The ABCs of hemoglobin disorders and pregnancy
November 26, 2024
You’ve probably heard of sickle cell disease (SCD) – it's the most common inherited blood disorder, affecting more than 100,000 people in the U.S. Sickle cell disease is caused by a genetic mutation that affects hemoglobin, the protein in red blood cells that transports oxygen throughout the body.
Sickle cell disease is one of several hemoglobin disorders, which also include alpha thalassemia (AT), beta thalassemia (BT), and hemoglobin C disorders. When we talk about hemoglobin, you’ll see it is an alphabet soup!
Let’s go over the “ABCs” of the most common hemoglobin disorders and how they can affect pregnancy.
Symptoms of hemoglobin disorders
Alpha and beta thalassemia and hemoglobin C disease are less common than sickle cell disease, but all four types can cause complications with mom during pregnancy, the most common being anemia. Symptoms of anemia include:
- Exhaustion
- Weakness
- Feeling out of breath with activity
- Pale or yellowish skin, or cold hands or feet
- Dizziness or light headedness
- Irregular heartbeat
- Headache
- Chest pain
- Pica (Latin for magpie) – craving items such as ice, corn starch, or dirt
Hemoglobin disorders are genetic, meaning the gene mutation that causes these disorders is passed down from parents to their children. In the past, carrier screening tests were offered only to patients with Southeast Asian or African ancestry, since these populations were most likely to have the mutations that cause hemoglobin disorders.
However, it’s possible for anyone to carry these mutations. With our current recommendation to provide carrier testing for genetic abnormalities to any patient who requests it, we’ve identified plenty of patients who claimed European ancestry as carriers.
In severe cases, hemoglobin disorders can cause pregnancy complications, including pregnancy loss. Being a carrier of one of the ABCs means you and the baby may need additional care during and after pregnancy for the best chance of healthy outcomes.
What is a hemoglobin disorder?
Adult hemoglobin is composed of two alpha (α) and two beta (β) polypeptide chains. A polypeptide chain is like a long necklace made of amino acids, which together form proteins that do important jobs in our bodies. Hemoglobin disorders can affect the alpha chain or the beta chain, changing the shape of the red blood cell or damaging its ability to carry oxygen.
Hemoglobin disorders are passed down through recessive traits. This means that a child needs a gene mutation from both the egg and sperm to have the disorder. However, children can still be a carrier of the disorder with a mutation from only one parent. That can cause various effects, ranging from no symptoms to mild anemia, depending on the disorder.
When both parents carry the trait for beta chain disorders (beta thalassemia, hemoglobin C, and sickle cell disease), every child has a:
- 25% chance of getting two copies of the trait and developing the disorder
- 50% chance of only getting one copy of the trait and being a carrier, like their parents
- 25% chance of not having the trait or the disorder at all
Alpha thalassemia impacts the alpha chain, and the inheritance is a little more complex. There are four potential mutation sites and varying degrees of effects. The disorder also requires both parents to have mutations.
The ABCs of hemoglobin disorders
A: Alpha thalassemia
About 5% of the world’s population carries an AT trait. This disorder affects the alpha chains in hemoglobin. It leads to fewer healthy blood cells, and the ones that do exist are smaller and carry less oxygen. AT can cause symptoms of anemia. It’s most often found in people of Mediterranean, African, Middle Eastern, Indian, and Central Asian descent. AT is particularly common in Southeast Asia.
Everyone inherits two alpha chain genes from each parent, so AT can involve changes in up to four genes. With increasing numbers of mutations in the alpha genes, symptoms worsen.
AT types include:
- AT silent carrier: One gene is damaged or missing (no symptoms at all).
- AT carrier or AT trait: Two genes are damaged or missing (mild or no symptoms).
- Hemoglobin H (HbH) disease: Three genes are damaged or missing. Due to fewer alpha hemoglobin chains, the excess beta hemoglobin chains form hemoglobin H (significant symptoms).
- AT major (hemoglobin Barts): Four genes are damaged or missing due to the inability to produce functional alpha hemoglobin chains. This leads to severe anemia. Without intervention, this will cause hydrops in the fetus, which most commonly results in stillbirth. It can also lead to maternal complications such as early onset severe preeclampsia (mirror syndrome). With awareness of this risk, fetal intrauterine transfusion can allow survival until delivery. Subsequent care may include ongoing transfusions with iron chelation treatments or more advanced therapy such as a bone marrow transplant. This is a target for gene therapy.
B: Beta thalassemia
About 1.5% of the global population is a carrier for BT, with about 60,000 children born with symptoms each year. Like sickle cell, BT affects the beta chain in hemoglobin. This results in reduced oxygen-carrying capacity and more fragile red cells with shorter lifespan. This lower frequency of healthy and stable red blood cells leads to anemia.
BT is most often found in people of Mediterranean, North African, Middle Eastern, Indian, Central Asian, and Southeast Asian descent. The most common types of this disorder are:
- BT minor: Only one gene is damaged (inherited from only one parent), and symptoms are minor.
- BT major (Cooley’s anemia): Two genes are damaged (inherited from both parents), and symptoms are more pronounced. This does not cause issues until after birth due to the presence of fetal hemoglobin (HbF) in the fetus and newborn. As levels of HbF fall after birth, this can lead to the child being transfusion dependent. It can also lead to long-term complications of iron overload and damage to the liver, spleen, and heart. This is treated with ongoing transfusions, iron chelation, and possibly a bone marrow transplant. This is also a target for emerging gene therapy.
- BT intermedia: Interestingly, some people with BT major have an ongoing presence of HbF (hereditary persistence of fetal hemoglobin) that leads them to have no symptoms or an intermediate impact.
C: Hemoglobin C disorder
Hemoglobin C disorder affects the beta chain in hemoglobin. It changes the shape of normal hemoglobin, making it inflexible. The rigid shape can cause blood cells to clump together, which forms crystals and leads to an increased chance of clots and shorter lifespan of red cells.
Those with only one mutation (HbC) are typically unaffected and would not be aware that they are carriers unless tested. For those with two mutations (HbCC), symptoms are less intense than with sickle cell disease. A hemoglobin C disorder often does not require treatment. Patients may develop mild anemia.
Hemoglobin C disease most commonly affects people in Africa and those of African descent, but it has been found in individuals with no known African ancestry. Interestingly, it may allow for resistance to clinical malaria infection, which could be advantageous for those living in an area where malaria is common. HbC can also be co-inherited with a sickle cell mutation, leading to a clinical situation that is similar to sickle cell disease.
S: Sickle cell disease
With sickle cell, the beta chain in hemoglobin is affected. Sickle cell trait (SCT) is caused by inheriting one mutation, leading to hemoglobin S (HbAS). Sickle cell disease (SCD) is caused when a mutation is inherited from both parents (HbSS).
Sickle hemoglobin differs from the normal hemoglobin by just a single amino acid substitution. This seemingly minor change causes red blood cells to become rigid and take a characteristic crescent or sickle shape. These sickle-shaped cells are less efficient at transporting oxygen and can block blood flow in small vessels, leading to pain, organ damage, and increased risk of infection.
The sickle cell trait does not usually cause a notable increase in pregnancy complications, but it can lead to anemia. Importantly, we do not recommend supplemental iron for pregnant people with sickle cell as there is a risk of iron overload and extra iron does not remedy the anemia. There is also a risk of having a child with a more severe hemoglobin condition if the genes from the sperm also carry a mutation. For those with sickle cell disease, pregnancy can lead to a higher likelihood of fetal growth restriction, low amniotic fluid, miscarriage and stillbirth, preterm delivery, and preeclampsia as well as infection, gallstones, blood clots, and cardio-pulmonary complications.
Sickle cell traits are most common in people of African, Middle Eastern, Asian, Indian, and Mediterranean descent. They are also prevalent in people from Central and South America.
Related reading: How does sickle cell disease affect pregnancy?
How are hemoglobin disorders diagnosed in pregnancy?
The primary test for hemoglobin disorders involves taking blood samples from both parents. The samples are checked in a laboratory for abnormal hemoglobin factors that signal beta chain conditions. Genetic testing is used to check for alpha chain conditions. Testing both parents can tell you the likelihood of your child having a hemoglobin disorder:
- If the likelihood is zero, no further testing or treatment is required.
- If there is a possibility of a major hemoglobin disorder, doctors will likely recommend fetal testing.
Fetal testing is often done through amniocentesis, a safe procedure to sample a small amount of amniotic fluid from around the baby. Single gene cell-free DNA testing is another emerging option for AT, BT, and sickle cell disease. We can sample placental cells from blood drawn from the pregnant patient’s arm to search for abnormal hemoglobin factors.
What treatments are available?
If you or your fetus are diagnosed with a mild form of hemoglobin disorder, treatment likely isn’t needed. Severe forms may require one or more types of treatment, some of which will have to wait until after your baby is born.
- Blood transfusion: Healthy red blood cells from a donor are given to a patient through an IV. Blood transfusions are safe in pregnancy and do not harm the fetus. If your fetus has a major form of alpha or beta thalassemia, they may need an intrauterine transfusion, with donor red blood cells given through an injection in the umbilical cord or the baby’s abdomen.
- Iron chelation therapy: Altered blood cells can carry less iron, which means the digestive tract absorbs more iron than needed. Excess iron can damage the spleen, heart, and liver. Iron chelation therapy removes excess iron and safely filters it out as urine. The treatment is given by IV, mouth, or injection. Iron chelation therapy is not recommended during pregnancy. It is safe before or after pregnancy.
- Stem cell transplant: In a hemoglobin disorder, precursor cells in the bone marrow don’t develop into healthy red blood cells. A stem cell transplant willStem cell transplants replace the cells that will eventually become blood cells with healthy cells from a donor. This helps the patient’s body produce normal red blood cells and correct the underlying cause of the disease. A stem cell transplant is safe before or after pregnancy but is not performed during pregnancy.
- Splenectomy: The spleen breaks down damaged red blood cells faster, so surgery to remove it can reduce the need for frequent blood transfusions and improve overall red blood cell counts. Unless it is an emergency, a splenectomy is not recommended during pregnancy.
Testing and communication can lead to better results
If you or your child has a hemoglobin disorder or trait, your health care provider may recommend other tests before and during pregnancy that will check:
- Thyroid
- Liver function
- Heart function
- Bone density
- Blood iron levels
- Urinary tract infection
You’ll also likely be seen more often by your provider; at least once a month for the first two trimesters and more frequently in the last trimester. Regular check-ups and communication with your care team can help manage your condition and ensure the best outcomes for you and your baby.
To talk with a hemoglobin disorder expert, call 214-645-8300 or request an appointment online.
