Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Outline the diagnosis of hemoglobinopathies, including thalassemia.

2. Differentiate and recognize medical associations and potential complications of thalassemias.

3. Summarize key principles of pregnancy care for individuals with thalassemias and other hemoglobinopathies.

Thalassemias encompass a group of inherited blood disorders characterized by reduced or absent synthesis of globin chains of hemoglobin. These conditions result in a range of phenotypic manifestations from asymptomatic to lethal.1,2 Thalassemias are typically inherited in an autosomal recessive pattern where both parents are obligate carriers of the condition. As carriers, most individuals are asymptomatic. Carrier status in pregnancy is initially suspected after routine blood count detects variable degree of anemia.1 Early recognition of carrier status in the parents is vital for determination of risk to the fetus. Accurate diagnosis enhances the ability of the obstetrician to describe options for prenatal diagnosis, to optimize the management of the pregnancy, and ultimately to minimize maternal and fetal complications.3 Accurate prenatal diagnosis requires that the obstetrician must have a basic understanding of genetic and molecular considerations with thalassemias. Additionally, the practitioner should be aware of the important preconception and pregnancy considerations to optimize maternal care in pregnancy regarding transfusion-dependent thalassemias.4

There are 2 main categories of hemoglobinopathies: thalassemia syndromes (decreased or absent synthesis of one or more subunits of normal hemoglobin) and structural hemoglobin variants (specific alterations in the amino acid content of hemoglobin) with each having effects on hemoglobin function.3 The primary purpose of this review is to provide fundamental genetic knowledge about [alpha]-thalassemia and [beta]-thalassemia and to review hemoglobin structure and location of hemoglobin genes, epidemiology of hemoglobinopathies, and phenotypes of different thalassemias. This review highlights and synthesizes considerations for prenatal screening and diagnosis and management pearls for pregnant persons with these conditions. For the purpose of this article, structural hemoglobin variants have been briefly discussed in relation to understanding thalassemias, but their importance for screening, diagnosis, and treatment in pregnancy is beyond the scope of this review.

Epidemiology

Inherited hemoglobin disorders are the world's most common genetic blood conditions manifesting as anemia, accounting for 3.4% of deaths of children younger than 5 years.5 Traditionally, specific regions of the world (Mediterranean, Middle East, southern India, Southeast Asia, and South China) where malaria was endemic had a higher prevalence of these conditions; this seems a likely result of evolutionary adaptation as changes in hemoglobin made these populations less susceptible to malaria.6,7 Immigration patterns have influenced the geographic distribution of these conditions, with a 20-fold increase in Asian and other at-risk populations emigrating to the United States over the past 4 decades. This has led to increasing prevalence of thalassemias in the United States.8-10 As of 2008, roughly 330,000 cases of hemoglobinopathy are diagnosed each year per the World Health Organization. Of these, 83% are sickle cell anemia and 17% are thalassemia. Approximately 7% of pregnant patients worldwide carry a type of thalassemia.11

Review of Hemoglobin Structure

To understand the hemoglobinopathies, it is important to first review normal hemoglobin structure in embryonic, fetal, and adult life. Normal hemoglobin molecules are tetramers of 2 pairs of globin chains ([alpha] and [epsilon], [gamma], [delta], and [beta]) that interlock, with each attached to its own heme molecule (Figure 1). [alpha]-Globin chains are coded for by 2 homologous genes on chromosome 16 whereas a single [beta]-globin chain gene is found on chromosome 11.12 The structure of hemoglobin changes during development. Embryonic hemoglobin has [epsilon]- and [zeta]-chains. Fetal hemoglobin, known as hemoglobin Hb (F), predominates from 12 to 24 weeks' gestation and has [alpha]- and [gamma]-chains. Adult hemoglobin contains 2 [alpha]-chains and either 2 [beta]-chains (Hb A), 2 [gamma]-chains (Hb F), or 2 [delta]-chains (Hb A2).3 Approximately 97% of adult hemoglobin is Hb A ([alpha]2[beta]2), with Hb A2 [alpha]2[gamma]2 accounting for 2% to 3%.12

Figure 1. Structure and genetics of normal hemoglobin. The alpha globin chains are encoded by two homologous genes on chromosome 16, while single beta hemoglobin chains are coded by one gene, found on chromosome 11. The structure of hemoglobin changes during development from fetal hemoglobin, composed of alpha and gamma chains, to adult hemoglobin. Adult hemoglobin contains two alpha chains and either two beta chains (HbA) or two alpha gains and two delta chains (HbA2). Normal hemoglobin is a tetramer of two pairs of globin chains interlocking, each with its own heme molecule.

Thalassemia Syndromes

The 2 most common thalassemias are [alpha]-thalassemia and [beta]-thalassemia. In these conditions, there is decreased production of the [alpha]- or [beta]-globin subunit, and this imbalance of subunits impacts the formation of Hb A.3

[alpha]-Thalassemia

Genetics and Clinical Presentation of [alpha]-Thalassemia

The normal complement of [alpha]-globin genes is 4 copies of the gene.13 With [alpha]-thalassemia, deletions or pathogenic variants in one or more [alpha]-globin genes result in decreased or absent functional [alpha]-globin chain production. A vast majority of [alpha]-thalassemia is secondary to deletions in [alpha]-globin genes and the severity of the phenotype is directly related to the number of [alpha]-globin genes deleted.1

The redundancy of the 2 [alpha]-globin genes on 1 chromosome creates a unique inheritance pattern such that the location of the gene deletion has a significant impact on the risk of having an affected neonate in [alpha]-thalassemia (Figure 2).14 A single deletion also known as [alpha]-carrier state does not result in any clinical symptoms. Two gene deletions, known as "[alpha]-thalassemia minor," involve 1 [alpha]-globin gene on each chromosome or 2 genes on the same chromosome. Cis deletions (2 [alpha]-gene deletions from the same chromosome) are more common among Asian populations, leading to increased risk of passing down 2 gene deletions in a pregnancy. Trans deletions ([alpha]-deletion from each chromosome), on the other hand, reduce the risk that a child will inherit more than 2 missing genes.14 Individuals with [alpha]-carrier state or [alpha]-thalassemia minor may have mild hypochromic, microcytic anemia.

Figure 2. Alpha thalassemia: classification of genotype and phenotypic expression. Alpha thalassemia occurs with deletion of one or multiple alpha globin genes with increasing severity inversely correlating with number of normal alpha chains.

Hb H disease is the most severe form of [alpha]-thalassemia that is still compatible with life (Figure 2). It is characterized by deletion of 3 of the 4 [alpha]-globin genes and resultant accumulation of Hb H (4 [beta]-chains) and distinguished from Hb Barts (4 [gamma]-chains).13,14 Hb H and Hb Barts have extremely high oxygen affinity and thus are unable to effectively deliver oxygen to tissues.1 These individuals usually produce less than 30% of the normal amount of [alpha]-globin and the predominant feature of Hb H is anemia.1 Hb H accumulates in red blood cells, leading to removal by the reticuloendothelial system and subsequent hemolytic anemia that may be severe in some cases. These patients can have splenomegaly, potential jaundice, infections, leg ulcers, gall stones, folic acid deficiency, and acute hemolytic episodes in response to drugs or infections.15

Homozygous hydrops fetalis and hemoglobin Bart's hydrops fetalis are terms used to describe deletion of all 4 [alpha]-chains, usually not compatible with life (Figure 2).13,14 Most frequently this condition results from inheritance of no [alpha]-globin genes from either parent and in rarer cases it results from a severe nondeletion mutation from one parent and no [alpha]-globin genes from the other parent. There is severe, ineffective erythropoiesis with extramedullary hematopoiesis leading to massive organomegaly, heart failure, body edema, and eventual intrauterine demise.16 There have been a few cases described of survival after in utero transfusion or exchange transfusion after birth; however, nearly half of the offspring were found to have neurologic and/or developmental issues.17 Pregnant individuals with a hydropic fetus are at increased risk for pregnancy-induced hypertension, preeclampsia, and hemorrhage.

Nondeletional [alpha]-Thalassemia Variants

There are many types of nondeletional forms of [alpha]-thalassemia that are named after their place of origin. The clinical phenotypes of Hb H disease with nondeletional pathogenic variants are more severe and less common than the deletional forms of [alpha]-thalassemia. One example of the nondeletional variants is Hb H-Constant Spring.18 Individuals with Hb H-Constant Spring commonly have complications in the first decade of life including growth delays, recurrent need for transfusions, and iron overload. They are at risk for sudden, severe anemia after a febrile illness, cholelithiasis, and thrombosis.19

[beta]-Thalassemia

Genetics and Clinical Presentation of [beta]-Thalassemia

[beta]-Thalassemia is an autosomal recessive disorder characterized by reduced or absent synthesis of [beta]-globin chains and compensatory overproduction of [alpha]-chains. The excessive [alpha]-chains form [alpha]-globin tetramers, which can precipitate and bind to red blood cells. These [alpha]-globin tetramers cause oxidative membrane damage and premature destruction by apoptosis of red blood cell precursors in bone marrow leading to ineffective erythropoesis.20 This group of blood disorders is most common in people of Mediterranean, Middle Eastern, or Asian descent who typically present with microcytic hypochromic anemia, reduced amounts of Hb A on hemoglobin electrophoresis, and abnormal peripheral blood smear with nucleated red blood cells.21 The severity of this disease is dictated by the degree of underproduction of the [beta]-globin chain.

There are 2 alleles for the [beta]-globin gene, and 3 major forms of [beta]-thalassemia (Figure 3). From least to most severe, these are [beta]-thalassemia minor, [beta]-thalassemia intermedia (TI), and [beta]-thalassemia major (TM).20 [beta]-Thalassemia minor is also known as [beta]-thalassemia trait and is caused by a heterozygous genotype (Figure 3). People with [beta]-thalassemia minor are usually asymptomatic but can have varied symptoms depending on the amount of normal [beta]-globin chain that is produced. Typical laboratory evaluation will show mild anemia with mild to moderate microcytosis and red blood cell membrane rigidity.21

Figure 3. Beta thalassemia: classification of genotype and phenotypic expression. With beta thalassemia, there is reduced or absent synthesis of beta globin chains. The amount of normal beta globin is inversely related to the severity of the disease with the most severe presentation having absence of beta globin production.

[beta]-TI can have a range of presentations. Persons with TI are mostly homozygotes for [beta]⁺ or compound heterozygotes (Figure 3). They usually develop anemia symptoms later than individuals with [beta]-TM and can be asymptomatic until adult life. They do not require routine blood transfusions. At the severe end of the spectrum, however, patients can have growth and developmental delays starting at 2 to 6 years of age.2 Clinical findings related to extramedullary hematopoiesis, a compensatory mechanism of the bone marrow to chronic anemia, can include deformities of the bone and face, osteoporosis with pathologic fractures and splenic enlargement.2 Other clinical features are pallor, mild to moderate jaundice, cholelithiasis, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, thrombosis, high-output cardiac state, and pulmonary hypertension.20 Iron overload in nontransfused persons can occur secondary to increased intestinal absorption of iron from expanded but ineffective erythropoiesis. The rate of iron overload is much slower in TI patients compared with those with TM; however, the complications of iron overload seen with TM can also occur in individuals with TI.20

[beta]-TM, also known as Cooley's or Mediterranean anemia, is caused by a homozygous mutation in the [beta]-globulin gene on chromosome 11. [beta]-Chain production may be reduced ([beta]⁺) or absent ([beta]⁰) (Figure 3), and consequently [alpha]-chain production predominates. [alpha]-Chains are unstable and accumulate, then precipitate, leading to ineffective erythrocyte production and hemolysis. A fetus or neonate with TM is initially protected by production of [gamma]-chains but loses this protection around 3 to 6 months of age with the onset of severe anemia that requires blood transfusion, splenomegaly from sequestration, pallor, and failure to thrive. With regular transfusions, growth and development can be relatively normal.2

With appropriate management by monthly blood transfusions and iron sequestration to prevent iron overload, life expectancy can extend beyond 30 years of age.22 Historically, the most common cause of death was cardiac-related complications from chronic iron deposition including dilated cardiomyopathy and arrhythmias.23 The prognosis has dramatically improved over the past 15 years with advent of noninvasive methods to measure organ iron before development of clinical symptoms, the development of new chelators, and increased blood safety measures. Patients with TM may experience hypothalamic hypogonadism resulting in amenorrhea and infertility due to chronic iron-induced oxidative stress and iron deposition in the hypothalamus and pituitary gland.20,24 Other complications of iron overload include liver fibrosis/cirrhosis and diabetes mellitus.20

Structural Hemoglobinopathies and Their Relation to Thalassemia

Pathogenic variants in the sequence of the [beta]-globin gene (such as globin S, C, and D) result in structural hemoglobinopathies (Figure 4). These conditions have been briefly described, as they can sometimes occur in combination with thalassemias as compound heterozygotes.

Figure 4. Structural hemoglobinopathies: classification of genotype and phenotypic expression. Pathogenic variants in the sequence of the beta globin gene results in structural modifications to the red blood cell. These pathogenic variants can have compounding effects when inherited along with thalassemia.

Sickle Cell Trait

Sickle cell trait (Hb SA) occurs with inheritance of 1 normal [beta]-globin allele and 1 globin S allele. It is common among African American women (~8%).25

Sickle Cell Anemia

Sickle cell anemia (Hb SS) occurs upon inheritance of 2 S globin alleles and is characterized by hemolysis, vasoocclusive disease leading to multiorgan dysfunction and acute pain crises, and increased risk of systemic infection and growth retardation. Pregnant patients with sickle cell anemia are at higher risk of complications in their pregnancy including fetal growth restriction, preeclampsia, preterm birth, preterm premature rupture of membranes, obstetric shock and transfusion, and intra-amniotic infection.26

Hemoglobin SC Disease

Hb SC disease represents heterozygosity with both Hb S and Hb C genes. Hemoglobin electrophoresis results in 40% Hb C, 60% Hb S with Hb SC disease, and peripheral blood smear shows target cells, few if any sickle cells, and hemoglobin crystals in elongated hyperchromatic cells. Early in pregnancy mild anemia and splenomegaly are often asymptomatic; the disease may be diagnosed later in pregnancy with a pain crisis, similar in presentation to patients with sickle cell anemia.12

Hemoglobin S-[beta]-Disease

Hb S-[beta]-disease occurs with compound inheritance of 1 [beta]-thalassemia allele (either [beta]⁺ or [beta]⁰) and 1 hemoglobin S allele. Hemoglobin electrophoresis reveals 60% to 90% Hb S, 0% to 30% Hb A, 1% to 20% Hb F, and an increased A₂ level. The risk of having a neonate with Hb S-[beta]-disease is 25% when one parent is a carrier of sickle cell anemia and the other is a carrier of [beta]-thalassemia.12 When there is a deficiency of [beta]-globin chains, free [alpha]-globin chains accumulate in red blood cells causing ineffective hematopoiesis and hemolysis. In Hb S-[beta]⁰, there is no production of Hb A. Presentation in these patients is often identical to that seen in patients with sickle cell anemia and management is similar to sickle cell anemia patients. In Hb S-[beta]⁺, there is reduced Hb A production and symptoms may be less severe, including maintenance of spleen function and fewer pain episodes.12 Among individuals with Hb S-[beta]⁺, clinical management may vary as higher Hb A levels are associated with less severe manifestations.27

The frequency of each genotype of Hb S-[beta]-disease varies around the world. Hb S-[beta]⁰ occurs more frequently in Greek, Middle Eastern, and Mediterranean regions, whereas Hb S-[beta]⁺ has a higher incidence among the African American population.28

Hemoglobin C Trait and Disease

Heterozygous Hb C trait is an asymptomatic benign state, whereas Hb C disease (the homozygous mutation) presents with mild anemia and no known increased morbidity or mortality in pregnancy.29

Hemoglobin E

Hb E is common in Southeast Asia and is caused by a mutation in the [beta]-globin gene. It is typically asymptomatic in and outside of pregnancy but may present with splenomegaly in the setting of a concomitant [beta]-thalassemia.30

Prenatal Genetic Screening and Diagnosis for Thalassemia

Patients suspected of having hemoglobin disorders based on their ethnicity or family history should initially be screened with a complete blood count (CBC) to detect the presence of anemia with or without microcytosis. A low (<80) mean corpuscular volume (MCV) should raise suspicion for a possible thalassemia versus iron-deficiency anemia. When one is considering a diagnosis of thalassemia, it is important to check iron studies (serum iron, iron-binding capacity, and ferritin) to rule out iron-deficiency anemia.

Hemoglobin electrophoresis can detect hemoglobin structural variants and assess for Hb F and Hb A₂ to differentiate between [alpha]^- and [beta]-thalassemia. A small reduction in Hb A₂ is potentially indicative of [alpha]-thalassemia trait, but only those with Hb H have a significant reduction in Hb A₂. In contrast, [beta]-thalassemia carriers have increased Hb A₂ levels. The only definitive method for diagnosis of [alpha]- and [beta]-thalassemia is genetic molecular testing with targeted deletion analysis, then sequencing and deletion/duplications for HBA1 and HBA2 genes.13,14,31

Pregnant carriers who are at risk for a child with thalassemia or sickle disease have options for prenatal diagnosis if the parental carrier pathogenic or copy number variants are known. Preimplantation genetic testing can be performed on embryos obtained through in vitro fertilization. Chorionic villus sampling can be performed at 10 to 12 weeks' gestation, and amniocentesis can be performed after 15 to 16 weeks' gestation for molecular genetic testing for thalassemias and sickle cell disease. Counseling regarding results may be challenging given the wide range of phenotypic expression and disease severity of affected children. For the discussion about genetic testing and interpretation of results, genetic counseling referral is recommended by the American College of Obstetricians and Gynecologists.31

Maternal Pregnancy With Thalassemias

Considerations for Patients With Significant Anemia Due to Thalassemia

Women with TI and TM can have successful pregnancies. A multidisciplinary team should evaluate cardiac and liver function, iron burden, glucose tolerance, and thrombotic risk. Individuals with TI usually do well in pregnancy; however, if they need blood transfusions, there is concern for a new risk for alloimmunization and fetal growth restriction. With TM, there are concerns regarding underlying disease complications leading to further exacerbations in pregnancy.

Cardiac Risk and Optimization

Cardiac complications are the leading cause of death for patients with thalassemia, with iron overload a precipitating factor. Many factors contribute to iron overload in these patients, including regular blood transfusions, inadequate iron chelation, and increased iron-absorption capacity. Dysfunctional erythrocyte production results in hepcidin suppression. This in turn causes a paradoxical increase in intestinal iron-absorption capacity. Iron overload increases free iron within cells, generating free radicals that induce peroxidation and damage cell membranes. Oxidative damage leads to mitochondrial electron transport chain dysfunction, resulting in decreased cardiac contractility and development of congestive heart failure.2,20

This effect is magnified in pregnancy as basal oxygen consumption increases. A large number of mitochondria located in the placenta produce free radicals and increase free iron. With adequate pregestational iron chelation therapy, pregnancy and delivery are often completed without cardiac complication among patients with normal resting cardiac performance. However, patients with impaired cardiac performance or myocardial hemosiderosis may not tolerate the hemodynamic changes of pregnancy. This effect is particularly dangerous in patients with [beta]-TM, as chronic hemolysis results in increased rigidity and resistance of vascular beds resulting in pressure overload. The combination of pressure and volume overload in these patients increases the incidence of heart failure. Cardiac MRI can be helpful in these instances to more accurately define iron overload and guide chelation therapy planning. All patients with thalassemia planning for pregnancy should be assessed by electrocardiogram (ECG), cardiac echocardiogram, 24-hour Holter monitoring of rhythm, and MRI T2 measurement, and should be seen by a thalassemia-specialist cardiologist.32

Iron Overload

Patients with [beta]-TM are often prescribed iron chelators to combat iron overload. Aggressive iron chelation is suggested before conception for patients with significant iron overload as assessed by MRI T2 measurement. Generally, the target MRI T2 reading is 20 ms or more whereas levels 10 ms or less suggest a higher risk of developing heart failure. Oral iron chelators, including deferiprone and deferasirox, deferoxamine, should be stopped before pregnancy, as safety in pregnancy has not been established.33

Transfusion Goals in Pregnancy

During pregnancy, transfusions may be used with a goal of maintaining hemoglobin above 10 g/dL. Patients should be informed that multiple transfusions put them at risk for alloimmunization; the rate of alloimmunization after transfusion of 1 unit of red blood cells is approximately 1.0% to 1.6%. For a patient receiving multiple regular blood transfusions throughout their life, this risk may be as high as 60%.34 Specifically, the rate of alloimmunization in patients with TM ranges from 4% to 37%.35 Alloimmunization poses significant fetal risks of anemia and potential high-output cardiac failure and hydrops. Alloimmunization additionally complicates cross-matching of blood for a patient.

Hepatic Complications May Mimic Pregnancy-Related Pathologies

Data are mixed regarding risks of hypertensive disorders of pregnancy among patients with thalassemias and/or sickle cell. Given the risk of iron deposition in the liver leading to hepatic dysfunction, baseline liver function tests should be obtained early in pregnancy to know baseline status, as chronic liver disease can mimic hypertensive disorders of pregnancy.

Conclusion

Thalassemia is characterized by varying degrees of anemia with severity ranging from asymptomatic to lethal. Obstetricians should recognize groups at higher risk for thalassemia and signs on CBC and electrophoresis that suggest the diagnosis of thalassemia. If suspicion is high, molecular genetic testing should be performed to confirm [alpha]- or [beta]-thalassemia. Prenatal diagnosis can be used to avoid severe homozygous disease.

Practice Pearls

* Individuals of African, Southeast Asian, and Mediterranean descent are at higher risk to be carriers.

* If both parents are found to be carriers, genetic counseling is recommended.

* For CBC with low MCV (<80 fL), first rule out iron-deficiency anemia and then consider thalassemia.

* With hemoglobin electrophoresis, [alpha]-thalassemias have small reduction in Hb A₂ and [beta]-thalassemia carriers have increased Hb A₂.

* If thalassemia is suspected, definitive diagnosis is performed with molecular genetic testing.

* With [beta]-TM, lifelong transfusions may lead to complications from iron overload and it is important to consider these complications in a person considering pregnancy. With a multidisciplinary team, a successful pregnancy with this condition is possible.

REFERENCES