What is alpha thalassemia?
Alpha thalassemia is an inherited disease that affects the ability of red blood cells to provide the body with enough oxygen. Changes in the alpha globin gene, which makes one of the important proteins inside a red blood cell, are responsible for causing alpha thalassemia.
How serious is alpha thalassemia?
Alpha thalassemia has varying degrees of severity. Every person has four copies of the alpha globin gene. How serious the disease is depends on the number of functioning alpha globin genes.
- “Silent carriers” have just one of the four copies of the alpha globin gene non-functioning and, therefore have no evidence of disease and, without a family history, are unlikely to know they are a carrier for this condition.
- “Symptomatic carriers” are individuals with smaller and fewer red blood cells (called “anemia’) on the complete blood count. These individuals appear anemic because two of the four alpha globin genes are non-functioning.
- “Hemoglobin H disease” is defined as having only one remaining functional alpha globin gene. Hemoglobin H disease can vary widely, with individuals developing symptoms anytime after birth through adulthood. Some patients may require treatment, including recurrent blood transfusions for managing their anemia.
- “Alpha thalassemia major” (ATM) occurs when all four genes are non-functioning. Alpha thalassemia major is almost uniformly fatal in utero without intervention. Potential fetal therapies are available, including transfusing the developing fetus with red blood cells to treat the anemia and allow the fetus to survive to birth. This disease is also sometimes called Hemoglobin Bart’s or hydrops fetalis.
How is alpha thalassemia inherited?
Alpha thalassemia major (ATM) is inherited in an autosomal recessive manner. This means that two non-functioning genes have to be passed to the fetus from each parent, resulting in loss of function of all four alpha globin genes in the fetus. A pregnancy is at risk for alpha thalassemia major 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 for the parents for alpha thalassemia is performed by a simple blood test called a “complete blood count" (CBC). If the results shows a reduced mean cell volume (MCV), and the parents have a normal iron status (the person is not anemic because of iron deficiency), then specific testing for hereditary anemias including alpha thalassemia should be performed.
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 the 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, intestines as well as thickening of the skin or placenta. The development of hydrops in a fetus with alpha thalassemia major 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, which is a condition 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 alpha thalassemia, prior to signs of fetal hydrops, is critical to prevent these severe symptoms in the mother.
What are my choices during this pregnancy?
Families who have had a previous pregnancy affected with ATM may choose to obtain genetic counseling in future pregnancies.
Couples at risk for alpha thalassemia in pregnancy have the option to pursue prenatal diagnosis to determine if their fetus has alpha thalassemia major. Prenatal diagnosis for alpha thalassemia major is usually done by either chorionic villus sampling (CVS), performed between10 weeks and 14 weeks of gestation, or by amniocentesis, performed after 16 weeks gestation. These procedures carry a small risk for 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 is offering intrauterine transfusions for fetuses with alpha thalassemia major. We are also starting a phase 1 clinical trial of in utero stem cell transplantation, which may become a more definitive treatment.
Intrauterine transfusion (IUT) is used to treat alpha thalassemia major 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 are able to successfully deliver oxygen. Fetuses can be treated with intrauterine transfusions throughout pregnancy starting at an early gestational age (18-25 weeks). We have shown that babies who were treated with serial IUTs for ATM have excellent neurological outcomes.
UCSF has years of experience performing intrauterine transfusions. It is a procedure commonly performed for other pregnancy complications causing fetal anemia, most commonly due to Rh mismatch between the mother and the fetus.
Babies with alpha thalassemia major treated with serial IUT in pregnancy still 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.
We are currently investigating the benefits of in utero stem cell transplantation in pregnancies with a diagnosis of alpha thalassemia major. Our aim is to correct this genetic disease before birth to provide a cure to the fetus.
What will happen after birth?
- Patients treated with IUT alone: Treating the infant with serial blood transfusion is the primary treatment to replace that individual’s non-working red blood cells with functioning red blood cells. Blood transfusion can be a life long treatment, although it is not a cure. Stem cell transplantation may cure alpha thalassemia, since the patient will then make his or her own functioning red blood cells from the transplanted stem cells. However, there are significant risks to stem cell transplantation that should be addressed, 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).
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 an email at email@example.com.
For more information about the postnatal management of alpha thalassemia major, please visit The Northern California Comprehensive Thalassemia Center.
Support Groups & Other Resources
- The Northern California Comprehensive Thalassemia Center
- The UCSF Center for Maternal-Fetal Precision Medicine - Improve our understanding and treatment of patients with congenital anomalies and pregnancy complications
- The UCSF Blood and Marrow Transplant Research web page
- Cooley's Anemia Foundation – Provide support for patients and families with thalassemia and sponsor medical research to increase the life expectancy and enhance the quality of life for those impacted by thalassemia.
- March of Dimes — Researchers, volunteers, educators, outreach workers and advocates working together to give all babies a fighting chance
- Kids Health — Doctor-approved health information about children from before birth through adolescence
- CDC - Birth Defects — Dept. of Health & Human Services, Centers for Disease Control and Prevention
- NIH - Office of Rare Diseases — National Inst. of Health - Office of Rare Diseases
- North American Fetal Therapy Network — NAFTNet (the North American Fetal Therapy Network) is a voluntary association of medical centers in the United States and Canada with established expertise in fetal surgery and other forms of multidisciplinary care for complex disorders of the fetus.