Sickle cell disease (SCD) is an inherited disorder of haemoglobin S synthesis. The genetic defects of haemoglobin (Hb) are the most common genetic disorders worldwide and homozygous sickle cell anaemia (HbSS) is the most frequent (Hoffbrand 2011).
Description of the condition
The inherited disorders of haemoglobin S are either in the homozygous form (HbSS) or in combination with another Hb variant such as haemoglobin C (HbSC), D (HbSD) or β-thalassaemia (HbSβo-thalassaemia and HbSβ+-thalassaemia). The homozygous form, HbSS (sickle cell anaemia), is the most common followed by HbSC and the HbSβ-thalassaemias (Hoffbrand 2011).
SCD is a relatively prevalent condition in Africa, the Mediterranean and the Caribbean; about 10% of the Jamaican population is estimated to carry Hb S. However, the disease prevalence now has a more global outlook as a result of immigration (RCOG 2011). Population estimates in the United States of America indicated that 72,000 to 98,000 people have SCD (Hassel 2010). Similarly, the United Kingdom currently has the largest population of people with SCD in Europe, a population that increased from approximately 5000 in 1995 (Howard 1995) to about 12,000 to 15,000 in 2011 (RCOG 2011).
Pregnancy in women with SCD carries significant risks of maternal and perinatal morbidity and mortality, particularly in resource-poor settings where facilities are lacking to adequately manage associated complications (Afolabi 2009; Odum 2002). Complications that may arise include various forms of crises resulting from haemolysis, vascular occlusion and sequestration (massive pooling) of damaged red blood cells in the liver and spleen, all having the potential to cause profound anaemia (Hoffbrand 2011). Another recognised complication, and an important cause of death in women with SCD, particularly in women with sickle cell anaemia is acute chest syndrome (ACS) which is characterised by cough, chest pain, dyspnoea, fever, increasing anaemia and fluid infiltrate on chest X-ray, all resulting from the sickling of red cells in the lungs. ACS is the most common cause of death in patients with SCD after puberty (Hoffbrand 2011), and it occurs in 7% to 20% of pregnant women with SCD (RCOG 2011). While all these complications are not specific to pregnancy in women with SCD, they are more frequent and exacerbated during pregnancy and are all major causes of severe ill health and death among women with the condition. Although the complications could arise in all forms of SCD, they are more frequent and severe among those with sickle cell anaemia (HbSS) (Nomura 2009; Odum 2002; RCOG 2011).
Pregnancy-specific complications include increased risk of spontaneous abortion (Serjeant 2004), urinary tract infection (Howard 1995) and proteinuric hypertension and thromboembolism (RCOG 2011). Pregnant women with SCD also have an increased risk of preterm birth, repeated antepartum hospitalisations, induction of labour, caesarean section and postpartum infection (ACOG 2007; Asnani 2011; Barfield 2010). As a result of chronic anaemia, women with SCD are also more likely to require blood transfusions (Grossetti 2009) and subsequent alloimmunisation of red cells which also increases the risk of haemolytic disease of the newborn. Fetal complications include intrauterine growth restriction, prematurity and its sequelae, low birthweight and death (ACOG 2007; Barfield 2010; Howard 1995).
Painful crisis secondary to vascular occlusion is the most frequent manifestation of SCD which is often precipitated by conditions such as infection, stress, acidosis, dehydration and hypoxia (low oxygenation state) (Hoffbrand 2011). Furthermore, visceral sequestration crises as a result of pooling of blood within the reticuloendothelial system (liver and spleen), as well as haemolytic and aplastic crises, are all associated with worsening anaemia (Hoffbrand 2011) that often have to be corrected to avert severe morbidity and mortality.
In spite of these complications, successful pregnancy outcomes have been reported in up to 57% of women with HbSS and 85% of women with HbSC (Asnani 2011; Serjeant 2004). These outcomes have been achieved with interventions to improve the complications occurring in these women. Measures to improve pregnancy outcomes have included the use of analgesia, intravenous fluid replacement, antibiotics and packed red cell transfusion for treatment of vaso-occlusive complications (ACOG 2007; RCOG 2011). However, there is no compelling evidence from randomised trials that regimens comprising the various combination of these interventions actually improve pregnancy outcomes (Marti-Carvajal 2009).
Description of the intervention
Pregnancy in women with SCD requires management by a multi-disciplinary team of haematologists, obstetricians and anaesthetists to reduce the likely complications. Although longitudinal follow-up studies of women with HbSC have reported a relatively benign course of pregnancy (Serjeant 2005), complications occurred in 96.6% of HbSS pregnant women (Odum 2002). While pregnant women with HbSβ+-thalassaemia share similarly mild clinical behaviour with those with HbSC, the clinical course of pregnancy in HbSβo-thalassaemia is quite similar to women with sickle cell anaemia (Hoffbrand 2011).
Blood transfusion for women with SCD during pregnancy could either be selective or prophylactic. Selective blood transfusion is performed when conditions such as anaemia, pain crises, or ACS necessitates blood transfusion. On the other hand, prophylactic blood transfusion is performed with the aim of optimising the oxygen-carrying capacity of the blood and reducing complications related to sickling of the red cells and anaemia in an asymptomatic pregnant woman with SCD. Prophylactic blood transfusion is often started early in pregnancy and performed at intervals to reduce the chances of transfusion on an emergency basis. Whenever blood is transfused, it is aimed at reducing the proportion of HbS in the circulation to less than 40% and also to achieve an Hb concentration of 10 gram/decilitre (ACOG 2007; Grossetti 2009).
Prophylactic blood transfusion can either be simple "top-up" (transfusion without prior withdrawal of blood from the recipient) or exchange blood transfusion (Howard 1995). Prophylactic exchange blood transfusion was first proposed by Ricks in 1965 (ACOG 2007). He recommended exchange blood transfusion four to six weeks before the delivery date to optimise the woman's Hb level towards the end of pregnancy when complications are most frequent (ACOG 2007). Prophylactic transfusion reduces the risk of sickling by reducing maternal erythropoiesis and thereby, increasing the partial O2 pressure (Grossetti 2009). It has the advantage of avoiding the risk of alloimmunisation from transfusion of inadequately phenotyped red blood cells and the transfusion-related reaction or overload that could occur with emergency transfusion (Grossetti 2009).
How the intervention might work
Depending on the institutional policy, prophylactic blood transfusion could be started during the first, second or beginning of the third trimester of pregnancy (Grossetti 2009; Howard 1995; Ngo 2010). When it commences during the third trimester of pregnancy, it preferably begins at 28 weeks (Gilli 2007) and repeated every two to four weeks until delivery. This intervention carries the risks of iron overload (from the woman's inability to adequately excrete iron released from sickled and dead red blood cells), blood-related infections and alloimmunisation (due to exposure to multiple sources of allogeneic blood) with significant cost implications, especially in resource-poor settings. Compliance to schedules of transfusion and the need for repeated hospitalisation are other issues of concern for affected women as well as health services (Makani 2007). On the other hand, selective blood transfusion which has a comparatively lower risk of transfusion-related morbidities, may become indicated and performed at a time when it is already too late to improve maternal, or fetal outcomes.
Why it is important to do this review
Pregnant women with SCD are at increased risk of severe complications as a result of chronic anaemia, sickling of red cells and their consequences. Repeated blood transfusions to optimise the Hb level is an intervention to avert some of the complications seen, despite the potential morbidity that such practice constitutes. In spite of its use, the benefit of prophylactic blood transfusion to improve the outcome of pregnancy is uncertain. For instance, 11.6% of women who had prophylactic transfusion still needed emergency blood transfusion for severe anaemia during the same pregnancy. This is partly related to the lack of consensus among clinicians, hospital and even countries regarding the optimal transfusion regimen which makes evaluation of their impact on pregnancy outcomes difficult and the fact that the usefulness of the practice had been largely derived from observational studies that have inherent limitations for policy formulation on the subject (Cunningham 1983; Grossetti 2009; Howard 1995; Ngo 2010). The existing variation in the approaches to care requires a systematic evaluation of the evidence in order to balance effectiveness with safety. This systematic review will replace an outdated and withdrawn review (Mahomed 2006) and intends to evaluate the use of blood transfusion in pregnant women with SCD based on rigorous studies derived from up-to-date searches.