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Management of Beta Thalassaemia in Pregnancy Green-top Guideline No. 66 March 2014
RCOG Green-top Guideline No. 66 2 of 17 © Royal College of Obstetricians and Gynaecologists Management of Beta Thalassaemia in Pregnancy This is the first edition of this guideline. 1. Purpose and scope The purpose of this guideline is to produce evidence-based guidance on the management of women with beta (β) thalassaemia major and intermedia in pregnancy. In this guideline, thalassaemia major women are those who require more than seven transfusion episodes per year and thalassaemia intermedia women are those needing seven or fewer transfusion episodes per year or those who are not transfused. Women who are thalassaemia carriers do not require transfusion. It will include preconceptual, antenatal, intrapartum and postnatal management and contraception in both primary and secondary care settings. It will not cover screening as the British Committee for Standards in Haematology has published guidelines for screening and diagnosis of thalassaemias.1 2. Introduction and background epidemiology Haemoglobinopathies are one of the most common inherited disorders. More than 70 000 babies are born with thalassaemia worldwide each year2 and there are 100 million individuals who are asymptomatic thalassaemia carriers. The basic defect in the thalassaemia syndromes is reduced globin chain synthesis with the resultant red cells having inadequate haemoglobin content. The pathophysiology of thalassaemia syndromes is characterised by extravascular haemolysis due to the release into the peripheral circulation of damaged red blood cells and erythroid precursors because of a high degree of ineffective erythropoiesis.3 Thalassaemia major (homozygous β thalassaemia) results from the inheritance of a defective β globin gene from each parent. This results in a severe transfusion-dependent anaemia. The heterozygous state, β thalassaemia trait (thalassaemia minor) causes mild to moderate microcytic anaemia with no significant detrimental effect on overall health. Thalassaemia intermedia is defined as a group of patients with β thalassaemia whose disease severity varies. At the severe end of the clinical spectrum of thalassaemia intermedia, patients are usually diagnosed between the ages of two and six years and, although they survive without regular blood transfusions, growth and development are impaired. At the other end of the spectrum, there are patients who are completely asymptomatic until adulthood, when they present with mild anaemia and splenomegaly often found by chance during haematological examinations or family studies. The diagnosis is dependent on the patient maintaining a satisfactory haemoglobin (Hb) level at the time of diagnosis without the need for regular blood transfusions. Patients with severe forms of β thalassaemia intermedia and those patients with thalassaemia major who had poor access to blood were previously offered splenectomy to help reduce transfusion requirements. Splenectomy is no longer the mainstay of treatment for these conditions but a considerable number of both thalassaemia major and intermedia patients have undergone splenectomy.2,4 The cornerstones of modern treatment in β thalassaemia are blood transfusion and iron chelation therapy.5 Multiple transfusions cause iron overload resulting in hepatic, cardiac and endocrine dysfunction. The anterior pituitary is very sensitive to iron overload and evidence of dysfunction is common.6 Puberty is often delayed and incomplete, resulting in low bone mass.7 Most of these women are subfertile due to hypogonadotrophic hypogonadism and therefore require ovulation induction therapy with gonadotrophins to achieve a pregnancy.8–10 Cardiac failure is the primary cause of death in over 50% of cases.11 Improved transfusion techniques and effective chelation protocols have improved the quality of life and survival of individuals with thalassaemia.12,13 The mortality from cardiac iron overload has reduced significantly since the development of magnetic resonance imaging (MRI) methods for monitoring cardiac (cardiac T2*) and hepatic iron overload (liver T2*) and FerriScan® liver iron assessment (FerriScan®, Resonance Health, Australia). These methods are now available in most large centres looking after patients with haemoglobinopathies.
RCOG Green-top Guideline No. 66 3 of 17 © Royal College of Obstetricians and Gynaecologists There are approximately 1000 individuals affected by thalassaemia major or intermedia syndromes in the UK. The absolute number of affected individuals is unclear and is currently being assessed nationally as part of the National Haemoglobinopathy Registry. Previously, the community affected was principally from Cyprus and the Mediterranean. However, currently the Asian communities of India, Pakistan and Bangladesh account for 79% of thalassaemia births with only 7% occurring in the Cypriot population who have taken advantage of the availability of prenatal diagnosis.14 High incidence areas include Greater London, Birmingham and Manchester. The NHS Sickle Cell and Thalassaemia Screening Programme in England during 2009/10 identified approximately 16 000 women as carriers of a haemoglobinopathy and partner testing was offered. 59% of screen positive women had partner testing and 1006 couples were identified as being at high risk of having a child with a clinically significant haemoglobinopathy (sickle cell disease or thalassaemia). 396 couples accepted the offer of prenatal diagnosis, which revealed 23 pregnancies affected by thalassaemia and 46 fetuses that were carriers of thalassaemia. The majority of pregnancies affected by thalassaemia major were terminated.15 3. Identification and assessment of evidence This guideline was developed in accordance with standard methodology for producing RCOG Green-top Guidelines. Databases searched included the Cochrane Database of Systematic Reviews, DARE, EMBASE, TRIP, Medline and PubMed. Search terms included: ‘beta thalassaemia’, ‘Cooley's anaemia’, ‘Mediterranean anaemia’, ‘hypogonadotrophic hypogonadism’, ‘ovulation induction’, ‘assisted reproduction’, ‘iron burden’, ‘serum ferritin’, ‘penicillin prophylaxis’, ‘iron chelation’, ‘fetal growth and measurement’ and ‘ultrasonography’. The search was limited to humans and the English language and from 1980 to July 2013. Exclusions were alpha thalassaemia or beta thalassaemia minor. There are no systematic reviews in this area and only small numbers of randomised controlled trials looking at particular interventions. The National Guideline Clearinghouse was also searched for relevant guidelines and reviews. Where possible, recommendations are based on available evidence. Areas lacking evidence are highlighted and annotated as ‘Good Practice Points’. 4. Preconception care 4.1 What are the additional risks to the woman and baby? Thalassaemia is associated with an increased risk to both mother and baby. In particular, there are the issues surrounding cardiomyopathy in the mother due to iron overload and the increased risk of fetal growth restriction (FGR). In addition, with around 9 months of little or no chelation, women with thalassaemia major may develop new endocrinopathies: in particular, diabetes mellitus, hypothyroidism and hypoparathyroidism due to the increasing iron burden.7,16 4.2 What is the optimum preconceptual care for women with thalassaemia? At each visit with the thalassaemia team, there should be a discussion and documentation of intentions regarding pregnancy. This should include screening for end-organ damage and optimisation of complications prior to embarking on any pregnancy. Each Specialist Haemoglobinopathy Centre should have a guideline for the management of pregnant women with thalassaemia. Women should be advised to use contraception despite the reduced fertility associated with thalassaemia. Fertility may be reduced in transfusion-dependent individuals where chelation has been suboptimal and iron overload has occurred resulting in damage to the anterior pituitary.8,10,17 They may require ovulation induction using injectable gonadotrophins to conceive. D P P Evidence level 2+
There is no contraindication to the use of hormonal methods of contraception such as the combined oral contraceptive pill, the progestogen-only pill, the Nexplanon® implant (Merck Sharp & Dohme Limited, Hoddesdon, Herts, UK) and the Mirena® intrauterine system (Bayer plc, Newbury, Berks, UK) in women with thalassaemia.18 Women with thalassaemia are best cared for in a multidisciplinary team setting, including an obstetrician with expertise in managing high-risk pregnancies and a haematologist. This team should provide prepregnancy counselling so that the woman is fully informed about how thalassaemia affects pregnancy and vice versa. The preconception evaluation involves a review of transfusion requirements, compliance with chelation therapy and assessment of the body iron burden. The assessment should include optimisation of management and screening for end-organ damage. At both local and specialist centres, the woman’s aspirations regarding pregnancy and contraception should be explored in consultation and discussion with the haemoglobinopathy team so that the decision making is shared. This should be done well in advance of the proposed pregnancy because a prolonged period of iron chelation therapy may be required to control iron overload prior to both induction of ovulation and pregnancy. 4.3 Are there any interventions which are beneficial at the preconceptual stage? Aggressive chelation in the preconception stage can reduce and optimise body iron burden and reduce end-organ damage. There is evidence from clinical trials that optimising body iron reduces end-organ damage and can reverse cardiac iron loading. Longitudinal studies show that patients who have been optimally chelated are less likely to suffer from endocrinopathies or cardiac problems.19–23 Due to lack of safety data, all chelation therapy should be regarded as potentially teratogenic in the first trimester. Desferrioxamine is the only chelation agent with a body of evidence for use in the second and third trimester.24–26 The optimisation of iron burden is therefore critical as the ongoing iron accumulation from transfusion in the absence of chelation may expose the pregnant woman to a high risk of new complications related to iron overload, particularly diabetes and cardiomyopathy. 4.3.1 Pancreas Diabetes is common in women with thalassaemia. Women with diabetes should be referred to a diabetologist. Good glycaemic control is essential prepregnancy. Women with established diabetes mellitus should ideally have serum fructosamine concentrations < 300 nmol/l for at least 3 months prior to conception. This is equivalent to an HbA1c of 43 mmol/mol. Diabetes mellitus is common in adults with thalassaemia. Diabetes is multifactorial, due to insulin resistance, iron-induced islet cell insufficiency, genetic factors and autoimmunity.27 Similar to women with diabetes without thalassaemia, an HbA1c of less than 43 mmol/mol is associated with a reduced risk of congenital abnormalities.28 HbA1c is not a reliable marker of glycaemic control as this is diluted by transfused blood and results in underestimation, so serum fructosamine is preferred for monitoring.29 4.3.2 Thyroid Thyroid function should be determined. The woman should be euthyroid prepregnancy. Hypothyroidism is frequently found in patients with thalassaemia. Untreated hypothyroidism can result in maternal morbidity, as well as perinatal morbidity and mortality. Patients should be RCOG Green-top Guideline No. 66 4 of 17 © Royal College of Obstetricians and Gynaecologists Evidence level 4 B Evidence level 1+ Evidence level 1- D P Evidence level 3 B Evidence level 2++