Introduction

The term sickle cell disease (SCD) or disorder refers to a group of conditions caused by the autosomal recessive inheritance of the ‘sickle’ gene which is a result of a point mutation on the gene encoding the B-globin chain in haemoglobin to produce sickle haemoglobin (HbS). SCD includes homozygous HbS disease (HbSS or sickle cell anaemia) as well as the compound heterozygotes combining HbS with other abnormal haemoglobins such as HbC causing HbSC disease, HbS with B-thalassaemia causing HbSB ⁺ thalassaemia disease or HbSB ⁰ thalassaemia disease and with other rarer haemoglobins such as HbD, and HbO- ^Arab .

SCD is the most common inherited condition worldwide with the World Health Organisation (WHO) estimating at the end of the last century that over 300 000 children born each year are affected by a haemoglobinopathy (70% of which are SCD) and 250 million people (4.5% of the world population) carrying a potentially clinically relevant haemoglobinopathy gene . In the UK it is thought that there are over 12 000 individuals with the disease and that there are 300 babies with SCD born each year. It is estimated that there are 100–200 pregnancies in women with SCD each year in the UK . SCD is prevalent in those with backgrounds from tropical regions, particularly sub-Saharan Africa, India, the Caribbean and the Middle-East with two-thirds of the 300 000 affected individuals born each year being born in Africa .

Pregnancy in women with SCD has long been identified as high risk with medical and pregnancy related risks being more common compared to women without SCD. A range of foetal risks have also been reported. Studies over time have not always been consistent with qualifying that risk in pregnancy but developed countries have seen an improvement in outcome with the improvement of obstetric and haematological care and the emphasis on multidisciplinary teamwork. The challenge is that as patients with SCD live longer more will go on to become pregnant with the potential of having organ impairment by time of conception. The goal in management of a woman with SCD who is of child bearing potential and wishes to conceive is to educate the patient and the health care providers, optimise her medical condition prior to conception, manage pregnancy with a multidisciplinary approach so as to reduce the risks to mother and baby and provide safe peri- and post-natal care.

Pathology and clinical presentation

Over the first year of life in an unaffected individual foetal haemoglobin (HbF) is replaced by adult haemoglobins (HbA and HbA2). HbA is made up of 2 alpha chains and 2 beta chains whilst HbA ₂ is 2 alpha chains and 2 delta chains and HbF is made of 2 alpha chains and 2 gamma chains.

Sickle cell anaemia (HbSS disease) is due to the production of abnormal haemoglobin due to a single amino-acid substitution in the beta globin chain resulting in glutamic acid being replaced by valine at the 6th position and HbS is produced instead of HbA. Someone with sickle cell trait (a carrier of SCD) will produce both HbA and HbS and is often described as HbAS .

HbS will form complex polymers in its deoxygenated state resulting in the abnormal shape of the red blood cells seen in sickle cells. This repeated polymerisation and depolymerisation also causes the sickle cells to be more rigid. These cells often fail to move through smaller blood vessels not just due to their rigidity but also due to an increased adhesion to other red blood cells and to the vascular endothelium by increased expression of adhesion receptors . This disrupted flow then causes regional tissue hypoxia which can lead to severe pain and tissue damage.

The abnormal red blood cells are also fragile and the polymers are held together by weak forces. In SCD, the red blood cells have a greatly reduced life span (often less than 25 days compared to the 120 days of normal red blood cells) and this is the cause of the haemolytic anaemia seen in the disease. The bone marrow, despite a markedly increased erythropoiesis, cannot match production to the rate of red cell destruction .

The main sickling disorders (HbSS, HbSC and HbSBthalassaemia) have similar clinical pictures with varying severity. Patients are anaemic with notable parameters of haemolysis (reduced haemoglobin concentration, raised reticulocyte count, raised lactate dehydrogenase and bilirubin.) They are usually hyposplenic having auto-infarcted their spleen in early childhood.

HbSS is usually the more severe phenotype with patients suffering from more complications and lower baseline Hb values compared to the compound heterozygotes such as HbSC and HbSBthal. Studies that have included patients from different genotypes show that individuals with the less severe genotypes can still suffer from severe complications during pregnancy and so all patients with a sickling disorder should be managed as those with HbSS disease .

Patients suffer from both acute events (‘crises’) and chronic organ involvement and impairment. The most common crisis is a vaso-occlusive painful bony crisis which presents, with or without a trigger such as dehydration or infection, with relentless, severe pain often requiring admission to hospital and treatment with opiates. At times acute events can be life threatening and this includes not only complications from acute painful crises but also haemorrhagic or ischaemic strokes, acute chest syndromes and over whelming infection. Chronic haemolysis can lead to chronic kidney disease (proteinuria, papillary necrosis), pulmonary hypertension, retinopathy, avascular necrosis and leg ulcers .

SCD is a life limiting disease previously associated with very early mortality but patients are now surviving longer with the average life expectancy in the a study from the mid 1990s reporting a life expectancy of over 40 in those with HbSS disease (and over 60 in HbSC disease) . This is continuing to improve and most affected children born in the UK are now expected to reach reproductive age, be in better health and consequently more affected women are attempting pregnancy.

Maternal and foetal risks

There are variable reports on the risks that can affect pregnant women with SCD and the foetus but it is clearly accepted that pregnancy is riskier in those with SCD than in those without. It is also clear that outcomes are improving with time.

The evidence regarding risks to both mother and foetus in SCD comes from variety of studies which are usually observational, often retrospective and sometimes the experience of a single centre.

Women with SCD appear to be susceptible to medical complications including increased infection, venous thrombo-embolism and an increase in sickle cell related painful episodes (‘crises’) and associated increased antenatal hospitalisation. There are also reports of increased pregnancy related complications affecting themselves and the foetus including pre-eclampsia, pregnancy induced hypertension, increased foetal morbidity, foetal growth restriction, lower gestational age at delivery (pre-term labour) and increased caesarean section rates .

One American study showed a marked fall in maternal death rate from before 1972 (4.1%) and after 1972 (1.7%) that was attributed to better medical and obstetric care. The same study showed improvement in foetal and perinatal deaths from 52.7% (pre 1972) to 22.7% (post 1972) .

For these reasons pregnant women should be managed as high risk, in a unit experienced in managing women with SCD with a multidisciplinary approach. Whenever possible, pregnancies should be planned, with pre-conception counselling and medical optimisation by the patient’s haematologist. These women should be considered at risk, not just for medical complications (including increased sickle cell crises) but also for pre-eclampsia, preterm labour and small for dates babies .

Management of pregnancy

In the UK there are clinical guidelines from the Royal College of Obstetricians and Gynaecologists for the management of sickle cell in pregnancy and standards of care from both haematology and the sickle cell community .

Management of sickle cell disease during pregnancy

It is well documented that there is often an increased risk of sickle cell crises during pregnancy and increased hospitalisation rates. The patients should be educated about new triggers during pregnancy that may precipitate a crises (dehydration, vomiting, infection and over-exertion).

Acute sickle crises are not uncommon in pregnancy and as in the non-pregnant cohort; an acute painful crisis is the most common presentation. Patients should be encouraged to present for medical review early and there should be a low threshold for admission.

Crises should be managed urgently and management is generally similar to that of patients who aren’t pregnant except for extra meticulous care about what medication including analgesia is allowed during pregnancy. In the case of an acute painful crisis patients should be seen in timely fashion and have analgesia offered within 30 minutes (often crises require parenteral opiates and patients may have their own protocols or pain plans). Patients should be reviewed for underlying triggers and any suggestion of infection or dehydration should be treated. It is important to vigilant for other severe manifestations of sickle cell crises such as an acute chest syndrome (chest pain, hypoxaemia, fever, lung infiltrates on radiographs) and stroke. Patients often require supplementary hydration and oxygen as well. Life threatening crises may require urgent exchange blood transfusion and management on a critical care unit .

Patients requiring analgesia should be reviewed regularly to monitor efficacy of their medication and for any signs of toxicity. Patients who are admitted should be managed on a haematology ward if they are presenting in early pregnancy and those presenting later should be managed in a level 2 obstetric bed .

There is no conclusive evidence that routine or prophylactic blood transfusions are of benefit during pregnancy though patients may benefit on individual basis. Some studies show improvement in painful crises but no affect on maternal or foetal outcomes . Transfusion is not without risk or burden; in particular the risk of alloimmunisation (the formation of additional red cell allo-antibodies) can be significant. Patients with SCD are immunogenic and it is not uncommon for them to form antibodies that can lead to delayed haemolytic transfusion reactions, haemolytic disease of the foetus and the new born and also make future cross matching of blood difficult. Blood is routinely fully matched for rhesus antibodies and Kell in the UK to reduce this risk.

Transfusions are usually reserved for the acute management of severe crises and this is often an exchange transfusion (to reduce the HbS fraction as well as raising the Hb and haematocrit). An exchange transfusion is the gold standard treatment for a life threatening crisis such as stroke or acute chest syndrome. Top up transfusions may be needed for the treatment an episode of acute anaemia. Acute anaemia may be due to severe haemolysis, sequestration or infection with parvovirus – B19. This virus is a self-limiting infection that temporarily halts red blood cell production for approximately 10 days with an associated reticulocytopenia. If an infection with parvovirus is confirmed in pregnancy, there is a risk to the foetus as well and patients should be managed by a foetal medicines unit as well .

Other roles for transfusion in SCD and pregnancy include the continuation of a transfusion programme for those managed that way prior to pregnancy, consideration of prophylactic transfusions in those with severe disease prior to pregnancy, those with a twin pregnancy (with an expected higher complication rate) and those who needed hydroxycarbamide prior to pregnancy. Those who need an emergency transfusion for the management of an acute severe crisis usually go on to have regular transfusions for the rest of the pregnancy .

Patients can suffer from any of the complications of SCD during pregnancy and so involvement of haematologists as part of their multidisciplinary care is essential.