Thalassaemia is one of the most common genetic blood disorders affecting women's ability to conceive and progress through a normal pregnancy and birth (Hanprasertpong et al, 2013). Currently, there are approximately 269 million carriers of thalassaemia worldwide; the condition affects approximately 4.4 of every 10 000 live births throughout the world, and a predicted 900 000 births will have clinically significant thalassaemia disorders expected to occur by 2025 (Vichinsky, 2005). Initially thought to be a disease originating from Mediterranean regions, migration of populations throughout Asia and Africa has seen the prevalence of thalassaemia spread to countries previously considered low in rates of diagnosed cases (Piel et al, 2013). Thalassaemia encompasses a group of autosomal-recessive conditions involving the abnormal production of red blood cells and reduced haemoglobin levels (Machin, 2014). The disease presents with various physical symptoms depending on the acuity of the condition, and is divided into three diagnostic groups determined by the level of severity of symptoms and degree of systemic involvement in the condition (Chakrabarti et al, 2014). These groups categorise thalassaemia into minor, major and intermedia conditions, classifying a range from asymptomatic carriers (thalassaemia minor) to infusion-dependent people with reduced prognosis and early morbidity (thalassaemia major). The disease simplified is a mutation in erythropoiesis caused by reduced or absent alpha and beta globin chains that combine to form a red blood cell (Voskaridou et al, 2014). Haemoglobinopathies occur, which cause the onset of thalassaemia traits.
The management of women diagnosed with thalassaemia is complex, requiring a multidisciplinary approach to care as the potential for maternal and fetal complications present risks during pregnancy and birth. Haematological disorders involve specialist care outside the scope of midwifery practice; therefore, collaborating with obstetric specialists, haematologists and appropriate allied health professionals will provide women with holistic management of the disease.
Clinical manifestations
Worldwide estimates suggest thalassaemia is present in up to 6.5% of the human population (Boe, 2013), with various degrees of clinical manifestation depending on the level of acuity at diagnosis. Women can remain silent carriers of the disease until childbearing years when pregnancy induces symptomatic haematological and coagulation changes, leading to diagnosis of thalassaemia. Anaemia is the most common diagnostic indication of thalassaemia, causing symptoms of pallor, lethargy and shortness of breath; reduced haemoglobin (Hb) levels determine the severity of the disease and classification of thalassaemia type, with the basic defect being ineffective red blood cell production leading to low Hb levels (Koh et al, 2013).
The effects of thalassaemia on both the woman and the fetus are summarised in Table 1, and discussed in more detail below.
| Maternal effects | Fetal effects |
|---|---|
| Delayed maturation of sex organs or infertility | Genetic inheritance of thalassaemia traits |
| Cardiac failure and arrhythmias | Anaemia |
| Pulmonary hypertension (leading to pre-eclampsia) | Intrauterine hypoxia |
| Reduced efficiency of pancreas (diabetes mellitus) | Intrauterine growth restriction |
| Enlarged and dysfunctional liver (cirrhosis, cholestasis) | Spontaneous abortion |
| Hypothyroidism | Preterm birth |
| Osteoporosis and abnormal bone growth (decreased bone density) | Infection from invasive procedures (amniocentesis, chorionic villus sampling) |
| Increased bone and joint pain during pregnancy | Macrosomic growth |
| Anaemia | Macrocephaly |
| Leg ulcers and skin pigmentation | Fetal Hb Barts hydrops fetalis (extreme fetal coagulopathies) |
| Thrombolytic episodes (cerebral vascular accidents, deep vein thrombosis) | |
| Increased risk of obstructive labour and instrumental birth |
Maternal risk factors
Despite medical innovations, the management of thalassaemia remains associated with significant risk factors for women during pregnancy, birth and the postnatal period. The Royal College of Obstetricians and Gynaecologists (RCOG) has published guidelines on the management of thalassaemia during pregnancy and recommends that women be considered high-risk and managed with multidisciplinary health-care involvement (Ansari et al, 2016).
Maternal and fetal outcomes are determined by the level of collaborative assistance women receive during pre-conception and antenatal care, with early intervention a primary factor in optimal outcomes. The major risks for maternal complications stem from organ damage caused by excessive iron stores deposited in target organs and surrounding tissue (Leung and Lao, 2012). The risks of cardiac, hepatic, endocrine and bone complications are exacerbated by repetitive blood transfusions and systemic iron overload caused by an imbalance in normal haemopoiesis (Eissa and Tuck, 2013). Therefore, this is amplified during pregnancy when systemic changes are occurring to maternal circulation, skeletal stability and cardiac requirements.
Anaemia during pregnancy is an obstetric risk amplified by thalassaemia, with many women who were previously asymptomatic needing transfusions to maintain therapeutic Hb levels. Transfusion of blood during pregnancy is more frequently indicated to maintain haemostasis and avoid an increase in cardiac exertion secondary to low circulating oxygen levels (Patterson et al, 2014). Pregnant women are also more susceptible to thromboembolism relating to increased plasma volumes and coagulopathies that occur as part of normal circulatory changes in blood composition and volume during pregnancy (Pillai, 2016). Women with thalassaemia have an increased risk of thrombolytic episodes due to abnormal production of red blood cells that produce and shed prothrombolitic agents. Clinically, this can present as deep vein thrombosis, pulmonary hypertension and cerebral vascular accidents (Pillai, 2016).
Risks associated with cardiac failure are the primary concern for women with thalassaemia during pregnancy. Iron-induced cardiac failure has been found to be responsible for up to 67% of all deaths associated with thalassaemia (Sayani et al, 2009), and these symptoms are aggravated during pregnancy. Heart failure and arrhythmia can occur as a result of increased demands on circulatory requirements, and damage to the heart can occur from an overload of iron. Another major risk for women diagnosed with thalassaemia is endocrine dysfunction leading to the development of diabetes mellitus, hypothyroidism and a reduced efficiency of endocrine glands (Li et al, 2014). Therefore, early diagnosis and management of thalassaemia during pregnancy can minimise symptoms that cause harmful outcomes on fetal development and maternal health.
Osteoporosis is a lifelong risk for women with thalassaemia and, during pregnancy, increased demands for calcium from the developing fetus place women at risk for further calcium deficiency and decreased bone density (Inati et al, 2015). This can cause fractures, increased pain and aching for women during pregnancy, as weight gain and hormonal changes soften skeletal structure, placing more pressure on pelvic and vertebral bones. There are also significant numbers of women with thalassaemia diagnosed with cephalo-pelvic disproportion, caused by abnormal bone growth in the maternal skeletal structure, which alters pelvic size and diameter, and leads to higher rates of caesarean section (Zafari and Kosaryan, 2014).
Fetal risk factors
The risks of fetal anomalies associated with thalassaemia are dependent on inherited genetic factors and parental health, determining the severity of symptoms and overall growth of the fetus. Maternal wellbeing during pregnancy has a large impact on fetal development with symptoms of anaemia, diabetes mellitus, iron overload and drug therapy potentially interfering with fetal growth. Macrosomic growth, intrauterine hypoxia, fetal abnormalities or miscarriage due to drug therapy are risks which present as the pregnancy progresses and fetal demands increase on the maternal circulation (Thompson et al, 2013). Fetal Hb Barts hydrops fetalis is a rare thalassaemia mutation that can occur during pregnancy, causing extreme haemoglobin instability, severe anaemia and hypoxia to the fetus (Alberry et al, 2013). The miscarriage rate is high for this condition as fetal prognosis is incompatible with life (He et al, 2015). Given the high risk of fetal anomalies and potential for maternal morbidity, early detection in the first trimester offers parents the chance to make informed decisions regarding high-risk pregnancies and known poor fetal outcomes.
Intrauterine growth restriction, preterm labour and an increased risk of infection from invasive procedures during pregnancy can potentially harm growth and development of the fetus, causing spontaneous abortion or early labour (Hanprasertpong et al, 2013). Diagnostic technology—for example, amniocentesis and chorionic villus sampling—should be replaced by a single maternal blood sample, reducing the risk of infection to the fetus (Rund, 2016).
As thalassaemia is an autosomal recessive genetic disorder, the risk of inheriting the disease is a consideration requiring counselling and antenatal screening. This can be an ethically sensitive dilemma for midwives and the women wanting to conceive and birth a healthy baby. Early detection gives women the choice to terminate pregnancies where fetal development is severely compromised, reducing the transfer of severe thalassaemia traits. This requires midwives to communicate with sensitivity and respect, as such decisions are life-changing for women and their families.
Drug therapy
Developments in the management of thalassaemia have seen improved outcomes for childbearing women. Pharmacological support for women diagnosed with thalassaemia increases reproductive potential, and women more commonly experience normal pregnancies with healthy fetal outcomes (Davis, 2014). Pregnant women with thalassaemia are often on a range of drugs to maintain their health, and those deemed teratogenic should not be prescribed during pregnancy and breastfeeding.
Iron chelation therapy is the most common pharmacological treatment, reversing the primary symptom of iron overload in thalassaemia. Iron chelation medicines, such as deferoxamine, deferiprone and deferasirox, bind to excessive stores of iron and facilitate its excretion to normalise iron levels in the body, and are the three current iron-chelating agents used globally (Borgna-Pignatti and Marsella, 2015). It is recommended that iron chelation therapy be maximised pre-conception to establish balanced iron levels in women, and then withheld during pregnancy, as there are divided opinions regarding possible adverse effects on the developing fetus. However, if women are considered high risk for cardiomyopathy and irreversible organ damage, iron chelation therapy may be considered (Fisher et al, 2013).
Folic acid is recommended for women with thalassaemia before and during pregnancy, as are calcium and vitamin D supplements, to support maternal bone density and fetal development (Egitto and Grogan, 2016). In the UK, folic acid and vitamin D are recommended for all women planning to conceive and during pregnancy (Richardson, 2015). Vitamin C is not recommended during pregnancy for women with cardiac symptoms resulting from thalassaemia, as it increases the risk of cardiomyopathies (Elalfy et al, 2016). Prophylactic benzyl penicillin may be recommended for women showing signs of infection, splenomegaly and immune insufficiencies (Smith et al, 2013).
Women at risk of thromboembolism can receive low-weight heparin prophylaxis treatment if clinically indicated, although this is not generally encouraged during pregnancy (Chowdary et al, 2015). Immunisation status should be checked and updated to include pneumococcal Haemophilus influenzae, hepatitis B and meningococcal C vaccines, as these provide protection from possible infection transfer during blood transfusions that may become necessary throughout pregnancy (Higgs et al, 2012).
Erythropoietin is a controversial drug known mostly for its use with elite athletes to enhance performance. In its synthetic forms (Epogen, Eprex, Procrit), it acts as a haemopoietin agent, stimulating the proliferation of red blood cells in bone marrow to increase oxygenation transfer throughout the body (Costa, 2013). Research into its effectiveness in treating abnormal blood haemoglobinopathies such as thalassaemia is promising (Fibach and Rachmilewitz, 2014); however, its high cost and subcutaneous injection route of administration creates barriers for its use and choice of treatment. Limited research (Sienas et al, 2013) has shown adverse effects on fetal development; however, the potential for the drug's short-term use during pregnancy may be warranted if maternal wellbeing is at risk.
Angiotensin converting enzyme (ACE) inhibitors—for example, Captopril and Enalapril—are common medications used to treat women with cardiac and endocrine symptoms in thalassaemia (Noori and Keshavarz, 2015). These drugs are not recommended during any stage of pregnancy as they have caused or are suspected of causing irreversible fetal damage (Morton and Hague, 2015). Hydroxycarbamide (hydroxyurea) is a cytotoxic drug successfully used to reduce the need for blood transfusion by improving Hb levels and erythropoiesis in individuals diagnosed specifically with thalassaemia major; however, it is not recommended for use with pregnant women owing to known teratogenic effects (de Dreuzy et al, 2016).
Alternative therapies
Complementary and alternative medicine (CAM) is becoming a popular option as either stand-alone treatment or in combination with pharmacological interventions used to treat thalassaemia. The most controversial treatment currently being used is Al-hijamah, or wet cupping therapy, a traditional Arabic practice of purifying blood and plasma pathogens, sometimes called blood-letting (El Sayed et al, 2014a). The term refers to the detoxification of blood through the application of sucking cups placed on various anatomical sites that facilitate the excretion of excessive iron stores, which is the dominant symptom of thalassaemia (El Sayed et al, 2014b). Wet cupping therapy has no known adverse side effects, is economical, requires no technology and is currently being researched to support its efficacy in thalassaemia treatment. Therapeutic benefits have been identified in circulation, respiration, haemotologic and anti-inflammatory improvements when used with a variety of diseases associated with blood chemistry abnormalities. There are also reported therapeutic benefits of combining oral honey with Al-hijamah for treatment of thalassaemia, specifically symptoms relating to iron overload, diabetes mellitus and lowered immunity status (El Sayed et al, 2014a). While there are reported benefits associated with this therapy, there is a dearth of research evidence to support it.
Chinese medicine has also been used to treat the symptoms of anaemia and haemolysis in thalassaemia with reported positive results. Yisui shengxue granule is a kidney and bone marrow replenishing therapy, consisting of herb granules that are taken orally over a 3-month period, and clinical symptoms of anaemia and erythropoiesis have been found to be significantly improved post therapy, particularly the composition of blood cells and structure (Chu et al, 2014).
There is a lack of robust, scientific evidence available to support CAM in midwifery practice (Hall et al, 2012). This, combined with the often poor methodological quality of primary studies concerning CAM, means that all therapies should be treated with caution in clinical practice.
Recent advancements in the diagnosis and management of thalassaemia are generating hope for childbearing women regarding their ability to conceive and experience a normal lifespan and quality of life. Genetic therapies, macrophage targeted treatments, heat-shock proteins and JAK2 inhibitors are subjects of innovative studies currently being trialled and showing positive results for improved health and, possibly, curative properties for thalassaemia in the near future (Rund, 2016).
Postnatal complications and breastfeeding issues
For most pregnant women with thalassaemia, birth is uncomplicated and requires similar intrapartum care to that provided for other women. Postnatally, however, surveillance and monitoring is required as there is an increased risk of unstable coagulopathies (Davis, 2014). Postpartum haemorrhage and symptoms associated with excessive bleeding can be a concern, and blood transfusion may be indicated if Hb levels are significantly low. Conversely, women can also be at risk of developing venous thromboembolism owing to a potentially hypercoagulable state. Heparin prophylaxis is recommended for 6 weeks postpartum in these women to prevent the risk of abnormal clotting and embolism (Eissa and Tuck, 2013).
Iron chelation therapy should be recommenced within 24 hours of birth to facilitate return of normal iron levels. Deferoxamine is the preferred choice of medication as this can be administered orally and does not interfere with breastfeeding or transfer across to the neonate. Women require follow-up management of additional complications that developed throughout pregnancy. Diabetes mellitus, cardiomyopathies and organ dysfunction require specialist care and collaboration between health professionals to optimise maternal wellbeing and return of haemostasis during the postnatal period (Voskaridou et al, 2014).
Conclusion
Global developments in the diagnosis and treatment of thalassaemia have seen vast improvements in the management of pregnant women diagnosed with thalassaemia. Normal pregnancy and birth can be achieved with collaborative health care and a multidisciplinary approach to women with thalassaemia. However, women remain high risk for maternal and fetal morbidity if not appropriately managed. Pregnancy outcomes are improved with early diagnosis, specialist involvement, and follow-up care of maternal and fetal health. Although pharmacological treatment is the first line of therapy in managing symptoms of thalassaemia, research into the value of complementary and alternative medicine suggests that non-pharmacological therapies may provide cost-effective, low-risk support to women during pregnancy and birth, with beneficial outcomes for both maternal and fetal wellbeing.