Fertility & Pregnancy in Thalassemia

Adult males and females with Thalassemia who are thinking of starting a family should have their fertility evaluated by a fertility specialist – especially if they have a prior history of severe iron overload.

In a woman with irregular or no menstrual cycles, the assessment should be performed as soon as the patient decides she would like to start a family. Since fertility decreases with increasing patient age, and since many fertility treatments can take time to work, earlier evaluation by a fertility expert is recommended. If a female with Thalassemia and normal menstrual cycles, or a male with Thalassemia has not been able to conceive within 6 months of trying, an evaluation by a fertility expert is recommended.

In general, a fertility expert will evaluate all potential causes of infertility – whether or not they are related to Thalassemia. Typically, both partners (male and female) are evaluated. The fertility expert will assess whether there are any hormonal deficiencies, problems with ovulation or sperm production, abnormalities in sperm motility, or abnormalities of the uterus (womb), ovaries or testicles. 

After stimulation of ovulation or sperm production, there are several available conception options including: (1) natural conception, (2) intra-uterine insemination (IUI) or (3) in vitro fertilization (IVF). In intra-uterine insemination, sperm is placed directly inside a woman’s uterus to facilitate fertilization.

In IVF, the egg and sperm are combined in a laboratory dish, and the resulting embryo is then transferred into the mother’s uterus. Several additional techniques can also be incorporated into IVF for improved outcomes: Intra-cytoplasmic sperm injection (ICSI) directly injects sperm into the egg, which can result in improved conception rates when low sperm count or defects in sperm motility are the underlying cause of male infertility.

For couples who are at risk of having a child with Beta Thalassemia, pre-implantation genetic diagnosis (PGD) can be combined with IVF to select embryos which are free of a clinically significant form of Thalassemia for implantation into the woman’s uterus.

For a female patient with significant complications who might be at high risk for carrying a pregnancy, surrogacy is also an option: her egg and her partner’s sperm can be combined in the laboratory, and then transferred to the uterus of a pre-arranged surrogate who would then carry the pregnancy to term.

Since there are many options available to aid with conception, it is important to work closely with your Thalassemia team, your gynecologist, fertility specialists, and a genetic counselor to ensure you have all the information on the many choices available. It is important to understand the benefits and risks, the success and failure rates, and the costs of each of the options before proceeding. These are very personal and emotional decisions. Your team will help and support you through this difficult process. 

A planned pregnancy is key to minimizing risks to the mother and the baby. Before conception, the following should be considered:

• The partner should undergo carrier testing for Thalassemia and hemoglobinopathy status, and if the partner turns out to be a Thalassemia carrier, the couple should be referred to a genetic counselor

• Fertility assessment as described above may be important based on risk of hypogonadism

• Iron overload status should be evaluated by serum ferritin levels, liver MRI and cardiac MRI (T2*). Ideally, the liver iron concentration should be less than 7 mg/g dry weight and the cardiac T2* greater than 20 milliseconds before attempting to conceive.

• All women should have their cardiac function evaluated by a cardiologist using electrocardiogram (ECG), 24-hour Holter monitor, echocardiogram and cardiac MRI. Pregnancy is discouraged if there are any abnormalities of heart function or rhythm due to the high risk of death.

• Liver function evaluation with biochemical testing is important. If there has been a history of high iron burden or hepatitis C infection, further testing and evaluation by a liver specialist is important.

• Evaluation by an endocrinologist with an emphasis on bone health and vitamin D levels, and screening for diabetes, hypothyroidism and other hormone abnormalities should be performed before conception and treated as needed

• Patients should be screened for infections prior to pregnancy including for HIV, hepatitis B and C, and rubella

• Medications – including iron chelators – should be reviewed and adjusted as needed. Since the demand for folic acid increases during pregnancy, all women with Thalassemia should be on folic acid supplementation prior to conception to prevent neural tube defects in the fetus. 

Women with Thalassemia who have a history of cardiac iron overload may be at risk for developing poor cardiac function and even cardiac failure if they become pregnant. This is because the mother’s metabolic demand and blood volume increases during pregnancy – which puts an additional burden on the heart. Pregnant individuals with compromised heart function due to iron overload are therefore at higher risk of heart rhythm abnormalities, heart failure, and even death.

It is therefore important to have a thorough evaluation of cardiac function before trying to become pregnant. A complete evaluation by a cardiologist including electrocardiogram (ECG), echocardiogram, 24-hour Holter monitor, and T2* MRI assessment for cardiac iron are recommended. Ideally, the cardiac T2* should be greater than 20 milliseconds before pregnancy is attempted.

Generally, women with a cardiac T2* < 10 milliseconds or other evidence of heart dysfunction are encouraged to chelate aggressively to reduce iron burden before attempting pregnancy. During pregnancy, patients should be closely followed by a cardiologist and evaluated every trimester by ECG and echocardiogram – or sooner if symptoms develop.

After delivery, a cardiac MRI T2* and cardiac evaluation should be performed again. Pregnancy in general increases the risk of developing blood clots. Women with Thalassemia, especially those with non-transfusion-dependent thalassemia who have had their spleens removed, are at higher risk of developing blood clots.

Other factors that increase the risk of clotting include prior history of a clot or an inherited predisposition to clotting. Although no guidelines are available for managing blood clots in pregnancy in women with Thalassemia, we generally aim to prevent clot formation by administering a prophylactic (preventative) dose of blood thinners during pregnancy and for the 6-8 weeks after delivery.

It is important to have a personal evaluation of your risk of developing blood clots with your hematologist. It is also essential to evaluate iron burden in the liver prior to pregnancy so as to minimize possible liver complications. In addition, the lower the liver iron level, the longer the pregnant mother may be able to hold chelation during pregnancy and following childbirth, since oral iron chelators are not recommended during pregnancy and while breastfeeding.

Prior to pregnancy, it is important to be evaluated by an endocrinologist to optimize bone health and to manage any problems with low thyroid function or diabetes. Bone mineral density testing and correction of vitamin D deficiency are important for optimal bone health. Individuals taking bisphosphonates for osteoporosis should stop therapy for at least 6 months prior to conception.

Patients with diabetes should strive for good control of blood sugars before and during pregnancy. Due to pancreatic iron deposition, even patients without diabetes prior to pregnancy are at risk of developing diabetes during pregnancy (this is called “gestational diabetes”). Pregnant women with Thalassemia should thus undergo earlier-than-usual screening for gestational diabetes at 16-18 weeks of gestation. If patients are negative at this time, they should be screened again at 28 weeks.

General pregnancy-related complications such as urinary tract infections, kidney stones, gallstones, and placental complications have been described in pregnant women with Thalassemia at approximately the same rate as in the general population.

It is thus important to plan for pregnancy, and to screen and monitor for complications prior to conception, during pregnancy and following childbirth. Family planning is important whether a patient chooses spontaneous conception or assisted reproduction, in order to reduce the risks to mother and baby. 

In general, chelators are not recommended during pregnancy. Current recommendations advocate stopping all chelation as soon as pregnancy is confirmed, and holding it throughout pregnancy, due to concern of birth defects. Animal studies have revealed bone changes in offspring that were exposed to large doses of deferoxamine (Desferal) during fetal development. Increased kidney abnormalities were seen in animals exposed to deferasirox (Exjade/ Jadenu) and deferiprone (Ferriprox) during fetal development. However, in women who accidentally continued with oral chelation therapy for some time prior to discovering that they were pregnant, no abnormalities were observed in their children. Nevertheless – due to minimal evidence from clinical studies – use of oral chelators is generally not recommended during pregnancy.

If a woman with Thalassemia has been well chelated prior to conception – with low liver iron, no cardiac iron, and no organ dysfunction – chelation can generally be held for the 9 months of pregnancy. However, in certain women, especially those with a prior history of cardiac iron, cardiac dysfunction, or high liver iron, chelation with deferoxamine (Desferal) in the late second and third trimesters has been used without major side effects. In each case, the evaluation of benefits and risks is important and should include input from a hematologist.

Are mothers with Thalassemia discouraged from using oral chelators while they are breastfeeding? Is desferal an acceptable chelation option while breastfeeding?

Oral chelators such as deferiprone (Ferriprox) and deferasirox (Exjade/Jadenu) are not recommended while breastfeeding due to lack of safety data. Deferoxamine (Desferal) can be used while breastfeeding since it is a large molecule and is generally not absorbed by the baby.

Published registry data shows that most pregnancies in women with thalassemia are delivered at full term, around 37.7 weeks. Most of the preterm births are due to carrying twins/multiple pregnancies or are undertaken for precautionary reasons.