Alpha thalassemia major: Prenatal and postnatal management

INTRODUCTION — 

Alpha thalassemia major (ATM; deletion of all four alpha globin genes) was once considered incompatible with life. However, advances in prenatal and postnatal care have resulted in viability and good quality of life for an increasing number of individuals.

This topic discusses management of ATM from conception through early childhood.

Management of beta thalassemia and less-severe forms of alpha thalassemia are presented separately. (See "Management of thalassemia" and "Hematopoietic stem cell transplantation and other curative therapies for transfusion-dependent thalassemia".)

OVERVIEW

Disease definition — Alpha thalassemias are caused by reductions in alpha globin chains. (See "Molecular genetics of the thalassemia syndromes".)

Alpha globin is produced from two genes on chromosome 16, HBA1 and HBA2. Individuals normally possess four alpha globin genes (two from each parent); the genotype can be represented as αα/αα. Depending on the maternal and paternal genotypes, an individual can have pathogenic variants that affect one, two, three, or four alpha globin loci. These alpha globin variants decrease the production of alpha globin, leading to an imbalance in the ratio of alpha to beta globin chains.

●Four gene deletion (ATM) – ATM results from deletion of all four alpha globin genes (--/--) [1]. This condition is also known as homozygous alpha⁰ thalassemia and is a cause of fetal effusions (pericardial, pleural, skin edema and ascites) resulting in nonimmune hydrops fetalis. (See "Nonimmune hydrops fetalis", section on 'Anemia'.)

●Two or three gene deletion (Hb H disease) – Prenatal phenotypes including fetal effusions can also be caused by other alpha thalassemia genotypes including nondeletional or unstable alpha globin variants, even in the presence of one or two normal alpha genes (--/α^Tα or -α^T/-α^T). This condition, which is less common than ATM, is known as hemoglobin H hydrops fetalis. It is more severe in the intrauterine period. The postnatal course is highly variable depending upon the genotype, ranging from a non-transfusion-dependent moderate anemia to transfusion dependence [2-4]. Knowledge of the fetal genotype is important for determining prognosis and counseling the parents. (See 'Counseling and decision-making' below.)

Definitions of beta thalassemia syndromes and less-severe alpha thalassemia syndromes are presented separately. (See "Pathophysiology of thalassemia", section on 'Terminology and disease classification'.)

Pathophysiology — Lack of alpha genes results in homotetramerization of the corresponding beta globin chains. Hb Barts and Hb H are abnormal Hbs that only form when alpha chain production is significantly reduced, allowing beta-like chains to form homotetramers rather than binding to alpha globin.

Hb Barts and Hb H have extremely high oxygen affinity and therefore do not function in oxygen delivery.

●Hb Barts in the fetus – Hb Barts is composed of tetramers of gamma globin (gamma4); gamma globin is the beta globin-like chain used to make fetal hemoglobin (Hb F). Small fractions of Hb Barts (2 to 5 percent) on a newborn screen are seen with alpha thalassemia trait (two alpha gene abnormalities), and higher fractions are seen with severe alpha thalassemia. (See "Diagnosis of thalassemia (adults and children)", section on 'Hemoglobin analysis and genetic testing'.)

Individuals with deletion of all four alpha globin genes (--/--) produce Hb Barts in utero and develop hydrops fetalis that usually results in fetal death unless fetal intrauterine transfusions are performed. Hydrops fetalis can also result from deletion of 2 alpha genes with an unstable alpha chain variant (referred to as Hb H hydrops fetalis). (See "Nonimmune hydrops fetalis", section on 'Anemia' and "Diagnosis of thalassemia (adults and children)", section on 'Alpha thalassemias'.)

Hb Barts has an extremely high oxygen affinity, preventing or severely impairing oxygen delivery. The hemoglobin is unstable and nonfunctional, resulting in severe hemolytic anemia. (See 'Fetal complications' below.)

●Hb H in the child and adult – Hb H is composed of tetramers of beta globin (beta4). These form when alpha globin chain production is substantially reduced (see "Pathophysiology of thalassemia", section on 'Globin chain imbalance'). It is unstable and therefore not detected in alpha thalassemia trait.

Severe alpha thalassemia is also called Hb H disease. Hb H disease most often occurs in individuals with alpha thalassemia who have variants or deletions affecting three of the four alpha globin genes. It less commonly occurs when non-deletional and hyper-unstable mutations are involved. Hydrops fetalis can sometimes occur when a non-deletional mutation is involved (Hb H hydrops fetalis) [5]. In deletional Hb H disease (--/a-), Hb H comprises 5 to 30 percent of total Hb. In non-deletional Hb H disease (--^/aa^CS), Hb Constant Spring is present along with Hb H. (See "Pathophysiology of thalassemia", section on 'Terminology and disease classification' and "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb Constant Spring'.)

Hb H forms multiple small inclusions that can be visualized when RBCs are incubated in the presence of a redox dye such as brilliant cresyl blue (picture 1). (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Hb H staining'.)

Hb H is fast moving on gel electrophoresis, with a mobility at alkaline pH significantly faster than Hb A (figure 1). If Hb H is suspected and gel electrophoresis is being used, it is reasonable to reduce the length of time that electrophoresis is carried out in order to prevent Hb H, if present, from completely running off the gel and being considered absent. Hb H is unstable, and its abundance (and ability to be detected) will decrease over time.

Prevalence — ATM is a common condition in many regions of the world, especially Southern China, Malaysia, and Thailand, where ≥5 percent of the population can be carriers of alpha⁰ thalassemia (deletion of two alpha genes on the same chromosome [--/αα]). (See "Diagnosis of thalassemia (adults and children)", section on 'Epidemiology'.)

The number of pregnancies affected by ATM is vastly more than the number of reported births with ATM.

The number of live births with ATM is low but increasing, and in the absence of fetal therapy these newborns are acutely ill. In Southeast Asia, alpha⁰ thalassemia variants can be present in as many as 5 percent of individuals [6]. In areas of Southeast Asia where alpha thalassemia is prevalent, an expected 4500 pregnancies with ATM occur annually [7]. Commonly affected areas include Thailand and China.

With immigration, the prevalence of alpha thalassemia continues to increase in North America and Europe [8]. The United States population of people from Asia continues to increase, and the prevalence of alpha thalassemia variants is expected to rise. By one series of estimates from the United States, there were 980,000 individuals self-identified as Asian in 1960, which rose to 11.9 million by 2000, doubled to 22.4 million by 2019, and is projected to reach almost 50 million by 2060 [9].

Newborn screening data from California found 1 in 87 newborns have Southeast Asian ancestry and 1 in 10,417 newborns have a clinically significant alpha thalassemia syndrome (ATM, Hb H disease, or Hb H/Hb Constant Spring) [10].

PRENATAL MANIFESTATIONS

Timing of onset — Since alpha globin chains are required for synthesis of fetal hemoglobin (Hb F), manifestations of alpha thalassemia begin during the prenatal period. (See "Pathophysiology of thalassemia", section on 'Globin chain imbalance'.)

Complications specific to ATM include profound fetal anemia, a high proportion of nonfunctional Hb Barts (gamma globin tetramers), often >80 percent of total hemoglobin, along with massive organomegaly, thrombocytopenia, abnormal liver function, and congenital anomalies. (See 'Fetal complications' below.)

Anemia and Hb Barts develop as follows [6]:

●Embryo – Embryonic viability depends upon the preservation of zeta globin genes (ζ --/ ζ --, or - --/ ζ --). Zeta globin is upstream of the two alpha globin genes in the alpha globin gene cluster on chromosome 16 (figure 2).

Preservation of zeta globin occurs in a subset of deletions (ζ --); the most frequent of which is the Southeast Asian deletion ^(--SEA). (See "Structure and function of normal hemoglobins", section on 'Embryonic hemoglobins'.)

●Fetus – Early fetal development is supported by Hb Portland (ζ₂γ₂) and other embryonic hemoglobins up to approximately 14 weeks of gestation. (See "Structure and function of normal hemoglobins", section on 'Embryonic hemoglobins'.)

Subsequently, gene switching from zeta to alpha globin reduces the level of zeta gene expression, and a profound fetal anemia ensues from the failure to synthesize alpha globin chains [11-13].

In the absence of normal alpha globin chains to pair with gamma globin chains, the gamma globin chains self-associate into tetramers (γ₄), referred to as Hb Barts, which is the main hemoglobin in a fetus with ATM.

Hb Barts has extremely high oxygen affinity, which renders it ineffective in oxygen transport from placenta to fetal tissues. Consequently, most pregnancies that are not treated with fetal transfusions are nonviable (Hb Barts hydrops fetalis). If fetal ultrasound is not performed, the pregnancy continues without a diagnosis, resulting in fetal demise or neonatal death shortly after delivery in most cases.

Spontaneous survivors have been reported after a medically unstable neonatal period. Genotype-phenotype correlations have been proposed that suggest the value of preservation of zeta globin expression in these survivors [14]. Cord hemoglobin is approximately 6 g/dL, with Hb Portland comprising 17 percent of the total.

In contrast, actively managed pregnancies with early prenatal diagnosis and intrauterine transfusions (IUT) can produce viable offspring. Perinatal and postnatal events are heavily influenced by the adequacy of prenatal transfusion management, as discussed below. (See 'Fetal testing' below and 'Intrauterine transfusions' below.)

Fetal complications

Anemia and hyperbilirubinemia — In the absence of any intervention, the fetus develops severe anemia.

Mid-trimester hemoglobin analysis demonstrates an average hemoglobin of 6.4 g/dL [15]; this is mostly Hb Barts, which is nonfunctional. This is an important distinction from the anemia in immune hydrops due to hemolytic disease of the fetus and newborn (HDFN), where the predominant hemoglobin species (Hb F) has a normal capacity for oxygen transport. (See 'Pathophysiology' above.)

The profound fetal anemia and hypoxia in ATM is associated hydrops, characterized by organomegaly, severe hypoalbuminemia, cardiomegaly, heart failure, ascites, pleural and pericardial effusions, edema, and growth failure, often followed by fetal demise if interventions are not made [6].

Hemolysis and hyperbilirubinemia are typically present but are less severe than observed in newborns with immune hydrops fetalis due to HDFN.

Congenital anomalies — Urogenital anomalies are present in most males with ATM; hypospadias is most common [14,16-18]. Other abnormalities are undescended testes, bifid scrotum, hydrocele, and micropenis. (See "Hypospadias: Pathogenesis, diagnosis, and evaluation".)

Limb anomalies are also seen in 8 percent; these tend to be mild [13,16,19]. Approximately 10 percent of patients have atrial septal defect. Other anomalies are rare and not clearly associated with ATM.

The incidence of congenital anomalies is not affected by IUT, which suggests that hypoxia during organogenesis may be a factor [14,20].

Maternal complications — Pregnancy with a fetus with hydrops fetalis can cause mirror syndrome, characterized by the maternal edema, proteinuria, and hypertension. (See "Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)

Other potential maternal complications include dystocia, postpartum hemorrhage due to placental enlargement, and, for those who forgo fetal therapy, the psychological burden of requiring a fetal intervention to support fetal viability [21]. (See "Stillbirth: Maternal care and prognosis", section on 'Grief and bereavement'.)

The risk of mirror syndrome and other maternal complications can be reduced with IUT. (See 'Intrauterine transfusions' below.)

PRENATAL SCREENING AND DIAGNOSIS — 

Most couples are unaware of their risk for thalassemia in pregnancy. Ideally, screening for thalassemia (and other hemoglobinopathies) occurs during preconception counseling. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

Maternal and partner testing — The complete blood count (CBC) is assessed on the mother's initial prenatal laboratory testing.

●Mother – Thalassemia trait is suggested when microcytic anemia is present in females during pregnancy, irrespective of whether iron stores are replete. Screening for iron deficiency is a routine component of prenatal care. (See "Anemia in pregnancy", section on 'Screening during pregnancy'.)

We evaluate for thalassemia trait using maternal hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) and simultaneous alpha globin gene testing with polymerase chain reaction (PCR) to detect common deletions. This is because normal hemoglobin electrophoresis or HPLC results do not exclude alpha thalassemia, and it is important to distinguish between alpha⁺ thalassemia trait (deletion of one of the two alpha globin genes on a chromosome) from alpha⁰ thalassemia trait (deletion of both alpha globin genes on the same chromosome), which determines the risk of ATM in the fetus.

For patients with a high index of suspicion for alpha thalassemia carrier status, alpha globin gene sequencing should be pursued to identify non-deletion mutations such as Hb Constant Spring and Hb Adana. These variants result in an unstable hemoglobin, and when combined with alpha⁰ thalassemia trait they may present prenatally similar to ATM with fetal anemia and hydrops fetalis. (See "Diagnosis of thalassemia (adults and children)", section on 'Alpha thalassemias'.)

●Partner – Partner testing is also essential to determine fetal risk. If the father does not have alpha⁰ thalassemia trait and paternity is assured, then the fetus will not have ATM, although a less-severe form of thalassemia may be inherited from the mother. Consideration of alpha globin gene sequencing for non-deletion mutations is also essential.

If both parents have an alpha⁰ thalassemia trait, with deletion of both alpha globin genes on the same chromosome (--/αα) or (--/-α), then the fetus is at risk for ATM (table 1). (See "Gene test interpretation: HBA1 and HBA2 (alpha globin genes)".)

When one parent is a carrier for alpha⁰ thalassemia trait and the other carries a non-deletional alpha globin variant, there is a risk for fetal anemia and hydrops due to non-deletional Hb H disease. (See "Diagnosis of thalassemia (adults and children)", section on 'Alpha thalassemias'.)

Couples at risk for ATM and/or non-deletion Hb H disease in pregnancy should be educated regarding the risks and benefits of reproductive options and pregnancy management options (algorithm 1). These include [22]:

●In vitro fertilization (IVF) with preimplantation genetic testing (PAT)

●Use of donor gametes

●Adoption

●Termination of pregnancy (when available)

●Active fetal management

●Expectant management

Additional details are provided below and separately. (See 'Counseling and decision-making' below and 'Management (prenatal and neonatal)' below and "Preimplantation genetic testing" and "Donor insemination" and "In vitro fertilization: Overview of clinical issues and questions", section on 'Oocyte donation'.)

Fetal testing — Prenatal diagnosis should be offered to all patients whose fetus is at risk for ATM. For patients electing to proceed with active management, given the relatively low risk of invasive testing, the benefits of early prenatal diagnosis to allow for early introduction of fetal therapy should be emphasized.

Molecular prenatal diagnosis — Procedures for fetal testing include:

●Chorionic villus sampling – A small sample of placental tissue is obtained either transcervically or transabdominally under ultrasound guidance. This procedure is usually performed between 10 and 14 weeks. (See "Chorionic villus sampling".)

●Amniocentesis – Amniotic fluid is removed via a needle placed in the amniotic cavity under ultrasound guidance. It is usually performed after 15 weeks' gestation. (See "Diagnostic amniocentesis".)

●Fetal blood sampling – Percutaneous umbilical blood sampling (PUBS; cordocentesis) is performed under direct ultrasound guidance with a needle obtaining a fetal blood sample from the umbilical vein. The earliest gestational age PUBS is usually performed is 18 weeks. This may be used to simultaneously confirm fetal anemia and treat with intrauterine red blood cell (RBC) transfusion [23-25]. (See 'Intrauterine transfusions' below and "Fetal blood sampling".)

Molecular testing can be performed on any of the above specimens, including fetal DNA extracted from the fetal cord blood sample. Evaluation of Hb Barts (>80 percent) from the cordocentesis sample may also be useful in the diagnosis of an affected fetus.

Fetal ultrasound — In patients at risk for having a fetus with ATM who do not proceed with prenatal diagnosis, ultrasound may be used to detect features consistent with a diagnosis of ATM. (See "Overview of ultrasound examination in obstetrics and gynecology", section on 'Obstetric sonography'.)

Ultrasound findings in ATM include:

●Increased cardiothoracic ratio (≥0.5)

●Enlarged placenta (>18 mm before 15 weeks and >30 mm after 18 weeks)

●Signs of hydrops (fluid collection in any one compartment including pericardial effusion, pleural effusion, ascites, or skin edema)

●Elevated middle cerebral artery peak systolic velocity (MCA PSV)

●Amniotic fluid abnormalities (oligohydramnios and polyhydramnios)

●In our practice, we have also observed fetal growth restriction and echogenic bowel

An MCA PSV >1.5 multiples of the median (MoM) for gestational age is suggestive of moderate to severe anemia. However, MCA PSV is less reliable for assessing anemia in alpha thalassemia compared with other anemias, especially in early pregnancy [26-28].

Diagnosis — The diagnosis of ATM is confirmed by the finding of deletion of all four alpha globin genes (--/--), typically by alpha globin gene PCR. (See 'Disease definition' above.)

In unsuspected cases, the prenatal diagnosis of ATM is usually made by the observation of hydrops on fetal ultrasound during the second trimester. This must be followed by an evaluation for the cause. (See "Nonimmune hydrops fetalis", section on 'Postdiagnostic evaluation'.)

COUNSELING AND DECISION-MAKING — 

Confirmed diagnosis of ATM is followed by nondirective counseling to decide between continuation of pregnancy or termination [22]. The flowchart (algorithm 1) summarizes possible approaches, which include the following:

●Continuation with fetal therapy – If the pregnancy is continued, the adequacy of prenatal management strongly influences the perinatal and postnatal course [12,17,18,20]. Collaborative management by fetal medicine specialists and hematologists are essential to attain safe post-transfusion hemoglobin targets and suppress Hb Barts. Fetal hydrops resolves with effective intrauterine transfusion (IUT) regimens, and delivery is more likely to occur close to term, which markedly reduces neonatal complications. (See 'Management (prenatal and neonatal)' below.)

●Termination – Most pregnancies are terminated due to concerns over maternal health, technical difficulties in supporting IUTs, the prospect of lifelong transfusion dependence following a live birth, and the risk of poor neurodevelopmental outcome. A 2023 case series reported a termination rate of up to 61 percent [29]. (See 'Health maintenance and monitoring for complications' below and "Overview of pregnancy termination".)

●Continuation without fetal therapy – In some instances, the parents may decide to continue the pregnancy without fetal therapy. These individuals should be monitored closely due to the risks of mirror syndrome. (See 'Maternal complications' above.)

Education about options for future pregnancy should also be provided, including the use of in vitro fertilization (IVF) with preimplantation genetic testing for a monogenic disorder (PGT-M), donor gametes, and adoption. (See "Preimplantation genetic testing" and "In vitro fertilization: Overview of clinical issues and questions", section on 'Oocyte donation' and "Donor insemination" and "Adoption".)

Less severe forms of thalassemia do not require intensive fetal management and can be addressed after delivery. (See "Diagnosis of thalassemia (adults and children)", section on 'Diagnostic evaluation' and "Gene test interpretation: HBA1 and HBA2 (alpha globin genes)".)

MANAGEMENT (PRENATAL AND NEONATAL)

Intrauterine transfusions — Providing intrauterine transfusions (IUT) is the major prenatal intervention for ATM (algorithm 1).

Data from case series of active management of ATM provide support for early initiation of optimally provided IUT therapy to improve long-term outcomes. Acceptance of IUT followed by chronic transfusions after birth has increased following the observation of major improvements in the survival and quality of life of people with beta thalassemia major. However, despite the value of IUT, a 2021 consensus document reported that many individuals carrying a pregnancy with ATM are not offered this intervention [22]. (See "Management of thalassemia".)

●When to start – For patients electing to proceed with fetal therapy, IUT should be initiated as soon as technically possible (18 weeks at most fetal treatment centers) to reverse or prevent overt fetal and/or maternal complications due to anemia [22]. In cases where IUT is not feasible, intraperitoneal transfusions may be an alternative.

●Goal of therapy – The goal of IUT regimen should be to reverse and/or mitigate the development of hydrops in the pregnancy. (See 'Delivery and neonatal period' below.)

●IUT protocol – The protocol for IUTs is similar to standard protocols used for hemolytic disease of the fetus and newborn (HDFN), with the following exceptions:

•In ATM, the fetal hematocrit does not represent the amount of functional hemoglobin in fetal red blood cells (RBCs). This is because the major hemoglobin, Hb Barts, which accounts for nearly 100 percent of hemoglobin in the fetus, is functionally useless in oxygen delivery due to its extremely high oxygen affinity, which prevents oxygen release to fetal tissues. The optimal protocol establishing the transfusion volume for the treatment of fetuses affected with ATM remains an area of continued research.

•We do not administer phenobarbital, as is done by some experts for fetuses with HDFN. This is because severe hyperbilirubinemia does not occur in ATM. (See "Fetal transfusion of red blood cells", section on 'Phenobarbital'.)

In our practice, we perform percutaneous fetal blood sampling (PUBS) with IUT every two to three weeks after the initial transfusion. (See "Fetal blood sampling", section on 'Umbilical cord blood sampling' and "Fetal transfusion of red blood cells", section on 'Calculating transfusion volume'.)

Details of preparation (crossmatching, role of irradiation, washing) and technique (accessing the umbilical vein) are discussed separately. (See "Fetal transfusion of red blood cells".)

●Supporting evidence – Evidence for the benefits of IUT continue to emerge [17,18,20,29]. Adequate IUT started early in gestation can prevent most neonatal complications (except congenital anomalies). (See 'Delivery and neonatal period' below.)

•In a 2023 cohort of 19 singleton pregnancies with ATM, all of the 14 fetuses treated with two or more IUTs survived to delivery, and all five fetuses not treated with IUT died in utero or shortly after birth [29]. Analysis of these and other data concluded that compared with zero to one IUTs, receipt of two or more IUTs was associated with greater resolution of fetal hydrops, greater likelihood of delivery at 34 weeks or later, and greater likelihood of normal neurodevelopmental scores. Neurodevelopmental scores were normal in 17 of 18 recipients of ≥2 IUTs (94 percent) versus 5 of 13 recipients of 0 to 1 IUT (38 percent). The earlier the IUT was initiated, the higher the neurodevelopmental scores. The implication is that greater awareness leading to early diagnosis and standardized management with IUT that allows near-term birth will likely result in normal neurodevelopmental outcome for children with ATM in the future.

•In a 2021 cohort of 25 pregnancies with ATM, most cases using IUT prior to 28 weeks resulted in survival with full resolution of hydrops at delivery [18]. Of the 12 fetuses not treated with IUT, none survived. Four fetuses were treated with IUT starting after 28 weeks: two survived and two died due to complications of hydrops at delivery.

•A 2016 review of outcomes following IUT in 14 pregnancies with hydrops fetalis demonstrated generally favorable outcomes, with mild developmental delays in 4 (29 percent) and normal neurodevelopmental assessment in 10 (71 percent) [17].

•Active management with IUT that resolves fetal hydrops and should in turn reduce the overall risk for maternal complications such as mirror syndrome [18,29,30]. (See "Nonimmune hydrops fetalis", section on 'Maternal findings' and "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations", section on 'Approach to management of polyhydramnios in singleton pregnancies'.)

Transplant after birth is discussed below. (See 'Hematopoietic stem cell transplant' below.)

Delivery and neonatal period

●Risks – Delivery should occur in a facility that can provide high-level critical care. Typically, this involves a tertiary care center with specialized perinatology, pediatric hematology, and/or neonatology teams that can provide emergency management if needed [22]. Some neonates may need aggressive resuscitation and mechanical ventilation at birth, although this can generally be precluded by an adequate IUT program.

Newborn infants with ATM are at risk for severe complications, including:

•Preterm birth with fetal growth restriction

•Cesarean birth

•Birth trauma

•Intracranial hemorrhage

•Difficult resuscitation with need for intubation

•Need for mechanical ventilatory support

•Respiratory distress syndrome

•Persistent pulmonary hypertension

•Patent ductus arteriosus, cardiorespiratory collapse, organomegaly with effusions and ascites, thrombocytopenia, and hyperbilirubinemia

Most of these neonatal complications (except congenital anomalies) can be prevented with adequate IUT starting early during gestation. (See 'Intrauterine transfusions' above.)

General management of the hydropic newborn is presented separately. (See "Nonimmune hydrops fetalis in the neonate: Causes, presentation, and overview of neonatal management".)

●Cord blood sample – Cord blood hemoglobin and Hb Barts are tested at birth. Hb Barts can be measured by electrophoresis or high-performance liquid chromatography (HPLC). This may be helpful in appreciating the impact of fetal transfusion to reduce Hb Barts.

•Delayed cord clamping is not recommended due to the presence of Hb Barts in the fetal (and cord) blood.

•The cord blood hemoglobin value will vary based upon the interval from the last IUT. The proportion of Hb Barts at birth depends upon the adequacy of IUT and the duration between the last transfusion and birth.

●Urgent transfusion – An urgent simple transfusion with 5 to 10 mL/kg of a high-hematocrit RBC unit should be given initially, with subsequent management depending upon the cardiovascular status, cord blood hemoglobin, and proportion of Hb Barts. The purpose of transfusions is to manage anemia and suppress Hb Barts production and achieve total hemoglobin 11 to 13 g/dL with Hb Barts <20 percent at birth.

-If Hb Barts in cord blood is <50 percent of total hemoglobin, further simple transfusions are sufficient to raise total hemoglobin to >12 g/dL and suppress endogenous erythropoiesis.

-If Hb Barts in cord blood is >50 percent, an isovolemic exchange transfusion should be carried out to lower Hb Barts and improve oxygenation rapidly. Further simple transfusions should be carried out to maintain total hemoglobin >12 g/dL while critical care support continues.

•It is important to measure Hb Barts frequently to maintain it <20 percent of total hemoglobin, which will keep the functional Hb A >10 g/dL at all times.

●Transition to chronic transfusion program – Following discharge from the neonatal unit, infants are transitioned to a chronic transfusion program, and guidelines for managing infants with ATM should be followed. (See 'Chronic transfusion program' below and 'Management (infancy and childhood)' below.)

●Phototherapy – Hyperbilirubinemia can usually be managed with phototherapy if needed. Unlike HDFN, exchange transfusions are typically not required. As the total hemoglobin level is raised by simple transfusions, the decrease in erythropoiesis suppresses bilirubin production. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management", section on 'Initial intervention (phototherapy)'.)

MANAGEMENT (INFANCY AND CHILDHOOD)

Chronic transfusion program — All infants with ATM are transfusion-dependent from birth [6].

Transfusions begin in the prenatal period in ATM, unlike in beta thalassemia major where they are started six to nine months after birth. The transition from perinatal management to a stable chronic transfusion regimen lasts until six months of age. It is characterized by the switch from Hb Barts to Hb H, reduction of hepatosplenomegaly and cardiomegaly, improvement in thrombocytopenia and transaminitis, and establishment of consistent weight gain.

●Rationale – The pathophysiology of ATM differs from beta thalassemia major, which is reflected in the approach to transfusion therapy [6].

Infants with ATM synthesize Hb Barts (tetramers of gamma globin) in the newborn period and Hb H (tetramers of beta globin) after the first few months of life. There is a complete absence of endogenous Hb A, Hb F, and Hb A2, all of which require alpha globin chains.

Hb Barts and Hb H cannot transport oxygen and are considered non-functional hemoglobins. RBC transfusion is the only source of functional hemoglobin (mostly Hb A). Following an RBC transfusion, the patient with ATM has a mixture of Hb H and Hb A, and the total hemoglobin measured on complete blood count (CBC) is the sum of the two hemoglobins. The relative proportion of Hb H and Hb A cannot be assessed with the CBC alone and requires hemoglobin fractionation with electrophoresis or HPLC.

As the proportion of Hb A derived from RBC transfusion increases, endogenous erythropoiesis is suppressed, and the proportion of Hb H falls [31]. An inverse relationship between Hb A and Hb H is observed across a wide range of total hemoglobin values. When total hemoglobin is below 7.5 g/dL, Hb H can be above 40 percent and functional hemoglobin <5 g/dL. Conversely, with total Hb >11 g/dL, Hb H is reduced to below 10 percent, so that functional hemoglobin approximates the total hemoglobin.

The goal of transfusion therapy in ATM is to provide functional hemoglobin of 9 to 10 g/dL in the pretransfusion period. Ideally, both the CBC (total hemoglobin) and hemoglobin fractionation (Hb H percentage) are obtained simultaneously to calculate the functional hemoglobin:

As an example, if total hemoglobin is 11 g/dL and Hb H is 15 percent, then functional hemoglobin = 11 – (11 x 0.15) = 9.35 g/dL.

When Hb H measurement is not accessible, total hemoglobin should be maintained at 10.5 to 11 g/dL in the pretransfusion sample. A higher functional hemoglobin level (>10.5 g/dL) is associated with better suppression of endogenous erythropoiesis and markers of hemolysis. This is achieved with a more intensive transfusion regimen, but any practical benefit on growth and activity is uncertain. Instead, we recommend this higher total hemoglobin target during the first six months of life when suppression of erythropoiesis assists in reducing hepatosplenomegaly, which is necessary to decrease the transfusion volume and frequency. A gradual improvement in cardiomegaly and liver function abnormalities is seen three to six months after the institution of transfusion therapy.

●Hemoglobin targets, schedule, and monitoring

•First three to six months – During the first three to six months, total pretransfusion hemoglobin is maintained at >12 g/dL, of which the unmeasured, nonfunctional hemoglobin (Hb Barts plus Hb H) is 15 to 20 percent of the total, and the functional Hb A is >10 g/dL.

As Hb Barts is gradually replaced by Hb H in the first few months of life, estimating the proportion of these two nonfunctional hemoglobins requires expert laboratory support. It is our practice to send every pretransfusion blood sample for hemoglobin fractionation. RBC antigens should be determined by DNA testing so that antigen-matched blood can be provided to reduce the risk of alloimmunization. (See "Pretransfusion testing for red blood cell transfusion", section on 'RBC genotyping'.)

The transfusion interval is initially two weeks and gradually increased to three weeks. Smaller infants may require central venous access. Institutional newborn transfusion protocols are followed until three months of age. Close attention to nutrition and caloric intake is essential. Elective medical or surgical interventions are postponed, allowing time for the parents to bond with the infant.

•After six months – After the first six months, infants transition to the chronic transfusion protocol, which uses the following parameters: Hb A (functional hemoglobin) 9 to 10 g/dL, transfusion frequency every three to four weeks, and prevention of splenic enlargement.

Following Hb A instead of total hemoglobin in the pretransfusion sample is essential to account for the proportion of nonfunctional Hb H. This is a salient point of differentiation from beta thalassemia major, where the alternate Hb (Hb F) participates in oxygen transport and is counted towards the total functional hemoglobin. Children with ATM are at risk for under-transfusion if hemoglobin guidelines for beta thalassemia major are followed [32].

The unstable nature of Hb H is a barrier to calculating the absolute Hb A concentration. Accurate measurement of Hb H requires samples to be tested within hours of collection, while overnight or more extended storage reduces Hb H level, particularly with refrigeration. This creates a situation where the calculated Hb A level is falsely high and affects the calculation of transfusion volume.

Infusion centers lacking access to precise Hb H measurements can treat by maintaining pretransfusion total hemoglobin at 10.5 to 11 g/dL [32]. The typical requirement for RBCs stored in additive solution is 16 mL/kg on a three-week schedule and 20 mL/kg on a four-week schedule.

●Avoid splenectomy – Splenectomy is not recommended in the management of ATM [6].

●Platelet transfusions – Platelet transfusion support may be necessary during the first week, but spontaneous recovery from thrombocytopenia is seen with improvement in anemia.

Iron overload and chelation — Transfusional iron overload develops early, within a few months of birth. The assessment and management of iron overload in ATM is not well-defined, and hepatic complications of hydrops fetalis can increase serum ferritin, making it unreliable for determining the degree of iron overload.

Initially, liver injury causes ferritin to be elevated out of proportion to iron stores. (See 'Health maintenance and monitoring for complications' below.)

Later, inadequately transfused patients demonstrate lower ferritin levels compared with liver iron concentration [32]. Magnetic resonance imaging (MRI) is very important for assessing iron overload, but it is used sparingly due to the need for anesthesia in young patients. In a series of six children with ATM, moderate to severe liver iron overload was observed on the initial MRI performed between 18 months and 4 years of age [33]. Early extrahepatic iron deposition was observed in the pancreas in all cases, while pituitary iron was elevated in five. However, no patient had an increase in myocardial iron in this series.

The optimal age to start iron chelation is not well-studied. Management guidelines for beta thalassemia major suggest that starting chelation therapy after 12 months of transfusions is associated with acceptable long-term outcomes with no permanent iron-induced organ injury.

●Timing of initiation – Transfusion therapy is intensive in infants with ATM, with 16 to 20 transfusions expected within the first 12 months of life. However, we postpone chelation until 12 months of age, given concerns over liver inflammation and kidney immaturity and the lack of experience with iron chelators during the first year of life. Iron chelating agents are not approved for use in children under two years, but delaying chelation in ATM until two years could be harmful. (See "Iron chelation: Choice of agent, dosing, and adverse effects", section on 'Transfusion-dependent thalassemia'.)

●Agent and dose – Details are presented separately. (See "Iron chelation: Choice of agent, dosing, and adverse effects", section on 'Choice of chelating agent'.)

ATM-specific considerations include the following:

•Deferasirox – We usually start treatment with a low dose of deferasirox (Jadenu, 3 to 5 mg/kg, usually 45 mg, crushed tablet) and increase the dose by 45 mg every two months as long as transaminases are stable. The dose is increased to a maximum of 14 mg/kg until the child is two years old, after which the general guidelines for deferasirox are followed. (See "Iron chelation: Choice of agent, dosing, and adverse effects", section on 'Deferasirox dosing + AEs (Jadenu, Exjade)'.)

•Deferiprone – We reserve deferiprone for situations where deferasirox is not tolerated at therapeutic doses, in which case it can be added as a second chelator at a dose of 50 to 75 mg/kg. (See "Iron chelation: Choice of agent, dosing, and adverse effects", section on 'Combination chelation'.)

In a report of deferiprone use in 32 children with beta thalassemia major starting at a median age of 2 years, the drug was started at 25 mg/kg/day for two weeks followed by an increase to 50 mg/kg/day and then 75 mg/kg/day after two months [34]. No difference in adverse events was observed between the treatment and placebo groups except for the occurrence of neutropenia in four children and agranulocytosis in one child in the deferiprone group. (See "Iron chelation: Choice of agent, dosing, and adverse effects", section on 'Deferiprone dosing + AEs (Ferriprox)'.)

•Deferoxamine – Deferoxamine can be used in combination with one of the other chelators in children with severe hepatic iron overload. The dose of deferoxamine is limited to 20 to 30 mg/kg as a subcutaneous infusion on three to five days per week to reduce the risk of toxicity affecting bones and growth [35]. (See "Iron chelation: Choice of agent, dosing, and adverse effects", section on 'Combination chelation'.)

In a report of deferoxamine used as a single chelator in children with ATM at mean age 16.3 months with liver iron concentration ranging from 5.6 to 12.4 mg/gram, three children developed high-frequency hearing loss, requiring temporary cessation of therapy and reduction in dose [18]. An additional consideration with the use of deferoxamine in young children is toxicity affecting bone and growth [35]. For these reasons, we only use deferoxamine as a second chelator and limit the dose to 20 to 30 mg/kg given as a subcutaneous infusion over 8 to 10 hours on 3 to 5 days per week. (See "Iron chelation: Choice of agent, dosing, and adverse effects", section on 'Deferoxamine dosing + AEs (DFO, Desferal)'.)

●Monitoring and toxicities – The goal of chelation is to maintain serum ferritin in the range of 1000 to 2000 ng/mL during the second year of life, as attempts to achieve lower ferritin levels may increase the risk of toxicity from chelation. Transaminitis is the limiting toxicity of deferasirox in infants, and it can be difficult to distinguish from other causes of transaminase elevation such as iron overload or acute viral infection. Standard guidelines for monitoring deferasirox include [36]:

•Transaminases, especially alanine aminotransferase (ALT), are monitored every three to four weeks.

•Kidney function (eg, creatinine, potassium, bicarbonate, and phosphorus) is monitored at least every three to four weeks.

•Medications and potential drug interactions are reviewed every three to four weeks (more frequently if needed).

•Urine protein is monitored every three months.

•Retinal examination is performed annually.

•Tissue iron burden is monitored using ferritin and liver MRI. A baseline MRI is not necessary before initiating chelation, and we usually assess liver iron by MRI at two years when chelation is increased to therapeutic dosing. In under-transfused children, ferritin underestimates the systemic iron burden [37]. The initial liver MRI should be performed around two years of age, which is used to adjust the intensity of chelation therapy.

Hematopoietic stem cell transplant — The options for hematopoietic stem cell transplant (HSCT) should be explored early with the family or caregivers. Matched-related donors are found in a minority of cases, in which case HSCT is recommended at approximately two years of age.

If an HLA-matched related donor is not available:

●Some families or caregivers may elect to pursue pregnancy with preimplantation genetic testing (PGT) to produce an HLA-matched sibling for cord blood transplant. (See "Donor selection for hematopoietic cell transplantation", section on 'Umbilical cord blood donors'.)

●A small number of patients have undergone matched unrelated donor HSCT. In a series of five patients with ATM who were transplanted at a median of 22 months, the stem cell sources were 8/8 matched-sibling bone marrow in one, 5/6 matched sibling cord blood in one, 12/12 matched-unrelated peripheral blood stem cells in two, and haploidentical peripheral blood stem cells [38]. All the patients had nearly full donor chimerism at one month and remained transfusion-independent without significant morbidities at a median follow-up of 10 years. Counseling for unrelated donor transplant for ATM should follow the same guidelines as used for beta thalassemia major when discussing success rates, treatment-related mortality, and graft rejection. (See "Hematopoietic stem cell transplantation and other curative therapies for transfusion-dependent thalassemia".)

Studies of in utero HSCT are ongoing.

Surgery for congenital anomalies — Surgical consultation is arranged early to plan for correction of congenital anomalies [14,17,39]. The common surgical interventions are urethroplasty and orchidopexy. Depending on the severity of urogenital defects, staged procedures can be necessary. (See "Hypospadias: Management and outcome" and "Undescended testes (cryptorchidism) in children: Management".)

Transfusion should be scheduled a few days ahead of surgery to ensure adequate suppression of Hb H. (See 'Chronic transfusion program' above.)

Neurodevelopmental assessment — All infants should be followed by developmental specialists and undergo neurologic evaluation due to the risk of intrauterine and perinatal brain injury.

Generalizing neurodevelopmental outcomes is not feasible, as prenatal management of ATM is highly variable. In a series of five patients >6 years, full-scale intelligence quotient was average for four patients, while one had mild to moderate delay [18]. Attention and memory were below average in two patients, and cerebral white matter changes were observed in three of four patients evaluated by brain MRI.

Children treated with intrauterine transfusions (IUT) have improved long-term neurodevelopmental outcomes compared with children who did not receive IUT. However, even children treated with IUT have undergone a period of severe anemia early in gestation (before the diagnosis was made and the anemia corrected) that could potentially have an adverse impact on neurocognitive development. Evidence for the benefits of IUT in improving neurodevelopmental outcomes is discussed above. (See 'Intrauterine transfusions' above.)

Management depends upon the extent of intellectual disability and whether any visual, hearing, or motor deficits are present. (See "Intellectual disability (ID) in children: Management, outcomes, and prevention".)

Health maintenance and monitoring for complications — Children with ATM often exhibit growth retardation, but this may again vary with the quality of prenatal and postnatal care. Attention to diet and monitoring weight gain is important. (See "Management of thalassemia", section on 'Monitoring and management of disease complications'.)

●Monitoring – In addition to the above complications that arise prenatally (see 'Prenatal manifestations' above), the following may be seen after birth and should be assessed.

•Neurodevelopmental delay – Can present as speech and hearing difficulties, motor delay, spastic quadriplegia, and global developmental delay. In an international registry including 55 individuals evaluated for neurodevelopmental delay, 11 (20 percent) had a delay of ≥6 months [14].

Emerging evidence supports the value of IUT to preserve neurodevelopment. (See 'Intrauterine transfusions' above.)

•Abnormal liver function – Transaminases are frequently increased, presumably from intrauterine cardiac decompensation and hypoxia. Intrauterine transfusions may contribute.

•Thrombocytopenia – Observed in newborns born with hydropic features. This is probably caused by platelet consumption in an enlarged spleen. (See "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

●Immunizations and preventive care – Children should receive all routine immunizations and preventive care through primary care providers. (See "Standard immunizations for children and adolescents: Overview".)

Investigational therapies — The following therapies are under various stages of investigation:

●In-utero HSCT using maternal hematopoietic stem cells – (See 'Hematopoietic stem cell transplant' above.)

●Gene therapies

●Oral pyruvate kinase agonists such as mitapivat or etavopivat

●Luspatercept

Some of these are also being studied in beta thalassemia, and luspatercept is already used in transfusion-dependent beta thalassemia. (See "Management of thalassemia", section on 'Luspatercept for transfusion-dependent thalassemia'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

SUMMARY AND RECOMMENDATIONS

●Definition – Alpha thalassemia major (ATM) is caused by deletion of all four alpha globin genes (--/--); both parents are alpha⁰ thalassemia carriers (--/αα). Fetal hemoglobin (Hb F, alpha2 gamma2) cannot be synthesized without alpha globin, and severe fetal anemia develops. The main hemoglobin is hemoglobin Barts (gamma globin tetramers), which does not transport oxygen. Fetal anemia and hypoxia cause hydrops fetalis, which causes intrauterine demise unless intrauterine transfusions (IUT) are performed. In Hb H hydrops fetalis, Hb Barts is replaced by Hb H (another nonfunctional hemoglobin) over the first few months of life. In many regions of Asia, ≥5 percent of the population can be carriers of alpha⁰ thalassemia. (See 'Overview' above.)

●Prenatal course – Prenatal ultrasound findings are consistent with fetal anemia and may include nonimmune hydrops fetalis, increased cardiothoracic ratio, placental enlargement, amniotic fluid abnormalities (oligohydramnios and polyhydramnios), and congenital anomalies. We have observed fetal growth restriction and echogenic bowel. Maternal mirror syndrome can occur. (See 'Prenatal manifestations' above.)

●Prenatal evaluation – Screening of at-risk individuals is discussed separately. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

For known at-risk pregnancies, chorionic villus sampling or amniocentesis should be offered. For patients with ultrasound evidence of fetal anemia without confirmed molecular diagnosis who are interested in pursuing fetal transfusions, percutaneous umbilical blood sampling (PUBS) should be offered for diagnosis and therapy. A confirmed diagnosis of ATM is followed by nondirective counseling to decide between pregnancy continuation or termination, as illustrated in the flowchart (algorithm 1). (See 'Prenatal screening and diagnosis' above and 'Counseling and decision-making' above.)

●Management

•Prenatal – For individuals who chose to continue the pregnancy, IUT may be initiated as early as 18 weeks gestation. Simple or exchange transfusion is needed to suppress Hb Barts and improve oxygen delivery. Transfusions are performed every two to three weeks, using volumes based on protocols for hemolytic disease of the fetus and newborn. PUBS is used to monitor the hemoglobin and percentage of Hb Barts. If pregnancy is continued without fetal transfusions, close maternal surveillance is recommended for early recognition of maternal mirror syndrome. Suboptimal prenatal management is associated with preterm birth, fetal growth restriction, cardiorespiratory complications, organomegaly with effusions, anemia, thrombocytopenia, and hyperbilirubinemia. (See 'Intrauterine transfusions' above.)

•Neonatal – Delivery should occur in a facility that can provide high-level critical care. Cord blood hemoglobin and Hb Barts are tested at birth; all patients are transfusion dependent. An urgent simple transfusion with 5 to 10 mL/kg of a high-hematocrit red blood cell (RBC) unit should be given initially, with subsequent management depending upon the cardiovascular status and cord blood hemoglobin. (See 'Delivery and neonatal period' above.)

•Childhood – Chronic transfusion management is similar to beta thalassemia major except for the necessity to account for nonfunctional hemoglobins. The transfusion regimen aims to maintain functional adult hemoglobin (Hb A) 9 to 10 g/dL, either by testing hemoglobin fractions at each transfusion or by keeping the pretransfusion total hemoglobin (Hb A plus Hb H) 10.5 to 11 g/dL. The age to initiate chelation therapy is not well studied; we start a low dose iron chelator at approximately one year, with careful monitoring for toxicities. There is no role for splenectomy. (See 'Management (infancy and childhood)' above.)

●First-degree relatives (counseling and testing) – Preconception counseling and prenatal testing is appropriate for parents of an affected child and siblings of that child. (See "Diagnosis of thalassemia (adults and children)", section on 'Reproductive testing and counseling' and "Gene test interpretation: HBA1 and HBA2 (alpha globin genes)".)