patients are severely dehydrated or unable to take an adequate oral intake, they should have intravenous fluids. Patients in crisis lose more sodium in their urine so electrolytes need to be carefully maintained. Acidosis should be cautiously corrected with dilute sodium bicarbonate. Oxygen should only be given if the oxygen saturation is less than 95% or has dropped more than 3% from baseline but not be a routine measure as oxygen can cause a rebound in sickling when it is discontinued. The patient’s analgesic history can help to guide therapy since what has previously been most efficacious is probably going to continue to be the best choice at least initially. Analgesia can be given orally, subcutaneously, or intravenously but since absorption can be erratic, intramuscular injections are probably best avoided. Table 28-6 gives suggested doses. Consultation with a pain service may be beneficial.

A hemoglobin electrophoresis should be obtained, not to confirm the hemoglobinopathy but to determine the level of hemoglobin S. The level of hemoglobin S, the hematocrit, and the patient’s presentation guide the decision to do a transfusion. Transfusions can be given either as a “top-off” or as exchange transfusion. The intent of an exchange transfusion is to raise the hematocrit to greater than 35% and increase the amount of hemoglobin A to above 40% while decreasing the amount of hemoglobin S. Figure 28-2 illustrates an approach to an exchange transfusion.

Although an exchange transfusion or a “top-off’ transfusion is generally not necessary in most vaso-occlusive crises, certain patients are candidates for transfusion. Transfusions are indicated in severe anemia (Hb <5-6 g/dL), acute chest syndrome with hypoxia, congestive failure due to anemia, stroke, in selected patients with refractory pain and preoperatively. Patients who are undergoing surgery have fewer complications if their hemoglobin is maintained at 10 mg/dL or above.

Patients with sickle cell anemia and particularly those in crisis are at very high risk of thromboembolism due to dehydration, infection, and sickling. Many authors would give prophylactic anticoagulation to any pregnant patient with sickle cell anemia. If the patient is on prophylaxis, it should be continued. If she is not on prophylaxis, it should be started. Standard regimens are appropriate. Patients should have other measures in place as well such as ambulation and the use of sequential pneumatic compression devices.

The health of the fetus should be assessed. The estimated gestational age (EGA) should be confirmed and the fetus should be evaluated for IUGR. If the fetus has reached viability, the fetus should be monitored and consideration should be given to antenatal steroids. Every effort needs to be made to avoid subjecting a patient in crisis to the added stress of delivery for fetal indications as surgery during a crisis is fraught with maternal risk. It is very important to have patients well hydrated before surgery to reduce complications. General anesthesia has been associated with an increased risk of ACS.

Although it is not part of the initial management of a patient in crisis, there are other measures that will improve overall health and pregnancy outcome. Patients with sickle cell are reported to have dietary deficiencies including minerals and vitamins. A nutritional consult can be helpful. The patient’s vaccination status should be reviewed and appropriate vaccinations should be administered. Pregnant women with sickle cell anemia should receive an annual influenza vaccine and receive a vaccination for S pneumoniae every 5 years. Routine antibiotics are not necessary in adults as they have less risk of infection and sepsis than children. The patient should also be immunized against hepatitis B if this has not already been done. Smoking should be strongly discouraged and patients should be given appropriate smoking cessation therapies and counseling. Patients should attempt to plan their pregnancies so that they attempt to conceive during a period when their disease is quiescent. Women with sickle cell anemia have high rates of cesarean section and may desire sterilization at the time of their surgery. In addition, since many patients are folate deficient, preconceptual folate is essential to reduce the risk of birth defects.

It would be ideal to avoid a crisis or to minimize the number and severity of these painful episodes. Prophylactic transfusions have reduced the number and severity of vaso-occlusive crises in some studies but present a risk of immune suppression, sensitization to red cell antigens, and iron overload. During pregnancy, prenatal visits should be scheduled frequently. Patients should receive 4 to 5 mg of folate daily to reduce the risk of a megaloblastic crisis. Urine cultures should be obtained at least every trimester or if patients experience symptoms. Patients need to remain hydrated and reduce areas of stress in their lives. Unfortunately, the use of hydroxyurea is contraindicated in pregnancy and breast-feeding.

There are several approaches that have been used to treat sickle cell disease. Drugs such as hydroxyurea and butyrate are used to increase the production of hemoglobin F, genetic manipulation of the abnormal gene, and bone marrow transplantation to effectively “cure’ the hemoglobinopathy. Unfortunately, these drugs are considered contraindicated in pregnancy. There are reports of successful treatment with bone marrow transplantation although multiple complications have been described. It can be difficult to get an appropriate match and there are reports of failed engraftment and graft-versus-host disease following transplantation. Work is ongoing in these areas. Umbilical cord blood may provide additional sources for bone marrow transplant. However, even attempts to use umbilical cord have been met with the same type of complications described above: a high rate of engraftment failure and posttransplant graft-versus-host disease.

Patients with sickle cell now have longer life spans and are more likely to become pregnant than was previously possible. Although sickle cell disease in pregnancy presents many challenges, recent data suggest that most patients who are cared for in centers utilizing an appropriate multidisciplinary approach will deliver a viable infant at term. With the exception of careful surveillance of the fetus for IUGR, the management of a vaso-occlusive crisis during pregnancy does not differ substantially from the care provided to nonpregnant patients. The majority of patients with sickle cell anemia will do well if their underlying pathophysiology is understood and careful attention is paid to the specific complications seen during pregnancy.