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Alpha thalassemia major: Prenatal and postnatal management

Alpha thalassemia major: Prenatal and postnatal management
Literature review current through: Jan 2024.
This topic last updated: Jul 12, 2023.

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 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 (--/αTα or -αT/-αT). 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 nontransfusion-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'.)

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.

The number of live births with ATM is low but increasing, often with acutely ill newborns. In areas of Southeast Asia where alpha thalassemia is prevalent, an expected 4500 pregnancies with ATM occur annually [5].

With immigration, the prevalence of alpha thalassemia continues to increase in North America and Europe [6]. 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) [7].

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:

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 1). 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".)

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".)

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 [8-10].

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 [11]. 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 with an average midgestation hemoglobin 6.4 g/dL, most of which is the nonfunctional Hb Barts. 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.

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.

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

Abnormal liver function tests — Transaminases are frequently increased, presumably from intrauterine cardiac decompensation and hypoxia.

Thrombocytopenia — Thrombocytopenia is 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'.)

Congenital anomalies — Urogenital anomalies are present in most males with ATM; hypospadias is most common [11-14]. Other abnormalities are undescended testes, bifid scrotum, hydrocele, and micropezid. (See "Hypospadias: Pathogenesis, diagnosis, and evaluation".)

Limb anomalies are also seen in 16 percent but tend to be mild [12]. 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 [11,15].

Neurodevelopmental delay — 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 [11].

Emerging evidence supports the value of IUT to preserve neurodevelopment, as discussed below. (See 'Intrauterine transfusions' below.)

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 carrying a nonviable fetus [16]. (See "Stillbirth: Maternal care", 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 or iron deficiency anemia 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. (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.

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)".)

Couples at risk for ATM in pregnancy should be educated regarding reproductive options including in vitro fertilization (IVF) with preimplantation genetic testing (PAT), as well as the risks, benefits, and limitations of pregnancy management options including termination of pregnancy (when available), active fetal management, and expectant management [17]. (See 'Counseling and decision-making' below and "Preimplantation genetic testing".)

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 [18-20]. (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 [21-23].

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 [17].

Continuation with fetal therapy – If the pregnancy is continued, the adequacy of prenatal management strongly influences the perinatal and postnatal course [9,13-15]. Collaborative management by fetal medicine specialists and hematologists are essential to attain safe post-transfusion hemoglobin targets and suppress Hb Barts. Fetal hydrops resolve 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 [24]. (See 'Neurodevelopmental delay' above 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). (See "Preimplantation genetic testing".)

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)

Prenatal

Intrauterine transfusions — Providing intrauterine transfusions (IUT) is the major prenatal intervention for ATM. 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 [17]. (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 [17]. In cases where IUT is not feasible, intraperitoneal transfusions may be an alternative.

Goal of therapy – The goal of IUT regimen should be to achieve total hemoglobin 11 to 13 g/dL with Hb Barts <20 percent at birth. (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 "Intrauterine 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 "Intrauterine 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 "Intrauterine fetal transfusion of red blood cells".)

Supporting evidence Evidence for the benefits of IUT continue to emerge [13-15,24]. 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 that were not terminated, 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 [24]. 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.

In a 2021 cohort of 25 pregnancies with ATM that were not terminated, most cases using IUT prior to 28 weeks resulted in survival with full resolution of hydrops at delivery [14]. 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) [13].

Active management with IUT that resolves fetal hydrops and should in turn reduce the overall risk for maternal complications such as mirror syndrome [14,24,25]. (See "Nonimmune hydrops fetalis", section on 'Maternal findings' and "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations", section on 'Management of polyhydramnios in singleton pregnancies'.)

Intrauterine hematopoietic stem cell transplant — Intrauterine haploidentical hematopoietic stem cell transplant (HSCT) using maternal bone marrow enriched for CD34+ cells is being studied in a phase I clinical trial. Maternal hematopoietic stem cells are administered as a one-time infusion immediately before the RBC transfusion through the umbilical vein at the time of IUT [26].

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 [17]. 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 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.

-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 rapidly lower Hb Barts and improve oxygenation. 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. In ATM, transfusions begin in the prenatal period compared with six to nine months after birth in beta thalassemia major. The transition to chronic transfusions lasts until six months of age and is characterized by 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 purpose of raising the hemoglobin (initially to >12g/dL) is suppression of erythropoiesis, including extramedullary erythropoiesis. Suppression of erythropoiesis assists in reducing splenomegaly, which is necessary to eventually decrease the transfusion volume and frequency. A gradual improvement in cardiomegaly and liver function abnormalities is seen by 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 interventions are postponed to allow 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: pretransfusion Hb A >9 g/dL, transfusion frequency every three to four weeks, and prevention of splenic enlargement.

It is important to follow Hb A instead of total hemoglobin in the pretransfusion sample to account for the nonfunctional Hb H. This is an important difference from beta thalassemia major, where the alternate hemoglobin (Hb F) participates in oxygen transport and is counted towards the total hemoglobin; children with ATM are at risk for under-transfusion if guidelines for beta thalassemia major are followed [27].

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 longer storage reduces Hb H level, particularly with refrigeration. This creates a situation where the calculated Hb A level is falsely high and affects calculation of transfusion volume.

Infusion centers lacking access to precise Hb H measurements can opt to treat by maintaining pretransfusion total hemoglobin at 10.5 to 11 g/dL and reticulocyte count <500,000/microL [27]. 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.

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 occurs 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 'Abnormal liver function tests' above.)

Management guidelines from 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. However, we postpone chelation until 12 months of age, given concerns over inflammation of the liver and immaturity of the kidneys, 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 of age could be harmful.

Agent and dose

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 up to a maximum of 14 mg/kg until the child is two years old, following which the general guidelines for deferasirox are followed. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

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. Safety and efficacy of deferiprone in children <2 years with beta thalassemia major was reported in abstract form [28].

DeferoxamineDeferoxamine 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 [29].

Monitoring and toxicities – The goal of chelation is to maintain serum ferritin in the range of 1000 to 2000 ng/mL in the second year, 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 [30]:

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

Kidney function (eg, creatinine, potassium, bicarbonate, 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 magnetic resonance imaging (MRI). In under-transfused children, ferritin underestimates the systemic iron burden [31]. The initial liver MRI should be performed around two years of age, which is used to determine 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. 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 for transfusion-dependent thalassemia".)

Correction of congenital anomalies — Surgical consultation is arranged early to plan for correction of congenital anomalies [11,13,32]. 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 also undergo neurologic assessment due to the risk of intrauterine and perinatal brain injury.

Generalization of neurodevelopmental outcomes is not feasible, as prenatal management is highly variable. Children treated with intrauterine transfusions (IUT) generally have improved long-term neurodevelopmental outcomes when compared with children who did not receive IUT (see 'Intrauterine transfusions' above). However, even children treated with IUT have had 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.

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 — 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'.)

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

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 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. (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 'Prenatal' 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 – Hb Barts is replaced by Hb H (another nonfunctional hemoglobin) over the first few months of life. 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 g/dL, either by testing hemoglobin fractions at each transfusion or by keeping the pretransfusion total hemoglobin (Hb A plus Hb H) >10.5 g/dL. Iron chelation is started at approximately one year, with careful monitoring for toxicities. (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)".)

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Topic 131582 Version 10.0

References

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