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Alpha Thalassemia Major

The UCSF Fetal Treatment Center and UCSF Benioff Children's Hospitals have established the first multidisciplinary center for alpha thalassemia major (ATM). We are offering fetal therapy for patients with ATM, including fetal transfusions and fetal stem cell transplantation.

Early diagnosis and treatment of a pregnancy affected by ATM are critical for the survival of the fetus and the health of the mother.

What is alpha thalassemia?

Alpha thalassemia is an inherited blood disease that affects the production of hemoglobin and the ability of red blood cells to provide the body with enough oxygen. Changes in any of four alpha globin genes, which make an important protein inside a red blood cell called alpha globin, are responsible for causing alpha thalassemia.

How is alpha thalassemia inherited?

Alpha Thalassemia Major (ATM) is an inherited autosomal recessive disease, in which two non-functioning alpha globin genes are passed from each parent to the fetus, resulting in loss of function of all four alpha globin genes in the fetus. A pregnancy is at risk for ATM only if both parents have two non-functioning genes, in which case the risk that the fetus will inherit both sets of non-functioning genes and have ATM is 1 in 4, or 25%.

Preliminary screening of parents for alpha thalassemia is performed by a simple blood test called a “complete blood count“ (CBC). If the results show a reduced mean corpuscular volume (MCV), and the parents have a normal iron status (not anemic because of iron deficiency), then specific testing for hereditary anemias including alpha thalassemia should be performed.

Individuals whose ancestry traces to Asia, the Pacific Islands, Mediterranean, Middle East, or Africa are at high risk for thalassemia. Specific testing for thalassemia should be performed for patients who are at high risk for thalassemia, such as hemoglobin typing and alpha-globin common mutation analysis.

Download our Prenatal Screening & Diagnosis Algorithm for Thalassemia

How serious is alpha thalassemia?

Alpha thalassemia has varying degrees of severity. Every person has four copies of the alpha globin gene. The severity of the disease depends on the number of functioning alpha globin genes.

  • Individuals with one or two non-functioning genes are usually asymptomatic. In some cases, individuals with two non-functioning genes may have anemia. A CBC for those with two non-functioning genes will show smaller and fewer red blood cells.
  • “Hemoglobin H disease” is defined as having only one functioning alpha globin gene. Hemoglobin H disease can vary widely, with individuals developing symptoms any time after birth through adulthood. Some patients may require treatment, including recurrent blood transfusions to manage their anemia.
  • “Alpha thalassemia major” (ATM) occurs when all four alpha globin genes are non-functioning. ATM is almost uniformly fatal in utero without intervention. Fetal therapies, including transfusing the developing fetus with red blood cells to treat the anemia, can allow the fetus to survive to birth. This disease is also sometimes called Hemoglobin Bart’s Hydrops Fetalis.

What is the outcome for a fetus with alpha thalassemia major?

Alpha thalassemia major is so severe that affected fetuses will develop anemia due to the lack of functioning red blood cells needed to provide oxygen. Progressive fetal anemia can lead to heart failure because of stress on the fetal heart, which can be seen on ultrasound as fetal hydrops. Fetal hydrops can be seen on ultrasound when the fetus accumulates excess fluid around the heart, lungs, or intestines, as well as thickening of the skin or placenta. The development of hydrops in a fetus with ATM is quite serious; these fetuses can die before birth without fetal intervention.

Maternal Mirror Syndrome

In cases with extreme fetal hydrops, the mother may be at risk for maternal mirror syndrome, where the mother's condition mimics that of the sick fetus. The mother develops symptoms that are similar to pre-eclampsia, such as vomiting, hypertension, peripheral edema (swelling of the hands and feet), proteinuria (protein in the urine), and pulmonary edema (fluid in the lungs). This condition is so severe that it requires delivering the baby immediately. Early diagnosis and treatment of pregnancies affected with ATM, prior to signs of fetal hydrops, is critical to prevent these severe symptoms in the mother.

What are my choices during this pregnancy?

Couples identified to be at risk based on their genetic screening, or those who have had a previous pregnancy affected with ATM, may choose to obtain genetic counseling.

Couples at risk for alpha thalassemia in pregnancy have the option to pursue prenatal diagnosis to determine whether their fetus has ATM. Prenatal diagnosis for ATM is usually done either by chorionic villus sampling (CVS), performed between 10 weeks and 14 weeks of gestation, or by amniocentesis, performed after 16 weeks gestation. These procedures carry a small risk of miscarriage (> 1 in 500).

When a prenatal diagnosis of ATM is confirmed, pregnancy management options include close fetal monitoring, pregnancy termination, or fetal intervention. The UCSF Fetal Treatment Center offers intrauterine transfusions (IUT) for fetuses with ATM. We also offer enrollment in a phase 1 clinical trial of in utero stem cell transplantation.

Fetal Interventions

Fetal therapy options for ATM include fetal transfusions or participation in our ongoing clinical trial of in utero stem cell transplantation.

Intrauterine Transfusion (IUT) for Fetuses with ATM

Intrauterine transfusion is used to treat ATM by providing red blood cells to the fetus though a blood transfusion. The goal of this treatment is to provide the fetus with functional red blood cells that can successfully deliver oxygen. Fetuses can be treated with intrauterine transfusions throughout pregnancy starting at an early gestational age (18-25 weeks).

UCSF has years of experience performing intrauterine transfusions, which are commonly performed for other pregnancy complications that cause fetal anemia (most commonly due to Rh mismatch between the mother and fetus). Risks of fetal transfusions for any indication include fetal loss and preterm delivery.

In utero transfusions help fetuses with alpha thalassemia major survive. We have shown that babies who were treated with serial IUTs for ATM have favorable neurological outcomes.

Favorable outcomes after transfusion in fetuses with alpha thalassemia major: a case series and review of the literature

Video: In utero transfusion gives meaningful survival to fetuses with alpha thalassemia major

Translations: Tagalog, Thai, Traditional Chinese, Vietnamese

Babies with ATM who were treated with serial IUT before birth will need chronic transfusions after birth to replace their non-working red blood cells and may eventually pursue a stem cell transplant. Although a stem cell transplant can cure the disease completely, it can also be problematic because of difficulties finding a suitable donor and possible complications during the long journey of transplantation.

In utero stem cell transplantation for ATM

We are currently investigating the benefits of in utero stem cell transplantation in pregnancies with a diagnosis of ATM. Our aim is to correct this genetic disease before birth to cure the fetus.

The UCSF Fetal Treatment Center is performing an FDA-approved phase 1 clinical trial of maternal stem cell transplantation in fetuses with ATM. In this trial, we harvest stem cells from the mother’s bone marrow, prepare the cells for safe injection, then transplant them into the fetus at the same time as a planned IUT. Performing the stem cell transplant at the same time as IUT minimizes additional procedural risk to the fetus and takes advantage of a unique time period in development when the mother can be an ideal stem cell donor for her fetus. We are testing whether this added in utero transplantation is safe and effective for patients with ATM.

With in utero stem cell transplantation, we aim to cure the baby of ATM before birth, thus eliminating the need for lifelong transfusions or the complications of stem cell transplantation after birth. Our goal for this phase 1 trial is to determine how well the mother and fetus tolerate stem cell harvesting and transplantation.

Who is a candidate for fetal therapy for ATM?

To be considered for fetal intervention, we must first establish a diagnosis of ATM in the pregnancy through testing by CVS (chorionic villus sampling), amniocentesis, or cordocentesis. Alternatively, pregnancies with evidence of fetal anemia or signs of fetal hydrops in which the parents are confirmed genetic carriers can be considered for treatment.

If you wish to pursue fetal therapy for ATM, call us at 800-RX-FETUS (1-800-793-3887).

We will arrange for you to visit our Fetal Treatment Center for a formal evaluation, which includes an ultrasound, ECHO (ultrasound of the heart), and counseling by members of our Fetal Treatment Center team (surgeon, hematologist, obstetrician, genetic counselor, social worker, nurse). We will discuss whether your are a candidate for IUT alone or IUT plus stem cell transplantation. With either intervention, we anticipate your fetus will need subsequent red blood cell transfusions until birth, which can be performed at UCSF or at your home institution.

What will happen after birth?

​Patients treated with IUT alone: Serial blood transfusion is the primary treatment to replace the baby’s non-functioning red blood cells with functioning red blood cells. Blood transfusion can be a lifelong treatment, although it is not a cure. Stem cell transplantation may cure ATM since the patient will then make his or her own functioning red blood cells from the transplanted stem cells. However, there are significant risks for postnatal stem cell transplantation that should be considered, and suitable “matched” donors are sometimes difficult to find (tolerance to the mother’s stem cells wanes after pregnancy so the mother may not be a suitable donor after birth).

Patients who have IUT plus in utero stem cell transplantation: After birth, we will monitor the baby for signs of engraftment (the number of mother’s blood cells that survive). If the levels are high, the baby may not need further treatment. If the levels are low but detectable (1-5%), the baby may need a “booster” transplant of maternal cells to increase the levels of engraftment. If there is no appreciable engraftment, the baby may need lifelong transfusions or another stem cell transplant.

The postnatal management of ATM is similar to beta thalassemia major, a more common disease in which patients also need chronic transfusions or a stem cell transplant. Patients with ATM who survive to birth after fetal therapy tend to have good neurologic outcomes.

For more information about the postnatal management of alpha thalassemia major, please visit The Northern California Comprehensive Thalassemia Center.

How to contact us

For more information about fetal treatment for ATM, or to refer a patient, please call 1-800-RX-FETUS (1-800-793-3887) or send us email at Please include a telephone number with your inquiry.

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