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PROTOCOL 12 Hemoglobinopathies in Pregnancy
Bradley Sipe and Judette Louis
Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
Clinical significance
Hemoglobinopathies are a group of disorders, including sickle cell disease and thalassemias, which affect the structure of hemoglobin. Annually, 300 000 people are born clinically affected by this group of diseases. There are over 270 million heterozygous carriers worldwide.
Sickle cell disease
Sickle cell disease (SCD) is a hemoglobinopathy caused by a single nucleotide substitution leading to abnormal hemoglobin structure. The abnormal shaped, “sickled,” red blood cells then create occlusion of the microvasculature, leading to painful crisis. These crises lead to hospitalizations, decreased quality of life, organ damage, and overall morbidity/mortality. The most significant form of the disease is HgbS‐S (sickle cell anemia). Other compound heterozygous conditions including HgbS‐C and HgbS‐beta‐thalassemia can produce similar, though often less severe clinical disease. Complications of SCD include infection, anemia, and infarction/vasoocclusion which can affect numerous organ systems including renal, cardiopulmonary, and vascular. Major complications associated with SCD include acute chest syndrome, pulmonary hypertension, stroke, renal disease, venous thrombotic events, and osteonecrosis. Patients with SCD are functionally asplenic and therefore are at risk of infections from Streptococcus pneumoniae and Haemophilus influenzae.
In pregnancy, SCD has been associated with adverse outcomes including small for gestational age neonates, pregnancy loss, preeclampsia, and maternal mortality. In the US, 1 in 12 African Americans has sickle cell trait (Hgb A‐S). Among African American newborns, 1 in 300 will have some form of SCD while 1 in 600 will have sickle cell anemia (Hgb S‐S). SCD is inherited in an autosomal recessive manner.
Thalassemias
Thalassemias are a group of disorders affecting the production of the interlocking polypeptides of hemoglobin which can lead to microcytic anemia. The two most common types are alpha‐thalassemia and beta‐thalassemia. Depending on the severity of disease, thalassemias may present a mild anemia or a severe anemia requiring regular transfusions and shortened life spans.
Pathophysiology
Normal hemoglobin structure consists of four subunits, each containing an interlocking polypeptide chain and heme molecule. Normal adult hemoglobin consists of two alpha chains and two beta chains (HbA) or two alpha chains and two delta chains (HbA2). Fetal hemoglobin (HbF) consists of two alpha chains and two gamma chains. Oxygen binds reversibly to the ferrous iron atom in each heme group, facilitating its delivery to tissues throughout the body.
Sickle cell disease is a group of autosomal recessive disorders that result from a single nucleotide substitution of thymine for adenine converting a glutamic acid codon for a valine codon in the beta‐globin polypeptide encoded by the HBB gene on chromosome 11. Carriers of the disease (HbA‐S) have sickle cell trait and are generally unaffected by the disease. Those homozygous for hemoglobin S (HbS‐S) typically have the most severe form of the disease. Compound heterozygotes include those individuals with one copy of the sickle cell gene paired with another abnormality in beta globin production including HbS‐C and HbS‐beta‐thalassemia. Hemoglobin C (HbC) is due to a single nucleotide substitution involving the same nucleotide as HbS but instead of thymine, it is a guanine substitution at the adenine site. Compound heterozygotes experience similar vasoocclusive crisis and anemia as those with HbS‐S; however, it is often less severe.
Alpha‐thalassemia results from a gene deletion involving the HBA1 and HBA2 genes which encode for the alpha globin protein located on the 16th chromosome. Normal individuals will have four copies of the alpha globin gene, two on each of the 16th chromosomes (αα/αα). Individuals who have one missing gene (αα/α‐) are said to be silent carriers without evidence of disease (Hb and MCV tend to be lower levels of normal). Individuals missing two of the four genes have alpha‐thalassemia trait. These genetic disorders can be inherited in either a cis or trans form, which is important for potential effects on the offspring of affected individuals. Trans‐thalassemia trait will have one missing gene on each chromosome (α‐/α‐) and is commonly seen among those of African descent. Cis‐thalassemia trait will have both missing genes on the same chromosome (‐‐/αα) and is most commonly seen among those of Asian descent. The most severe form of alpha‐thalassemia results from abnormalities in all four alpha globin genes resulting in no alpha globin formation (‐‐/‐‐). This leads to hemoglobin Barts which results in high‐output cardiac failure in utero, fetal hydrops, and fetal demise. HbH is the inheritance of one normal copy the gene (α‐/‐‐) and is the most severe form of the disease compatible with life. Clinically, it manifests as moderate microcytic anemia which does not typically require transfusion, although affected individuals may develop a severe anemia requiring transfusion during acute illnesses/infections and during pregnancy.
Beta‐thalassemia is an autosomal recessive disorder affecting the HBB gene on chromosome 11 which leads to underproduction or absent production of the beta globin protein. In the homozygous form, the severity of the disease depends on whether beta globin production is simply reduced (beta+) or if production is absent (beta0). In utero, patients with severe beta‐thalassemia are protected from anemia due to normal fetal hemoglobin production but quickly require treatment and transfusion within the first year of life. Heterozygous forms of beta‐thalassemia are called beta‐thalassemia minor (or beta‐thalassemia trait) and have a variable degree of anemia depending on the rate of beta globin production.
Diagnosis
Patients at risk of being a carrier or being affected by a hemoglobinopathy should be screened appropriately in order to assess fetal and maternal risks in pregnancy. The American College of Obstetricians and Gynecologists currently does not support universal hemoglobinopathy screening.
At‐risk groups for hemoglobinopathies include high‐risk ethnic groups and patients with unexplained microcytic anemia. Persons of African, Mediterranean, Southeast Asian, Middle Eastern, and West Indian descent
