Sickle cell disease in pregnancy

Authors

Eugene Oteng-Ntim
Apryll R. Chase
Jo Howard
Elizabeth N. Anionwu

Eugene Oteng-Ntim is (Consultant Obstetrician)  and Apryll R. Chase is  Specialist registrar  at the Women’s Services, and Jo Howard is Consultant haematologist at the Department of Haematology, Guys & St Thomas’ NHS Foundation Trust, London, and Elizabeth N. Anionwu is Emeritus professor  at the Mary Seacole Centre for Nursing Practice, Thames Valley University, London, UK  

Abstract

With advances in management, the majority of women in the UK with sickle cell disease now survive to have children. The high risk of fetal and maternal sequelae in their pregnancies mandates multidisciplinary management involving an obstetrician, a haematologist, an anaesthetist and a haemoglobinopathy specialist nurse. Hydroxycarbamide, a new treatment for sickle cell disease, is contraindicated in pregnancy. Exchange transfusion may be indicated in women with serious obstetric or haematological complications. In those with sickle cell disease, the entire pregnancy is a high-risk period that warrants close monitoring. It is thus important for every obstetrician to be familiar with the condition.

Keywords

Sickle cell disease

Pregnancy

Screening

Pathophysiology

Clinical presentation

Management

Introduction

Sickle cell disease (SCD) is among the most common inherited disorders in the UK.  Currently the UK has the highest number of people with sickle cell disease in Europe, with approximately 0.2% of those of African-Caribbean origin being affected. With advances in management, the majority of women with sickle cell disease in the UK now survive to have children. However, their pregnancies are associated with a high incidence of maternal and perinatal morbidity and mortality. In women with sickle cell disease, the entire pregnancy is a high-risk period that warrants close monitoring. With improved medical care, the frequency of sickle crises in pregnancy has decreased significantly; but they may still occur and constitute an obstetric emergency. Therefore, it is important for every obstetrician to be familiar with the condition. We review the pathophysiology, clinical presentation and management of sickle cell disease in pregnancy.

Normal haemoglobin

Haemoglobin is composed of four interlocking polypeptide chains, each of which has an attached haem molecule (which binds to, and subsequently releases, oxygen). The haem consists of an iron molecule attached to four pyrrole rings. Two pairs of globin chains (two α and two β) attach to the pyrrole rings and form haemoglobin. The physiological function of the haemoglobin molecule depends not only on the integrity of the haem moiety, but also on the amino acid sequence, which determines the structure of the globin chains, and the interaction between the four subunits of haemoglobin.

In the normal human, from 6 months of age, 95–97% of the total haemoglobin is haemoglobin A (HbA). The two pairs of globin chains in HbA are called the α and β chains. The remaining haemoglobin consists of HbA2 (2%: two α and two δ globin chains) and fetal haemoglobin (HbF, < 1.5%; two α and two γ globin chains). The amino acid sequences of these four different polypeptide chains have been determined; the α chain (identical in each of these three types of haemoglobin molecule) has 141 amino acid residues and its genetic locus is located on chromosome 16, whereas the β, δ and γ chains each have 146 residues and their genetic loci reside on chromosome 11.

Sickle haemoglobinopathy

There are over 100 structural haemoglobin variants described in the literature, many of which are not pathological. Haemoglobin S (HbS) is the most common of these variants and occurs when the negatively charged glutamic acid is replaced by the neutral amino acid valine at the sixth position from the N-terminus in the β chain. Haemoglobin C (HbC) is formed when glutamic acid is replaced by lysine. These structural changes are inherited as autosomal recessive traits.

The term sickle cell disease (SCD) refers to the inheritance of haemoglobin S, either in the homozygous form (HbSS) or as a compound heterozygote with another haemoglobin variant. The haemoglobin variants which cause SCD in combination with HbS are haemoglobin C, haemoglobin D, haemoglobin O-Arab and b-thalassaemia. These compound heterozygotes are referred to as HbSC disease, HbSD, HbS-OArab and HbSb-thalassaemia, respectively. There are many different b-thalassaemia genes, some causing a complete lack in production in b-globin (bO mutations) and some causing a decrease in production of b globin (b+ mutations). The bO mutations in combination with HbS are known as SbO-thalassaemia and give a more severe phenotype than HbSb+-thalassaemia. HbSS is the most common type of SCD followed by HbSC- and HbS-thalassaemia. HbSS- and HbSbO-thalassaemia show the most severe phenotype, but all of the complications of SCD can occur in all of the genotypes. SCD occurs in people of African, Asian and Middle Eastern descent, and carrier frequencies are shown in Table 1.

Table 1 Carrier frequencies of sickle haemoglobinopathies in some ethnic groups (data from Department of Health, 1993).

Haemoglobin type	Ethnic group	Estimated carrier frequency
Sickle cell trait (AS)	African-Caribbean	1 in 10
	West African	1 in 4
	Cypriot	1 in 100
	Pakistani, Indian	1 in 100
C trait (AS)	African-Caribbean	1 in 30
	Ghanaian	Up to 1 in 6
D trait (AD)	Pakistani, Indian	1 in 100
	White British	1 in 1000

Pathophysiology

The basic pathological processes in sickle cell disease are chronic anaemia and blood vessel occlusion leading to acute and chronic organ damage.

Chronic anaemia

In the oxygenated state, the solubility of HbS is nearly equal to that of HbA, and its oxyhaemoglobin form has the ability to function in a physiological manner. In the deoxygenated state, however, its solubility falls to one-fiftieth of that of HbA, resulting in aggregation to form liquid crystals. This causes the erythrocytes to assume the classical ‘sickle shape’. Re-oxygenation can restore these erythrocytes to their normal shape.
Repetitive cycles of sickling and polymerization lead to membrane rigidity, and irreversible sickle cells are eventually formed. These permanently damaged erythrocytes are then cleared by the reticuloendothelial system. Thus, the average lifespan of the red blood cells of sickle cell patients is 17 days compared with the 120-day lifespan of normal erythrocytes. This results in a chronic compensated anaemia (6.5–9.0 g/dl in HbSS) as the marrow’s capacity to generate new red blood cells is limited. As the red blood cells are removed, their concentration falls, reducing the rate of destruction until it just balances the maximal rate of red blood cell production by the marrow. Bone marrow aspirate will show erythroid hyperplasia and the blood film will show sickle-shaped red blood cells and polychromasia.

Painful sickle cell crisis

The most common manifestation of SCD is the acute painful crisis which occurs secondary to vaso-occlusion. These painful crises can be precipitated by infection, stress, dehydration and cold damp conditions. There is an increased risk of painful crisis during pregnancy, especially in the latter half of pregnancy and the puerperium, and they may even occur in women who have previously had very few episodes of sickle pain.

Acute chest syndrome

This life-threatening complication presents with cough, chest pain, dyspnoea, fever, worsening anaemia, leucocytosis, audible crackles and/or bronchial breathing on examination, and a florid infiltrate on the chest X-ray. The patient may need assisted or mechanical ventilation. This is among the most common causes of maternal death. The syndrome arises due to sickling in the lungs, possibly combined with infection. Although there are thought to be many causes, the underlying features are not totally understood. Treatment is often inadequate, although early detection and treatment may reduce the severity and prevent death. Dramatic improvements have been noted following exchange blood transfusion, therapeutic subcutaneous doses of heparin and antimicrobial agents.

Endocrine and metabolic changes

It is currently thought that iron overload is the main underlying cause of endocrine dysfunction in patients with SCD. Increased numbers of transfusions have been associated with greater risk of endocrine organ failure.
Growth failure and delayed pubertal development, gonadal failure, diabetes and carbohydrate intolerance and primary hypothyroidism have been documented.  Generally, treatment consists of replacement of particular hormones and improvement of nutritional status. An unanswered question is whether patients with SCD are prone to endocrine pathology in the absence of iron overload due to crises in the glands. Future work may allude to this.

Other complications

In patients with SCD splenic infarction has usually occurred by 5-6 years of age, leading to a lifelong increased risk of infection, especially due to encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae. Occasionally, splenomegaly or splenic sequestration, which is associated with profound anaemia, can occur in adults when splenic autoinfarction has not taken place.
Gallstone formation is common in SCD secondary to increased red cell breakdown and can lead to acute cholecystitis. Aplastic crises occasionally occur during pregnancy associated with infection of parvovirus B19, and are characterized by a rapidly falling haemoglobin level secondary to an aplastic bone marrow.
SCD is also associated with chronic organ damage and this can cause renal dysfunction, pulmonary hypertension, chronic lung disease, retinopathy and avascular necrosis. Any of these complications can occur de novo, or worsen during pregnancy, so the caregiver must be aware of them. Neurological complications such as stroke or silent infarction are also common in SCD, although there is no evidence that they increase during pregnancy.

Problems in pregnancy

SCD is a disease of tremendous clinical variability. It is only in the last half of the 20th century that women with SCD have survived to reproduce, with life-expectancy in the UK approaching 50 years. Early experience with SCD and pregnancy was a cause for pessimism, and the first report of a successful pregnancy in a woman with SCD was only in 1931. The first major review, in 1941, reported a 50% fetal loss. Since that time, there have been a number of observational reports on maternal mortality rates. The initiation of early aggressive prenatal care has dramatically improved perinatal outcome and reduced maternal mortality to less than 1%.Table 2 shows maternal deaths from the disease in the UK since 1964 from the Confidential Enquiries into Maternal Deaths series.

Table 2 Reported maternal deaths from sickle cell (SC) disease (data from Confidential Enquiries into Maternal Death, 1952–2005).
 

Confidential enquiry into maternal death (years)	Number of deaths from sickle cell disease	Complication causing the death
1952–1954, 1955–1957, 1958–1960, 1961–1963	Not reported	Nil reported
1964–1966	4	4 SC crises
1967–1969	3	2 SC crises 1 aplastic anaemia
1970–1972	3	3 SC crises
1973–1975	2	Cerebrovascular accident due to SC crisis
1976–1978	4	4 SC crises
1979–1981	1	1 SC crisis
1982–1984	0	0
1985–1987	1	GA complication (stroke) in AS carrier
1988–1990	0	0
1991–1993	3	2 SC crises 1 liver sequestration
1994–1996	0	0
1997–1999	1	1 SC crisis
2000–2003	3	2 myofibrosis 1 pulmonary embolism
2003-2005	2	1 amniotic fluid embolism 1 SUDEP*

<<footnote>>*Sudden unexpected death in epilepsy.

Maternal complications include those due to the women’s SCD, such as painful crises or acute chest syndrome, and those due to the pregnancy; these women have an increased risk of pre-eclampsia. Whilst all types of SCD can develop these complications, they are more common in women with HbSS- or HbSbO-thalassaemia. Fetal complications are also more common in women with SCD, with a 19% risk of spontaneous abortion, 21% risk of stillbirth, 32% risk of premature delivery and 42% risk of intrauterine growth restriction. Exchange transfusion may be indicated in patients with a serious obstetric or haematological complication. Hydroxycarbamide, which is now used to treat patients with severe SCD, is contraindicated in pregnancy and should be stopped at least 3 months before conception. Sickle cell crises, infection, pre-eclampsia and thromboembolic events are all important causes of mortality and morbidity.

It is now accepted that, with intensive antenatal care, many women can look forward to a successful outcome of pregnancy. Pregnancies associated with SCD must, however, be considered as high risk and should be managed as such. The high risk of fetal and maternal sequelae mandates multidisciplinary management involving an obstetrician, a haematologist, an anaesthetist and a haemoglobinopathy specialist nurse.

Screening

Newborn screening

The United Kingdom Newborn Screening programme functions to provide early identification of conditions for which appropriate, timely treatment can lead to a reduction in the associated mortality and morbidity. Children who have SCD are at increased risk of bacterial infection as neonates. Prophylactic penicillin in children who have the disease decreases the risk of pneumococcal septicaemia by 84%. A universal newborn screening programme has been implemented in the UK since 2006. All mothers, regardless of ethnic origin, are offered neonatal screening for SCD. The universal screening programme is expected to identify 250–300 babies with SCD and between 7500 and 9000 carriers each year.

Antenatal screening

The antenatal screening programme aims to identify women with haemoglobinopathies who need specialist care in pregnancy, and to offer couples who are carriers and at risk of passing on the disorders the option of fetal screening in the first (or second) trimester. Thalassaemia screening using routine blood indices is formally offered to all women in England and Wales.

The policy for implementing screening for sickle cell and other haemoglobin variants is dependent on whether the hospital is identified as high or low prevalence for sickle cell disorders. In high prevalence areas antenatal screening is universal, i.e. is offered to all women irrespective of ethnic origin.  In hospitals with a low prevalence (< 1.5 per 10 000 pregnancies affected by SCD), antenatal screening for sickle cell and other haemoglobin variants is offered based on an assessment of risk that is determined by asking a question about family origin. If the pregnant woman’s or baby’s father have relatives or ancestors outside northern Europe, they will be offered a screening test for sickle cell and other variants. For women who are test positive as carriers for an abnormal haemoglobin or thalassaemia, appropriate counselling should be offered, and haemoglobinopathy screening should be offered to their partners. Prenatal diagnosis can then be offered to those women at risk of having an affected fetus. This can be achieved by chorionic villous sampling, amniocentesis or fetal blood sampling.

Preimplantation genetic diagnosis

In couples who have a known risk of haemoglobinopathy, preimplantation genetic diagnosis (PGD) has been used successfully to achieve the birth of an unaffected fetus. This technique, although it has the disadvantage of requiring in vitro fertilization, avoids the need for termination of an affected pregnancy and may thus be more acceptable, or the only option, for some couples. There are issues with funding and availability of this procedure. Couples have also sought to use PGD to produce a stem cell donor for an affected sibling, although ethical concerns have been raised regarding this procedure and it is not readily available for this indication in the UK at present.

Preconceptual care

A preconceptual evaluation is highly recommended for a woman with SCD who is contemplating a pregnancy. This assessment should include the frequency of crises, previous transfusion needs and an assessment of end-organ damage, particularly to the kidneys (nephropathy), heart (pulmonary hypertension) and lungs (chronic lung disease). The incidence of pulmonary hypertension in SCD has been found to be as high as 30% in some studies. Maternal mortality is as high as 30–50% in patients with pulmonary hypertension, so pregnancy is contraindicated for these patients, and termination to protect maternal life should be offered if such women do become pregnant. All patients should be advised to continue their antibiotic prophylaxis and keep up to date with their immunizations. Folic acid should be increased from 1 to 5 mg once daily.

In women who are not pregnant, hydroxycarbamide has been used in sickling disorders because of its ability to induce HbF and to alter red cell endothelial cell interaction, and its myelosuppressive effects on neutrophils. It has been associated with poor reproductive outcome in rats, including post-implantation losses and reduced placental and fetal weight. Hydroxyurea should be discontinued 3–6 months before pregnancy because of possible teratogenicity. However, if a patient becomes pregnant while on hydroxyurea, the advice is to stop the medication and to continue the pregnancy. To date there have been no reports of teratogenicity in humans.

Antepartum management

Pregnancy in SCD should be considered to be high risk because of the underlying haemolytic anaemia, sickle cell crises and multiorgan dysfunction associated with the disorder. At present, there is no effective long-term method of reducing the chance of sickling. At the first antenatal visit, a detailed medical history should be taken with particular emphasis on previous crises and their pattern. The past obstetric history is relevant. Any intercurrent medical conditions should be identified and treated appropriately. Dating the pregnancy is important as women with SCD are at increased risk of intrauterine growth restriction and may need early delivery. A baseline full blood count and reticulocyte count, serum ferritin level, and liver and renal function tests should be obtained. Baseline oxygen saturations should be measured and, if they are low, the patient should be offered further investigation for pulmonary hypertension and chronic lung disease with an echocardiogram and lung function testing. Routine screening for hepatitis and human immune deficiency virus infection is essential, along with group and antibody screening, as these women are likely to have had blood transfusions in the past.

All women with SCD should be advised to take a supplement of 5 mg/day folic acid. Iron deficiency is uncommon in SCD, but can occur, so iron supplements should be given only if indicated by a low serum ferritin level. It is important to confirm that the patient has completed her hepatitis B and pneumococcal vaccinations. In addition, all patients should be taking penicillin V 250 mg twice a day as hyposplenism is common and encapsulated organisms pose a risk of overwhelming sepsis. Woman should be encouraged to remain well hydrated and avoid heavy physical exertion, a cold environment and stress. In view of the high risk of pre-eclampsia, and evidence for the efficacy of low-dose aspirin in reducing this by 15% in high-risk women, we advise the use of 75 mg soluble aspirin daily from early pregnancy (CLASP study).

The risks of both maternal and fetal mortality should be explained to the pregnant woman as the rationale for close monitoring. Women should be advised to report early if there are any signs of infection or impending crisis, and not to self-manage (as they might do out of pregnancy) but to have a low threshold for seeking medical help, particularly because of the risk of a rapidly developing chest crisis.

Women with SCD are at risk of premature birth, pre-eclampsia and placental abruption, so the signs and symptoms of these complications should be reviewed with the woman at each visit to allow an early diagnosis and appropriate obstetric management. Prenatal care for the first and second trimesters should consist of 2–4-weekly visits with close liaison with the haematologist and haemoglobinopathy nurse specialist. At each clinic visit, as well as a routine assessment of blood pressure and urinalysis, a full blood count and urinary microscopy and culture should be performed. Gestational age is confirmed by an early ultrasound scan, and serial growth scans should be performed in the third trimester. If intrauterine growth restriction or a co-morbid medical condition is present, an estimation of liquor volume and umbilical artery Doppler velocimetry are recommended. In the absence of an obstetric indication, spontaneous labour at term should be awaited.

Acute painful crises

The therapeutic goals for patients with sickle cell crises include pain relief, treatment of infections, oxygenation, correcting metabolic acidosis and maintaining an adequate haemoglobin level. A liberal use of parenteral analgesia, usually an opiate derivative, is indicated during these crises. Pethidine should not be used because of the risk of seizures. The pain may persist until the cycle of vaso-occlusion and tissue infarction has been reversed. A persistent and vigilant effort to identify any infectious process is important in these women, with the lungs and urinary tract being the most commonly involved. An infection can, however, occur in any organ. Hydration is one of the cornerstones of treatment. In those situations in which the vaso-occlusive crises are unresponsive to conservative management, exchange transfusion may be indicated.

Thromboprophylaxis in the form of low molecular weight heparin (LMWH) is indicated for any woman who is immobile in hospital for more than 24 h.

Transfusion therapy

Current evidence supports a conservative approach to blood transfusion therapy, i.e. to be used only for patients with life-threatening illness or when a crisis does not respond to standard therapy. This approach is supported by the finding of a randomized controlled trial comparing prophylactic transfusion to a conservative approach. There was no difference in perinatal outcome between the two groups, but there was decreased pain in the transfused group. The major advantage of conservative therapy is a reduction in exposure to blood products which can be associated with transfusion reactions, alloimmunization and exposure to infections. Sickle cell patients form red cell antibodies at a higher frequency than other patient groups. This can result in difficulties with blood cross-matching, and possible subsequent haemolytic disease in the newborn.
Some obstetric units have adopted prophylactic transfusion regimens (as shown in case 1 below), even though the benefit of such regimens remains to be established. Blood transfusions can be administered as top-up transfusion or as exchange transfusions where the person’s own blood is removed and replaced with donor blood. This can either be done manually or can be automated using an apheresis machine. The reason for exchange transfusion is to decrease the concentration of HbS, thus increasing the overall oxygen-carrying capacity of the blood, which in turn reduces the chances of sickling and hence tissue damage, without increasing viscosity. Exchange transfusion is certainly preferable to top-up transfusion in the acutely unwell patient with acute chest syndrome or acute neurological symptoms. Prophylactic transfusion is probably best used on an individualized basis depending on the physician’s experience, the type of facilities available, the severity of the SCD and obstetric factors (e.g. past obstetric history or twins).

Case study

A 35-year-old G4 P2+1 from Sierra Leone attended the joint antenatal/sickle cell clinic at 12 weeks’ gestation. She had two previous normal vaginal deliveries at term and an early miscarriage.
She was known to have homozygous SCD and chronic sickle lung with significant pulmonary fibrosis for which she was on prednisolone. She was well known to the haematology team, having had frequent admissions for sickle cell crisis in the past, although she was currently stable.

She was also well known to the respiratory team and had had a CT scan 2 years prior to this pregnancy which was suggestive of pulmonary hypertension. However, an echocardiogram done 2 months prior to her antenatal clinic appointment did not confirm this. She had developed increasing breathlessness since becoming pregnant and because of this and the concern of possible pulmonary hypertension, she was referred to and assessed in the joint obstetric cardiac clinic at 15 weeks’ gestation. Her saturations in clinic were 97% but dropped rapidly to 91% on minimal exertion. The echocardiogram was repeated in the clinic and demonstrated a dilated right pulmonary artery, a TR-derived pressure of 30 mmHg above JVP and a pulmonary acceleration of 90 m/s. This in combination with the earlier CT findings was suggestive of significant pulmonary hypertension. The decision was made to undertake a right heart catheter which confirmed mild but definite pulmonary hypertension.
As mentioned above there is a 40-50% maternal mortality associated with pulmonary hypertension in pregnancy. These women cannot increase their pulmonary blood flow to match the increase in cardiac output and therefore tolerate pregnancy poorly. She was counselled about the risks of continuing with the pregnancy and of termination of pregnancy (up to 7% mortality). She agreed to and underwent a medical termination of pregnancy at 16 weeks’ gestation which was uneventful.

Intrapartum care

Generalized and supportive measures involving stress reduction in labour have a beneficial effect. It is important to avoid dehydration, hypoxia, sepsis and acidosis. Blood should be grouped and saved when labour is diagnosed in case a cross-match is needed. If patients have previously been transfused, there may be an increased risk of atypical antibodies, thus increasing cross-matching times.
In order to limit the increase in cardiac demand during painful contractions, and in anticipation of the known high rate of emergency caesearean section , the liberal use of epidural analgesia is encouraged. However, nitrous oxide (which is a mixture with 50% oxygen) via a face mask can be used for short-term pain relief without the risk of precipitating a sickling crisis. Continuous fetal heart rate monitoring is advised to detect fetal hypoxia, which is more common in the fetuses of sickle cell patients, particularly those with intrauterine growth restriction or oligohydramnios.

The aim should be for vaginal delivery unless operative intervention is required for an obstetric indication. In the event of caesarean section, the haematologist should be contacted for advice, but pre-operative transfusion is only usually necessary for severe anaemia. Routine exchange transfusion prior to caesarean is not necessary. During labour and operative deliveries, precipitating factors for sickle crisis include immobilization, hypoxia, acidosis, infection, dehydration, hypertension and blood loss. All measures to prevent or reduce these insults must be taken. Regional block is preferable to general anaesthesia because it largely avoids the risk of iatrogenic hypoxia.

Postpartum care

The immediate postpartum period is a time of critical importance for women with SCD. There is an increased risk of postpartum haemorrhage, hypovolaemia and tissue hypoxia, infections, thromboembolism and vaso-occlusive crises. Early ambulation, thromboembolic deterrent stockings, appropriate hydration and oxygenation are encouraged. Thromboembolic prophylaxis in the form of daily subcutaneous heparin (e.g. 40 mg enoxaparin) is advisable until the woman is fully ambulant, and for 6 weeks postpartum in all women following a caesarean section. Adequate pain relief is essential, and in some cases parenteral analgesia, in the form of patient-controlled analgesia, may be required. Breastfeeding is encouraged, and adequate hydration and an appropriate calorific intake are required.

Cord blood should be sent for haemoglobin electrophoresis. If it is not, the universal neonatal screening ensures a foolproof method of knowing the baby’s haemoglobinopathy status. In equivocal cases, repeat electrophoresis should be performed at 6 weeks of age. Prophylactic penicillin therapy beginning at 3 months of age is advised for all infants who have SCD in order to decrease the incidence of pneumonia.

Contraception

Controversy surrounds recommendations for contraception for women with SCD. Family planning is, however, an important issue as several pregnancies in a short time can increase the frequency of crises.
The use of progestogen-only contraceptive pills is not contraindicated, and the highly effective protection against unwanted pregnancy conferred by the combined oral contraceptive pill is a positive advantage. Depot medroxyprogesterone acetate is an effective contraceptive, and a controlled study has demonstrated beneficial effects on haematological indices as well as bone pain. Full counselling and instructions must be provided before these methods are used.

The risk of uterine and tubal infections from using an intrauterine contraceptive device, particularly in nulliparous women, makes them relatively contraindicated in SCD. They may be required in special circumstances for those in whom other methods are considered to be unsuitable. There is evidence to suggest that use of the levonorgestrel intrauterine system is associated with a lower rate of pelvic infection than is copper intrauterine device use. Barrier methods are widely used but may carry a higher risk of unwanted pregnancies compared with other methods.

When childbearing has been completed, sterilization should be considered with respect to the woman’s desire for family size and the risk of genetic transmission.

Umbilical stem cell transplantation

SCD is among the most common genetic disorders worldwide and the only proven cure for this disorder is correction of the genetic defect by haematopoietic stem cell transplantation. This is normally reserved for those with clinical evidence of severe disease such as stroke, frequent crises and recurrent acute chest syndrome in the hope of avoiding the development of permanent end-organ damage. Preliminary results are promising with the main challenges being infection, rejection and graft-versus-host disease.
Currently families at high risk of passing on a genetic condition to their child can bank cord blood for the future use of a family member. This can be done in an established public sector cord blood bank such as the NHS Cord Blood Bank and the Anthony Nolan Trust. There are funding issues with regards to its use in SCD as the use of cell transplantation in this condition is not yet established. As mentioned above, the ethical concerns regarding couples producing an unaffected child in the hope of providing a donor for an affected sibling remain.

Conclusion

Sickle haemoglobinopathies are among the most common genetically transmitted conditions and have a worldwide distribution. During the past three decades, it has been shown that women with major sickle haemoglobinopathies can have a good reproductive outcome. This has been achieved through appropriate counselling, aggressive prenatal care and effective intervention by care providers with a high index of suspicion for predisposing factors to untoward outcomes. The advent of universal newborn screening for SCD and an improved awareness for antenatal screening will increase the detection of sickle cell disease in the population. This in turn will allow for appropriate care and management to reduce the morbidity and mortality of sickle cell disease. The increasing number of people with sickle cell disease living in the UK and surviving to reproductive age means that healthcare professionals need to become more aware of the associated clinical problems, and to provide appropriate medical care in pregnancy.

Practice points

Pre-pregnancy

• Defer conception until the disease status has been optimized
• Counsel with regard to appropriate contraception
• Educate about the risks of pregnancy and strategies to minimize these risks
• Screen the woman’s partner - if sickle trait or disease is found, provide counselling about prenatal diagnosis

• Antenatally

• Selective or universal screening depends on the prevalence in the local population
• Screen the woman’s partner and consider prenatal diagnosis if sickle trait or disease is found
• Blood transfusion should not be used routinely but should be used only in those patients with haematological or obstetric indications
• Treatment of crises should consist of adequate pain relief, hydration and oxygen, treatment of infection and, in severe cases, exchange transfusion
• Fetal surveillance and tests for fetal well-being
• Consider induction of labour/delivery at term

• Intrapartum

• Ensure adequate hydration, oxygenation and analgesia
• Continuous cardiotocography should be used

• Postnatally

• Offer universal screening for sickle cell disease in the newborn
• Prophylactic heparin should be used while the woman is in hospital
• Maintain good hydration and oxygenation, particularly for the first 24 h
• Contraception: intrauterine devices are relatively contraindicated

Table 3 A comparative analysis of outcomes of preimplantation genetic diagnosis (PGD) for sickle cell disease in the UK (ACU Guy’s and St Thomas’ NHS Foundation Trust) and elsewhere.

	Xu et al 1999 (USA)	DeRycke et al2001 (Belgium)	Chamayou et al 2002 (Italy)†	Trager-Synodinos et al 2003 (Greece)‡	Fiorentino et al 2006 (Italy)	Harper et al. 2008 (ESHRE PGD consortium)		ACU GSTT UK. (2008)
						†Cycle I –VI**	†Cycle VII**
No of couples	1	2	2	41	3	8	3	12
No of cycles started	2	9	3	63	5	36	(not stated)	16
No of cycles reaching oocyte retrieval (OR)	2	9	3	43	5	31	19	14
No of oocytes retrieved	34	122	63	606	(Not stated)	438	268	168
No of successfully fertiliZed oocytes	12	72	28	340	(Not stated)	231	176	70
No of embryos available for biopsy	12	58	12	302	42	173	125	58
No of successfully biopsied embryos	10	58	12	256	38	171	125	56
No of transferable embryos	6	35	8	(Not stated)	12	92	57	31
No of cycles reaching embryo transfer (ET)	2	9	3	43	5	28	17	11
No of embryos transferred	4	27	6	100	12	61	37	18
No of HCG +ve pregnancies (per PGD cycle started)	1 (50%)	2 (22%)	3 (100%)	16 (25%)	2 (40%)	7 (19%)	5 (26%)*	4 (25%)
No of clinical preg(s)    Per PGD cycle started Per cycle reaching OR Per cycle reaching ET	1 (50%) (50%) (50%)	1 (11%) (11%) (11%)	2 (67%) (67%) (67%)	13 (21%) (30%) (30%)	1 (20%) (20%) (20%)	4 (11%) (13%) (14%)	5 (not known) (26%) (29%)	2 (13%) (14%) (18%)
No of pregnancies with live births (LB)	1 preg (1 twins)	1	1	9 preg (1triplet, 2 twins,6singletons)	1	(not stated)	(not stated)	2
LB per PGD cycle (%)	½ (50%)	1/9 (11%)	1/3 (33%)	9/63 (14%)	1/5 (20%)	(not stated)	(not stated)	2/16 (13%)

<<footnotes>>OR, oocyte retrieval; ET, embryo transfer; HGC+ve, human chorionic gonadotrophin (positive); preg – pregnancy.
*Calculated per PGD cycle reaching OR.
†Included cases of HbSβ-thalassaemia.
‡Included cases of HbSβ-thalassaemia and β thalassaemia.
**ESHRE PGD consortium data collection, cycle I-VI (before June 1997 to Dec 2003), Cycle VII (Jan–Dec 2004).

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