Haemoglobin abnormalities result from either synthesis of abnormal haemoglobin (e.g. sickle cell anaemia) or reduced rate of synthesis of normal haemoglobin chains (the thalassaemias).
Problems and special considerations
Sickle cell disease
Patients with sickle cell disease are homozygotes for an abnormal haemoglobin (haemoglobin S). Heterozygotes have a significantly attenuated form (sickle cell trait), which is not normally of clinical significance except when combined with another abnormal haemoglobin (e.g. haemoglobin C). Haemoglobin S is poorly soluble in its deoxygenated form and therefore crystallises at a variable oxygen concentration dependent on relative concentrations of normal and abnormal haemoglobin within the red cell.
Haemoglobin S in heterozygotes appears to have some protective action against malaria and is therefore more common in Africa, Asia, Arabia and southern Europe, particularly coastal Greece and Turkey. The disease is characterised by haemolysis, reticulocytosis, anaemia, recurrent sepsis, vaso-occlusive and sequestration crises and hypersplenism followed by splenic infarction. Diagnosis is based on demonstration of sickling (Sickledex test) followed by haemoglobin electrophoresis.
Sickle cell disease (homozygous SS) is a particularly aggressive disease. Affected patients may not survive into their third decade. Maternal and perinatal mortality rates are variable and in some countries may reach 11% and 20%, respectively. Careful management can, however, significantly reduce the morbidity and mortality associated with the disease.
Problems in pregnancy include vaso-occlusive and thromboembolic phenomena, infection and an increased risk of obstetric complications such as preterm labour, pre-eclampsia, placental infarction and fetal loss. Cardiorespiratory morbidity includes systemic and pulmonary hypertension, and cardiomyopathy. Despite earlier evidence to the contrary, recent work has demonstrated that sickle cell trait is not associated with a higher incidence of preeclampsia, although these women may be at an increased risk of venous thromboembolism.
Thalassaemias
This disease is classified according to the haemoglobin chain affected (a or β). It is common in Mediterranean countries and also occurs in a narrow band of distribution crossing Africa, the Middle East, India, Myanmar and Southeast Asia. Its distribution therefore closely follows that of sickle cell disease, and both diseases are said to give some protection against falciparum malaria.
a-Thalassaemia
The a-haemoglobin gene is encoded twice on each chromosome 16, giving a total of four genes controlling its production. When all four genes are deleted, a-chain synthesis is completely suppressed and death occurs in utero (hydrops fetalis). Three a-gene deletions lead to a moderately severe microcytic, hypochromic anaemia with splenomegaly (HbH disease). Precipitation of relatively insoluble HbH within cells induces mild haemolysis. Crises of haemolysis associated with infection may occur. Patients with two (thalassaemia trait) and one (silent carriers) a-chain deletions are asymptomatic.
Pregnancies complicated by hydrops fetalis (Bart’s hydrops) are associated with preeclampsia, retained placenta and ante- and postpartum haemorrhage.
β-Thalassaemia
In contrast to a-thalassaemia, the β-haemoglobin gene is coded by a single gene; thus patients can be homozygous or heterozygous for the faulty gene. However, about 125 individual mutations of the β-gene have been described, which can markedly affect the clinical picture. Hence the terms thalassaemia major, intermedia and minor have been used to describe clinical pictures of varying severity. Furthermore, the geographical distribution of thalassaemia and sickle cell trait means that it is possible to have a mixed sickle cell-thalassaemia genotype.
In thalassaemia major either no β-haemoglobin chains are produced or small amounts are produced (5-30%). Anaemia results from ineffective erythropoiesis and haemolysis and inadequate supplies of haemoglobin for formed red cells. Features include skeletal abnormalities because of bone marrow hyperactivity and chronic multi-organ failure including the pancreas, liver and heart. Patients may be thrombocytopenic because of hypersplenism or thrombocythaemic following splenectomy. Thrombocythaemic patients require thromboembolic prophylaxis and may also develop arterial thrombosis including cerebral thrombosis. Frequent cannulation may make venous access difficult (many patients have permanent indwelling intravenous catheters). There is a high incidence of blood transfusion reactions and a small incidence of transfusion-related HIV and hepatitis C. Splenectomised patients are at risk of infection.
Treatment of β-thalassaemia includes frequent transfusion, with iron chelation therapy to reduce iron overload. Modern haematological management means that more women with thalassaemia major are becoming pregnant. There is an increased incidence of fetal growth restriction, fetal loss and obstetric intervention because of cephalopelvic disproportion resulting from skeletal abnormalities.
In thalassaemia intermedia there are usually few symptoms. Women may have chronic anaemia and require folate therapy in pregnancy. In severe cases, however, they may develop iron overload, with a clinical syndrome that lags behind the progression seen in thalassaemia major.
Women with thalassaemia minor have few symptoms but may have a higher incidence of fetal growth restriction.
Management options
In sickle cell disease, the haemoglobin concentration is usually maintained above 80 g/l (optimum haematocrit 0.26) with blood transfusion. Exchange transfusion may decrease the rate of maternal complications in pregnancy but does not change fetal or obstetric outcome. A detailed plan made in collaboration with a haematologist is essential for delivery. In general, patients should be warm, well hydrated, not acidotic or hypercarbic, and venous stasis should be avoided. Around a third of parturients with a history of multiple transfusions will have atypical red cell antibodies; cross-matched blood must therefore be made available for delivery. It must be noted that the use of cell salvage is not advised in women with homozygous sickle cell disease because of the potential for reinfusing sickle cells and the precipitation of sickle cell crisis. Its use in women with sickle cell trait remains controversial.
Management of a sickling crisis is by correction of the precipitating factors, organ support, analgesia and blood transfusion if required. The clinical picture of acute chest syndrome may overlap with that of pneumonia or pulmonary embolism, and therefore a high index of suspicion must be maintained.
Parenteral opioids may be used for labour analgesia but pethidine is not recommended due to its epileptogenic potential. An epidural provides analgesia without respiratory depression, although mobility is beneficial. Regional anaesthesia is preferable for operative delivery. Oxygen administration is essential postoperatively, especially after general anaesthesia. The safety of blood patch in sickle cell disease has not been assessed, but colloid patches have been used successfully.
a-Thalassaemia rarely results in maternal disease sufficient to cause significant problems with anaesthesia. Related problems such as haemorrhage and pre-eclampsia are covered elsewhere. In β-thalassaemia, haemoglobin should be kept above 100 g/l with transfusion. Complications such as thrombocytopenia, diabetes, hypothyroidism, cardiomyopathy and facial and vertebral abnormalities require the choice of anaesthesia and analgesia to be assessed on an individual basis.
Key points
• Patients with sickle cell disease should be kept warm, well hydrated, mobile and well oxygenated.
• Haemoglobin should be kept above 80-90 g/l in sickle cell disease.
• Exchange transfusion reduces maternal and fetal complications of sickle cell disease.
• Thalassaemia major causes significant multisystem compromise including cardiac, endocrine and skeletal abnormalities; it may cause intrauterine death and concomitant maternal disease.
• Non-fatal a-thalassaemias are of variable significance.
Further reading
Boga C, Ozdogu H. Pregnancy and sickle cell disease: a review of the current literature. CritRev Oncol Hematol 2016; 98: 364-74.
Royal College of Obstetricians and Gynaecologists. Management of Sickle Cell Disease in Pregnancy.
Green-top Guideline 61. London: RCOG, 2011. www.rcog.org.uk/en/guidelines-research-services/ guidelines/gtg61 (accessed December 2018).
Royal College of Obstetricians and Gynaecologists. Management of Beta Thalassaemia in Pregnancy. Green-top Guideline 66. London: RCOG, 2014. www.rcog.org.uk/en/guidelines-research-services/ guidelines/gtg66 (accessed December 2018).