The thalassaemias

The thalassaemias are a heterogeneous group of genetic disorders of haemoglobin synthesis, named after the haemoglobin that is deficient. The mutation may result in a reduced rate of production of the affected gene or result in no chain synthesis at all (reviewed in [13]). The majority of thalassaemias are inherited in a Mendelian recessive manner. Given the diversity of genetic defects and the possibility of genetic combinations, thalassaemias, irrespective of their molecular basis, are often classified by their clinical effects into thalassaemia minor, thalassaemia intermedia and thalassaemia major. In general, thalassaemia carriers are often symptomless and fall into the minor category. Intermediate levels are more severely affected and may often have anaemia, although this does not require regular transfusion. In its major form, thalassaemia presents with a lifelong transfusion dependency.

Alpha thalassaemia

Women with one or two out of four alpha gene deletions are usually symptom free and have a normal pregnancy outcome. With Hb H Disease, where three of the four alpha-globin genes are absent, there are variable clinical features ranging from mild asymptomatic anaemia to severe transfusion-dependent anaemia, with jaundice, hepatosplenomegaly, growth restriction and bone abnormalities. Mild to moderate haemolysis is the predominant feature. This is worsened by pregnancy; so prophylactic folic acid (5 mg/day) is needed. Gallstones are not infrequent. Infections, drugs and fever may also worsen the anaemia. A fetus affected by Hb Barts with no alpha chain production (both parents carrying two alpha deletions on the same chromosome) will develop hydrops, polyhy-dramnios, and placentomegaly [14]. There is a high risk of pre-eclampsia in the mother. The fetus is also at risk of congenital abnormalities. Carriage of alpha thalassaemia is associated with an MCV of less than 80 fl (often less than 70 fl), a mean corpuscular haemoglobin (MCH) of less than 27 pg, with, very often, no evidence of anaemia and normal mean corpuscular haemoglobin concentration (MCHC). If iron deficiency is excluded, then carriage of thalassaemia should be suspected and the diagnosis confirmed with polymerase chain reaction (PCR) and globin gene analysis.

Beta thalassaemia

This condition is due to a defect in beta chain synthesis caused by heterogeneous point mutations within the beta-globin gene, with nearly 180 different mutations associated with its phenotype. It interferes with red cell maturation and increases red cell destruction within the marrow and spleen. Major forms have lifelong chronic dyserythropoietic anaemia with splenomegaly and skeletal deformity. With inadequate transfusion profound anaemia, marked skeletal deformity of the long bones and skull, recurrent infections and death occurs. With adequate transfusion anaemia is controlled but transfusion-related iron overload will result in endocrine abnormalities, pancreatic, hepatic and cardiac failure. This results in failure of pubertal growth, delayed sexual development and hypogonadotrophic hypogonadism affecting fertility. Thus only a small number of successful pregnancies are reported [15-17]. With significant left ventricular dysfunction or arrhythmias pregnancy may be best avoided. Serum ferritin reflects hepatic iron stores, but does not relate well to cardiac deposition, although MRI can now quantify cardiac iron deposition. When pregnancy does occur Caesarean section is common for cephalo-pelvic disproportion due to the small stature of the mother and the fact that the unaffected fetus has normal growth. Spinal abnormalities should be considered with neuraxial anaesthesia. With beta-thalassaemia intermedia there is a reasonable pregnancy success rate with well-controlled disease. Transfusion requirements increase with increasing gestation with the aim to maintain Hb over 10 g/dl and thereby correct anaemia, suppress hyperactive erythropoiesis and inhibit iron absorption. Most often, chelating agents are discontinued on diagnosis of pregnancy, and restarted after delivery, but folic acid supplements are required throughout pregnancy.

Beta-thalassaemia minor is usually symptom free, but anaemia is common in pregnancy [18]. Carriers have normal / low Hb, low MCV and MCH but normal MCHC. More severe anaemias may be encountered in those with dietary deficiencies. Folic acid supplementation should be prescribed (and oral iron, if ferritin low) throughout pregnancy. There is also possibly an increased risk of neural tube defects.

Screening for thalassaemia

Population screening for haemoglobin disorders has been practised for over 20 years. Carriers are reliably detected by screening red cell indices, traditionally the MCV <83 fl, but an MCH <27 pg is more reliable. Electrophoresis is then used to make the diagnosis (increased HbF and HbA2 (3.5-7% in beta heterozygotes). If the haemoglobin A2 percentage is within the normal range, and the MCH is less than 25 pg, the woman should be investigated for alpha thalassaemia trait [13]. Prenatal diagnosis (chorionic villous sample (CVS), amniocentesis, fetal blood sample (FBS)) is possible by a mutation specific polymerase chain reaction (n.b. pre-implantation diagnosis is also possible) and the diagnostic accuracy is high in specialist centres.

Sickle cell disease

Sickle cell disease varies in presentation from a lifelong crippling haemolytic disorder (characterized by crises caused by infection, aplasia, infarction and haemolysis), to a diagnosis only made on a routine blood film examination. This variation may be due to the co-inheritance of persistence of fetal haemoglobin. With repeated crises bone deformity, osteomyelitis, renal failure, myocardial infarction, leg ulceration, gallstones and cardiac failure may develop. With repeated transfusions there is an increased risk of blood borne infections and iron overload. The outcome of pregnancy in mothers with sickling disorders is heavily dependent upon the adequacy of maternal health care [19]. In the USA, a maternal mortality rate of 0.25-0.5% has been reported, with 99% of pregnancies, which were viable after 28 weeks, resulting in a live birth. Around half of the pregnancies are complicated by at least one painful crisis and hospital admission is often required. There is likely to be an increased risk of pre-eclampsia and of a small-for-date baby, possibly through placental infarction [20]. In developing countries the outcome of pregnancy with a major sickling disorder may be substantially worse with high maternal and perinatal mortality.

Sickle cell trait results in no change to the haematolog-ical indices. It is diagnosed by a positive sickle test and the demonstration of both an HbA and HbS band on gel electrophoresis.

Sickle cell disease is diagnosed by the presence of anaemia, the presence of sickled red cells on the blood film, blood film appearances of hyposplenism, a positive sickle test and the pattern of HbS and HbF, with no HbA, on haemoglobin electrophoresis. The presence of a microcytosis may suggest the co-inheritance of tha-lassaemia, or the presence of iron deficiency. Higher haemoglobin (11-13 g/dl) may indicate the presence of haemoglobin C or co-inheritance of another haemoglobin variant.

In all subjects with a major sickling disorder treatment includes the prevention of infection. This is achieved with prophylactic penicillin and the use of pneumococcal, meningococcal and Haemophilus influenzae vaccinations with antimalarial prophylaxis if appropriate. The management of a painful crisis involves adequate pain control, treatment of any infection, maintenance of oxygenation, hydration and thromboprophylaxis [21]. Regular blood transfusion is not usually required. If, however, haemoglobin is falling (indicating an increase in haemolysis) and, especially, if there is evidence of a falling reticulo-cyte count (indicating an impending aplastic phase), then transfusion should be given. When transfusion is required and the haemoglobin is already less then 5 g/dl, it may be that a top-up transfusion to 12-14 g/dl will result in sufficient dilution of the sickle cells to the desired target level of <30% of the circulating red cells. When transfusion is required at a higher haemoglobin level (8-10 g/dl), then a partial exchange transfusion should be carried out (removing 500 ml by phlebotomy while transfusing two red cell units). The mainstay of management of a pregnancy in women with a severe sickling disorder, is folic acid supplementation (throughout pregnancy), regular haemoglobin estimations, regular monitoring of fetal growth and consideration of the need for transfusion. Randomized studies have shown no benefit in prophylactic blood transfusions in pregnancy, although there may be a reduction in the frequency of vaso-occlusive events when prophylactic transfusion has been used [22]. Transfusion should be considered when there is an acute anaemia (Hb<5 g/dl), pre-eclampsia, septicaemia, acute renal failure, acute chest syndrome, recent cerebral ischaemia of arterial origin, and when preparing for surgery. Multiple pregnancy will require assessment for transfusion on a more regular basis.

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