Management of Thalassaemia in Pregnancy
Thalassaemia becomes a global health problem. Most women with thalassaemia trait can be picked up by universal prenatal screening for thalassaemia using mean corpuscular volume/haemoglobin, followed by haemoglobin pattern with or without DNA analysis. If the partner is a carrier of same type of thalassaemia as the woman, prenatal counselling and diagnosis, invasive or non-invasive, should be offered and carried out by experienced personnel and laboratories. Conventionally, the prenatal diagnosis is achieved by DNA analysis after a chorionic villus sampling or an amniocentesis. A non-invasive approach consisting of serial two-dimensional ultrasound examinations can effectively reduce the need for invasive testing in the majority of pregnancies unaffected by homozygous α0-thalassaemia. The prognosis of α-, β- or E-thalassaemia trait in pregnancy is favourable apart from the small risks of anaemia, preterm birth, foetal growth restriction, low birthweight and bacteriuria. General obstetric care is usually appropriate. The risks of haemoglobin H disease in pregnancy are similar to thalassaemia trait. Regular monitoring of haemoglobin is required because sometimes transfusion is required for severe anaemia. In the other end of the spectrum, the risks to the mother and foetus are high for β-thalassaemia major, requiring a specialised care by a multidisciplinary team. The major concern is iron overload due to multiple blood transfusions and its associated hepatic, cardiac and endocrine dysfunction. The risk of iron overload is increased when iron chelation is stopped or reduced in pregnancy. The severity of β-thalassaemia intermedia varies from mild to severe depending on the type of β-thalassaemia mutation. Folic acid during periconception and pregnancy can prevent foetal neural tube defects and maternal anaemia respectively.
Thalassaemias, previously prevalent in Mediterranean area, India, Southeast Asia and Sub-Saharan Africa, now becomes global because of population migration.1-2 In some Southeast Asia areas, for example, the prevalence of thalassaemia trait or heterozygous carriers of α- or β-thalassaemia was 7.8% in Hong Kong,3 and 16.5% in Guangdong province of China.4 In Thailand where E-thalassaemia trait is also common, the total thalassaemia rate was as high as 25.4%.5
Thalassaemias, being characterised by the reduced synthesis of the globin chains of haemoglobin, consist of a wide spectrum of disorders ranging from asymptomatic thalassaemia trait, through haemoglobin (Hb) H disease with mild to moderate anaemia and beta-thalassaemia intermedia with variable severity, to severe thalassaemia including homozygous α0-thalassaemia and β-thalassaemia major. Homozygous α0-thalassaemia, without functional α-genes, is associated with hydrops fetalis, stillbirth or neonatal death, and severe maternal complications or rarely death.6 In β-thalassaemia major, both β-globin genes are defective either in homozygotes or compound heterozygotes, and affected individuals are transfusion-dependent.
While the risks to mother and foetus are small for thalassaemia trait,7-9 they are high for β-thalassaemia major.10-13 The objective of this article is to review the current management of thalassaemia trait, Hb H disease, and beta intermediate and major in pregnancy.
Most women with thalassaemia trait can be picked up by universal prenatal screening for thalassaemia. A mean corpuscular volume (MCV) cut-off of 80 fl or mean corpuscular haemoglobin (MCH) cut-off of 27 pg has been shown to detect all α0-thalassaemia traits and β-thalassaemia carriers,14 although some laboratories may use a higher cut-off of 82 fl for MCV. The presence of occasional Hb H inclusion bodies and elevation in Hb A2 (>3.5%) on Hb pattern are diagnostic of α0-thalassaemia trait and β-thalassaemia, respectively. The presence of large amount of Hb H inclusion suggests the diagnosis of Hb H disease. Absence of Hb H inclusion bodies cannot exclude the diagnosis of α0-thalassaemia trait, and DNA analysis is required for the diagnosis. As the MCV/MCH of some Hb E-and α+-thalassaemia trait can be between 80 and 85 fl,15 the diagnosis of the former and later require Hb pattern and DNA analysis respectively.
When a pregnant woman is found to have thalassaemia, her partner should be screened to identify whether the couple has the same type (α and β) of thalassaemia. If the partner has a normal MCV/MCH, their foetus is usually not at risk of severe thalassaemia except unusual cases of homozygous α0-thalassaemia or β-thalassaemia major due to maternal uniparental disomy or non-paternity.16 Couples discordant for α- and β-thalassaemia should be offered a DNA study to exclude coexistent α-thalassaemia in partner with β-thalassaemia.
Thalassaemia is an autosomal recessive disorder. If both the woman and her partner are heterozygous carriers of the same (α or β) thalassaemia, their offspring will be at 1 in 4 risk of having homozygous thalassaemia. If the woman is having Hb H disease and her partner is a carrier of α0-thalassaemia, their foetus is at 25% risk of having homozygous α0-thalassaemia and 25% risk of Hb H disease. If the woman is a β-thalassaemia major and her husband is a carrier of β-thalassaemia, their foetus will be at 50% chance of having β-thalassaemia major.
Counselling and prenatal testing, invasive or non-invasive, should be offered and carried out by experienced personnel and laboratories. Conventionally, the prenatal diagnosis is achieved by DNA analysis after a chorionic villus sampling or an amniocentesis. A non-invasive approach consisting of serial two-dimensional ultrasound examinations of foetal cardiothoracic ratio and placental thickness starting from 12 weeks’ gestation can effectively reduce the need for invasive testing in the majority of pregnancies unaffected by homozygous α0-thalassaemia.17-18 More recently, non-invasive testing for affected foetuses is feasible by examination of cell-free DNA in maternal plasma.
If a woman has a child affected by thalassaemia major, cord blood of the unaffected foetus after prenatal diagnosis may become a valuable source of stem cells for transplant in an affected sibling if they are HLA matched.19
Early screening is preferred to give an early relief of maternal anxiety in an unaffected pregnancy or offer an early option of termination of pregnancy for an affected pregnancy. In areas with a high prevalence of α0-thalassaemia carriers, antenatal thalassaemia screening should be offered to pregnant women even if they present after the mid trimester, in view of severe maternal risks associated with pregnancies affected by homozygous α0-thalassaemia.
If thalassaemia couple is noted before pregnancy, pre-implantation genetic diagnosis can be offered as an alternative to prenatal diagnosis. Periconceptual folic acid 5 mg is recommended to prevent foetal neural tube defects.20
α-, β- or E-thalassaemia trait
Women with thalassaemia trait usually present with mild microcytic hypochromic anaemia without clinical symptoms. Their severity of anaemia worsens as the pregnancy progresses because of the physiological haemodilution and thus drop in Hb level. Folic acid is indicated to prevent folic acid deficiency and anaemia. Blood transfusion is usually not required.
The prognosis of thalassaemia trait in pregnancy is favourable apart from the risks of anaemia and bacteriuria.7-9 Maternal anaemia is associated with preterm and low birthweight.21 The risks of foetal growth restriction (FGR), preterm birth and low birthweight are increased in thalassaemia in pregnancy.22-24 Miscarriage rate was also increased.24 In one study,25 the risk for pre-eclampsia was slightly increased in women with thalassaemia trait, especially among nulliparous and high body mass index pregnant women.
Hb H disease
In Hb H disease, only one α-globin gene is functional, and thus the degree of anaemia is more severe than α-thalassaemia trait. Regular monitoring of haemoglobin level is required, and sometimes transfusions for severe anaemia. Similar to α-thalassaemia trait, Hb H disease is associated with increased risks of FGR, preterm birth, and low birthweight.26 Besides, the perinatal mortality rate was slightly higher.26
With advance in the medical management of β-thalassaemia major, affected women can survive to age of reproduction and achieve a pregnancy.27 However, β-thalassaemia major is associated with an increased risk to both mother and baby. The major concern is iron overload due to multiple blood transfusions and its associated hepatic, cardiac and endocrine dysfunction.11-13 After cessation of iron chelation in the first trimester because of its potential risks on the foetus, new endocrinopathies including diabetes mellitus, hypothyroidism and hypoparathyroidism may develop as a result of the increasing iron burden.10-11 Besides, iron load in heart can lead to cardiac decompensation during pregnancy, and peripartum cardiac dysrhythmia when the woman is under the stress of labour.12 In addition, chronic anaemia increases the risk of FGR. Royal College of Obstetricians and Gynaecologists has published detailed guidelines on the management.28
Depending on the type of β-thalassaemia mutation, the severity of β-thalassaemia intermedia (TI) varies from mild to severe. While the phenotypes of severe TI are similar to thalassaemia major, women with mild TI are not transfusion dependent and thus do not have the problems of iron overload as β-thalassaemia major. However, if there is worsening of maternal anaemia or evidence of foetal growth restriction, regular transfusions should be considered, with the targets similar to thalassaemia major.28 FGR complicates more than half of pregnancies with TI.47 Transfusions are required in majority of women with TI, even in non-transfusion dependent women.47 In the latter, antibodies may develop, and contribute to worsening of anaemia and then repeated transfusions.47 Occasionally, life-threatening complications including haemolytic anaemia, thrombocytopenia, and enlargement of spleen occurred.48
Similar to β-thalassaemia major, women with TI also have a prothrombotic tendency, and require similar prophylactic therapy for thromboembolism.49
Ideally, the pregnancy should be planned after an adequate pre-pregnancy counselling on the risks of thalassaemia major in pregnancy and vice versa. As multiple transfusions cause iron overload resulting in hepatic, cardiac and endocrine dysfunction, comprehensive assessment for these end-organ damage should be performed, including glucose monitoring, thyroid function, cardiac function, liver function, and iron status in heart and liver.28 For glucose control, measurement of fructosamine is preferred to HbA1c as the latter is diluted by transfused blood and thus underestimated.29 It is preferred to optimise complications including diabetes, hypothyroidism, and cardiac failure.28 As iron burden will increase and new endocrinopathies may occur after stopping chelation therapy in pregnancy,10-11 aggressive chelation in the preconception stage can reduce endocrinopathies or cardiac problems.30-33
Besides, bone density scan should be performed as osteoporosis is commonly resulted from delayed and incomplete puberty.10 Vitamin D levels should be optimised.34
Red cell antibodies should also be screened because of the associated risks of haemolytic disease of foetus and newborn,35 and maternal transfusion reactions.36
Hepatitis B surface antigen (HBsAg) status should be checked, and if the result is negative, hepatitis B vaccination should be given. Checking Hepatitis C status is also required.28 All women with splenectomy should be given penicillin prophylaxis or equivalent and vaccinated for pneumococcus and Haemophilus influenzae type b.28
Subfertility due to hypogonadotrophic hypogonadism is common, and can be treated by ovulation induction therapy with gonadotrophins.37
Ideally, the antenatal care is provided by a multidisciplinary team including obstetrician, experienced midwife, haematologist, diabetologist and cardiologist.28 The frequency of antenatal visit depends on the gestational age and the severity of end-organ damage.28
Diabetes mellitus, if present, should be controlled. Hypothyroidism, if present, should be corrected.28
Serial ultrasound examinations should be offered: (a) early scan before 10 weeks’ gestation to confirm viability and exclude multiple pregnancy; (b) first trimester scan together with Down syndrome screening; (c) mid-trimester detailed scan to exclude anomalies; and (d) serial growth scans in the third trimester to exclude foetal growth restriction.28 Serial measurement of middle cerebral artery peak systolic velocity to exclude foetal anaemia is also required if red cell antibodies are found.
Haemoglobin level should be regularly monitored, and severe anaemia corrected by transfusions with an aim to maintain a pre-transfusion haemoglobin of 10 g/dl.28
Splenectomy and high platelet count (>600 x 109/l) are additional risk factors for thromboembolism in women with thalassaemia major. Low-dose aspirin 75 mg/day is recommended if a woman has one of these two risk factors, and low-molecular-weight heparin and low-dose aspirin if both risk factors are present or during antenatal hospital admissions.28
Cardiac assessment is required at 28 weeks’ gestation or when a woman complains dyspnoea, palpitation or other related symptoms. If myocardial iron loading is found on cardiac MRI, regular assessment by a cardiologist will be required.28 Low-dose subcutaneous desferrioxamine 20 mg/kg/day, a chelation therapy, should be given when there is evidence suggestive of cardiac decompensation including the cardiac T2* value falls below 20 ms,38 or falling ejection fraction or increasing ventricular volumes on echocardiography.32,39-40
When there is severe hepatic iron loading, low-dose desferrioxamine iron chelation should also be considered after 20 weeks41 because of the associated risk of myocardial iron load. Low-dose desferrioxamine has been used safely after 20 weeks, but should be avoided in the first trimester because of lack of safety data.42
Ideally, intrapartum care should be provided by a multidisciplinary team including obstetrician, experienced midwife, anaesthetist, and haematologist. β-thalassaemia major itself is not an indication for Caesarean section or induction of labour.28 The latter can be considered for an obstetric indication like FGR or diabetes mellitus.
Anaemia is common. In the presence of red cell antibodies, which may cause transfusion reactions, blood should be cross-matched. Continuous electronic foetal heart rate monitoring is recommended in view of increased risk of foetal hypoxia.43 Active management of the third stage of labour can minimise blood loss.44
When there are medical complications such as cardiomyopathy, appropriate precautions should be taken. Peripartum chelation therapy by intravenous desferrioxamine 2 g over 24 hours should be administered in view of high serum concentrations of non-transferrin bound iron, which may cause free radical damage and cardiac dysrhythmia when the woman is under the stress of labour.12
In view of a high risk of venous thromboembolism, prophylactic low-molecular-weight heparin should be given while in the hospital,45-46 for at least 10 days following vaginal delivery or for 6 weeks following caesarean section.46
Breastfeeding is safe. Although desferrioxamine is secreted in breast milk, it is not orally absorbed and thus not harmful to the newborn. Resumption of iron chelation and bisphosphonates treatment is needed after birth.13
The prognosis of thalassaemia trait in pregnancy is good, and general obstetric care is appropriate. The risks to the mother and foetus are high for β-thalassaemia major, requiring specialised care by a multidisciplinary team. If the partner is a carrier of same type of thalassaemia as the woman, prenatal diagnosis will be required. Folic acid during periconception and pregnancy can prevent foetal neural tube defects and maternal anaemia respectively.
About the authors
Dr Helena HL Lee is an Associate Consultant in the Department of Obstetrics & Gynaecology, Queen Elizabeth Hospital, Hong Kong SAR. Conflict of interest: None.
Dr Annisa SL Mak is an Associate Consultant in the Department of Obstetrics & Gynaecology, Queen Elizabeth Hospital, Hong Kong SAR. Conflict of interest: None.
Dr KY Leung is Chief-Of-Service in the Department of Obstetrics & Gynaecology, Queen Elizabeth Hospital, Hong Kong SAR. Conflict of interest: None.