Hemoglobinopathies are inherited disorders that result in abnormal hemoglobin. 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 about 5% to 7% of the world’s popu­lation. Sickle cell anemia is the most common monogenic disease. The prevalence of hemoglobinopathies is increasing as more affected children survive to adulthood and subsequently pass on the genotype. Approximately 300,000 children are born worldwide every year who are affected with sickle cell anemia. The prevalence of disease is high in Africa, particularly the sub-Sahara, but also in areas in the Mediterranean, Middle East, and India. Sickle cell trait occurs in about 1 in 8 African Americans and about 1 in 600 African Americans have sickle cell anemia. A variant of sickle cell anemia, sickle-thalassemia (HbSC) is seen in Middle Easterners. It is generally milder than sickle cell anemia but may present for the time in pregnancy which is why it is important to obtain a hemoglobin electrophoresis in the evaluation of anemia in pregnancy.

Sickle cell anemia is a multisystem disease. (Fig. 28-1) Pregnancies complicated by sickle cell anemia are marked by an increase in maternal and fetal complications. The maternal complications relate to the effects of the multi­organ involvement, chronic hemolysis, increased susceptibility to infection and thrombosis, intermittent crises, increased rates of hypertensive disorders, narcotic dependence, increased potential for sensitization to red cell antigens, hemorrhage, and operative delivery. The fetal effects include increased rates of intrauterine growth restriction, low birth weight, prematurity, and the genetic implications of being either a heterozygote or a homo­zygote for the sickle cell gene.

Hemoglobin is the iron-containing transport protein responsible for oxygen delivery from the lungs to the cells. Adults normal have about 95% of their hemoglobin in the form of hemoglobin A1 which consists of two α and two β chains. In addition, there is a small amount of hemoglobin A2 which consists of two α and two δ chains. The predominate fetal hemoglobin has two α and two ϒ chains. As pregnancy progresses, the fetus converts more fetal hemoglobin to adult hemoglobin, a process that continues after birth. Fetal hemoglobin has been reported to increase in pregnancy to as much as 4% of maternal hemoglobin.

In sickle cell anemia, there is a point mutation in the chain in which valine is substituted for glutamic acid. This results in the formation of hemoglobin S which distorts the normal red cell architecture such that the normal shape and deformability are lost. The crescent shaped cells have 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 which further contributes to a viscous cycle of vascular occlusion, thrombosis, and tissue damage. These cells are more easily dehydrated which shortens their lifespan from the normal 120 days to less than 20. This results in a chronic state of intravascular and extravascular hemolysis.

The tendency of the 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 more the risk. Patients who are homozygous have 80% to 100% of their hemoglobin in the 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 thrombosis, and multiorgan involvement (see Fig. 28-1). Sickle cell disease (SCD) is complicated by a predilection for infection (Table 28-1). Patients should be considered immunocompromised and are at high risk of infections especially from encapsulated organisms as they are generally functionally asplenic by adulthood. The anemia and stasis lead to widespread hypoxic damage but particularly affect the liver, kidneys, heart, spleen, and subcutaneous tissues. The marrow is hypercellular but the low oxygen content combined with the increased demand increases the risk of infection due to hypoxic injury. Lower extremity ulcers of the skin and subcutaneous tissues are common. Damage to retinal vessels can lead to vision loss. Patients can develop cor pulmonale. Pulmonary hypertension is increasing recognized as a long-term complication as patients survive other complications and live longer. Thrombosis is common and stroke remains an important cause of morbidity and mortality. Fat emboli may be released. The hematopoiesis initially occurs in the liver and spleen but by adulthood most patients are functionally asplenic with enlarged livers. The chronic hemolysis causes hemosiderosis and cholithiasis. Patients are iron overloaded which can add an additional source of injury, particularly to the heart and lungs. There are multiple renal complications (Table 28-2). The kidney is particularly vulnerable as the low oxygen content in the medullary increases sickling. Renal papillary necrosis and infarcts affect 30% to 40% of patients. Renal medullary carcinoma is more common in both homozygotes and heterozygotes. Proteinuria, hematuria, urinary tract infections, and hyposthenuria (an inability to concentrate urine) are common and dehydration can increase the risk of a vaso-occlusive crisis. There is cardiomegaly due to chronic anemia and the effects of multiple pulmonary infections, infarctions, and thrombosis. The left atrium and both ventricles can be enlarged. The precordium is hyperdynamic and grade II-III systolic murmurs are common even outside of pregnancy. Patients may have diastolic dysfunction and a marked reduction in exercise tolerance. The cardiac output is elevated at rest and patients may have a limited capacity to increase cardiac output as needed. Myocardial infarctions have been reported even in children. Sudden death—originally erroneously attributed to narcotic overdose—is not uncommon.

The lungs are damaged as a result of hypoxia, infection, infarction, thrombosis, and iron overload. The functional pulmonary vascular tree is reduced. Pulmonary hypertension is increasingly being recognized as a major problem especially as treatment for other complications improves and patients survive longer. The incidence of pulmonary embolism in patients with SCD who are hospitalized has been shown to be 50-100 times that of the general population. A pulmonary embolism has been found in up to a third of deceased patients who undergo an autopsy.

The diagnosis of sickle cell anemia is suspected on the basis of a hemolytic anemia in a patient who is a member of a high-risk group. High risk groups include those of African ancestry but also patients from the Caribbean, Middle East, India, the Mediterranean and South and Central America. Although most patients have a hemoglobin in the range of 6 to 9 g/dL, some may have one that is higher and closer to normal particularly in HbSC disease.

The diagnosis of SCD 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 and different hemoglobins will separate based on their electrical charges. Normally, about 95% of an adult’s hemoglobin should be in the form of A₁ (α₂ β₂) with 3% to 5% A₂ (α2δ2) and less than 1% fetal hemoglobin (α₂ ϒ₂). 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 be compound heterozygotes by virtue of inheriting another abnormal hemoglobin, usually C or hemoglobin β thalassemia. However, other types of abnormal hemoglobin have also 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.

There are several types of sickle cell crises (Table 28-3). As with many conditions, the course of sickle cell anemia and the number and types of crises that pregnant women experience closely parallels their course outside of pregnancy with the exception that some patients experience an increase in vaso-occlusive crises. The most common crisis is a vaso-occlusive crisis in which a patient experiences severe pain, typically in the long bones or joints and which is thought to be due to the low oxygen content of 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 can last for days to weeks and can be precipitated by many factors including infection, infarction, dehydration, acidosis, stress, drug or alcohol use, exposure to temperature extremes or high winds, and pregnancy (Table 28-4). As many as a third of crises are due to infection and patients should be thoroughly evaluated for one (see Table 28-1). However, many crises can occur without a clear precipitating event. Although bone pain is most commonly due to a vaso-occlusive crisis, it can also be the result of infection or fracture. It may be difficult to distinguish infection from a crisis as both can present with pain, increased warmth, swelling, and a leukocytosis. Generally, the temperature and leukocytosis will be greater in osteomyelitis. Other orthopedic complications are common as well (Table 28-5).