Sickle cell disease in obstetrics

Definition

Sickle Cell Disease (SCD) is an autosomal recessive disorder caused by valine replacing glutamic acid at position six on the haemoglobin (Hb) beta chain. This abnormal haemoglobin leads to the formation offragile rigid sickle- shaped red cells in low- oxygen conditions.

Background

SCD is the commonest inherited disorder worldwide, with over 300,000 affected children born each year (145, 146), with two-thirds of these births occurring in Africa (147). In the United Kingdom, there are over 300 affected children born and 100-200 pregnant women affected each year (148).

Pathophysiology

The polymerisation of abnormal haemoglobin in low-oxygen conditions leads to formation of fragile rigid red blood cells that are prone to increased breakdown causing haemolytic an­aemia, which in turn leads to a decrease in red cell lifespan. Vaso­occlusion of small blood vessels is the main event that leads to the clinical features of this condition. Vaso-occlusion in the bone causes acute bony pain and is associated with chronic multiorgan complications.

Clinical features

SCD is a multiorgan disorder with lifelong complications. Most patients will have a chronic anaemia with a haemoglobin level of 6-9 g/dL, although patients with the milder HbSC type may have higher or normal haemoglobin levels. Recurrent acute, severe epi­sodes of bone pain are the predominant clinical feature; it affects the fingers and toes in children and the trunk and long bones in adults.

Pregnancy may unmask any of these conditions and they may be diagnosed for the first time in pregnancy. Previously, SCD was as­sociated with early mortality, but with improved medical care the average life expectancy has improved and most children born in the United Kingdom will reach childbearing age (149, 150).

Effect of pregnancy on sickle cell disease

There is a large variation in reported maternal mortality, varying from 0.07% in the studies from the United States (151) to over 9.2% in Nigeria (152). A national cohort study—the UK Obstetric Surveillance System(UKOSS)—comparing sickle cell anaemia (HbSS) with HbSC disease, showed a high rate of maternal and fetal complications in mothers with SCD, even in women with HbSC, who were previously considered to be at lower risk of complications during pregnancy (153).

Pregnancy can increase the frequency and severity of painful episodes leading to multiple hospital admissions even in patients with mild disease outside of pregnancy (154-156). There is also an increase in infections, pulmonary complications (157-159), and thromboembolic events (160).

Effect of sickle cell disease on pregnancy

Maternal

• Painful crisis

• Antepartum haemorrhage

• PET

• Pulmonary thrombosis

• Thromboembolism

• Bone marrow embolism

• Sepsis.

Fetal

• Miscarriage

• Intrauterine growth restriction

• Stillbirth

• Placental abruption

• Preterm labour

• Four- to sixfold increase in perinatal mortality.

Diagnosis

Most patients have an established diagnosis prior to pregnancy and are regularly reviewed in a haematology or specialist clinic.

High-pressure liquid chromatography (HPLC) is the most com­monly used diagnostic test.

Management

Preconceptual care

• Partner screening should be offered ideally prior to pregnancy, this enables clinicians to offer the couple appropriate counselling about the risk of having an affected child.

• The risk of pulmonary hypertension is increased in patients with SCD (161); an echocardiogram should be offered prior to any planned pregnancy if it has not been performed in the preceding year.

• Patients with SCD commonly have elevated blood pressure and proteinuria which may progress to end-s tage renal dis­ease. Measurement of blood pressure, urinalysis, and assess­ment of renal function is important to identify patients with nephropathy.

• Women who are on prophylactic antibiotics (penicillin or erythro­mycin if allergic to penicillin) to reduce the risk of infection par­ticularly from encapsulated bacteria, are encouraged to continue them throughout pregnancy (162).

• Other medication such as hydroxycarbamide given to re­duce the incidence of acute chest syndrome is teratogenic and should be stopped 3 months before conception (163). Women on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be switched to a suitable alternative antihypertensive that is safe in pregnancy.

• High dose—5 mg folic acid per day is recommended due to asso­ciated folate deficiency (164).

• Pneumococcal vaccine is recommended every 5 years and the in­fluenza vaccine is recommended annually.

• Some patients with SCD are at a high risk of developing prolifera­tive retinopathy. An assessment by an ophthalmologist should be offered preconceptually in such patients.

• Iron overload is common in women who require multiple transfusions. A cardiac and hepatic magnetic resonance imaging scan should be offered preconceptually, and iron chelation therapy offered prior to pregnancy if indicated.

Antenatal care

Antenatal care should be provided by a multidisciplinary team: an obstetrician with special interest in high-risk pregnancy, a specialist midwife and a haematologist. It is important to have clear clinical pathways and referral channels to a specialist centre if complications arise during pregnancy.

Ideally patients with SCD should be booked early to enable clin­icians to make an appropriate plan for the pregnancy and arrange referrals as necessary. They should receive general advice about maintaining adequate nutrition, warmth, and hydration during pregnancy.

• If the patient has not been seen preconceptually, partner screening should be carried out as soon as possible and appropriate genetic counselling offered regarding the risk of having an affected child.

• Generally, patients should be seen every 4 weeks up to 28 weeks, then every 2 weeks thereafter—more frequent visits may be needed if there are any maternal or fetal complications.

• Medications that are teratogenic in pregnancy should be discon­tinued preconceptually.

• Blood pressure and urine should be checked each visit.

• Folic acid 5 mg daily and antibiotic prophylaxis should be taken throughout pregnancy.

• Aspirin 75 mg should be given daily to reduce the risk ofPET (165).

• There is an increased risk of venous thromboembolism in patients with SCD (166). Thromboprophylaxis should be offered if the pa­tient is admitted to hospital or if there are additional risk factors

• In addition to routine antenatal ultrasound scans, a uterine artery Doppler assessment should be offered at 24 weeks (167). Due to the increased incidence of fetal growth restriction, regular growth scans every 4 weeks from 24 weeks should be offered.

• There is conflicting evidence of benefit from prophylactic transfu­sion (168-170), although some centres offer it routinely. Women who are on a long-term transfusion protocol for secondary stroke prevention should follow the same protocol throughout pregnancy.

• Women with SCD will usually have a chronic anaemia due to haemolysis; however, an acute anaemia with a haemoglobin level of less than 6 g/dL or a decrease by more than 2 g/dL from baseline is an indication for blood transfusion.

• Red cell alloimmunization is common due to repeated transfusions and can occur in up to 29% (171, 172) of patients. Red cell phenotyping should be performed at booking, and only C-, E-, and Kell-matched blood given if a transfusion is needed.

• Delivery is recommended by 38-40 weeks due to the increased risk of perinatal mortality in late gestation. Vaginal delivery is re­commended, and caesarean section should only be performed for obstetric indications.

Intrapartum care

The stress of labour may potentiate crises in patients with SCD, so patients should be delivered in units that are able to manage high- risk pregnancy complications.

• Hydration—oral hydration is usually sufficient, but intravenous hydration may be needed in women who are unable to tolerate oral fluids. Patients should have strict fluid balance monitoring and early warning scoring charts should be used.

• Oxygenation—oxygen saturation should be monitored

throughout labour and supplemental oxygen given if the satur­ation falls below 94%.

• Progress in labour—prolonged labour should be avoided and an early recourse to caesarean section should be made if progress is not adequate.

• Antibiotics—prophylactic antibiotics are not indicated unless there is evidence of infection.

• Continuous fetal monitoring—continuous monitoring during la­bour is recommended due to the increased risk of fetal growth restriction, placental abruption, and fetal distress (172, 173).

• Analgesia/anaesthesia—patients may receive analgesia and re­gional anaesthesia as per normal, with the exception of pethidine as it may provoke seizures in women with SCD.

• Thromboprophylaxis—routine thromboprophylaxis should be offered in line with RCOG guidance (174).

Postnatal care

There is an increased incidence of acute sickle pain, occurring in 7-25% of patients in the postpartum period (175, 176).

• Thromboprophylaxis—should be given for the duration of hos­pital admission, for 7-10 days following vaginal delivery and 6 weeks following caesarean section.

• Breastfeeding—there are no restrictions on breastfeeding and women should be encouraged to breastfeed.

• Contraception—progesterone preparations such as the progesterone-only pill, injectable (Depo- Provera), Mirena coil, and the implant (Implanon) are the first-line recommended contraceptives. Progestogens have been shown to reduce the frequency and severity of painful crisis (177). Second-line contraceptives include the combined oral contraceptive pill, copper intrauterine device, vaginal ring, and combined contra­ceptive patch. Oestrogen-containing contraceptives are as­sociated with an increased risk of thrombosis—a careful risk assessment must be made prior to prescribing them to women with SCD.

Management of acute sickle crisis in pregnancy

There is an increased incidence of painful crisis in pregnancy, with some studies showing an occurrence in about 27-50% of women (13, 178, 179):

• Mild sickle pain: patients with mild pain can be managed as an outpatient with rest, fluids, and analgesia (paracetamol and weak opioids)

• Moderate to severe pain: these patients should be assessed promptly in hospital for signs of infection or acute chest syn­drome. The mainstay of management is rapid analgesia and hydration:

■ Analgesia—strong oral or parenteral opioids should be given rapidly with frequent reassessment of pain score and further an­algesia given until the patient is pain free (180).

■ Hydration—oral fluids should be given at 60 mL/kg/24 hours, or intravenous fluids if oral fluids are not tolerated.

■ Monitoring—fluid balance, oxygenation, and sedation score should be monitored using an early warning scoring chart. Patients should be managed jointly by the obstetric, haema­tology, and anaesthetic teams.

■ Investigations—urinalysis, full blood count, and renal func­tion, and blood cultures and chest X-ray if there is a suspicion of infection.

■ Thromboprophylaxis—should be given for the duration of hos­pital admission.

■ Antibiotics—should be prescribed if there is a risk or evidence of infection.

• Acute chest syndrome (ACS): this is seen in 7-20% (181-183) of pregnant patients with SCD and is associated with high morbidity and mortality.

■ It is characterized by new infiltrates on chest X-ray in conjunc­tion with respiratory signs and symptoms. One of the earliest signs is hypoxia, therefore women who develop hypoxia should have a clinical assessment, arterial blood gas measurement, and a chest X-ray to rule out acute chest syndrome.

■ The senior and multidisciplinary team should be involved in the management if acute chest syndrome is suspected, and the pa­tient should be nursed in a high dependency unit. Treatment is with respiratory support, antibiotics, and blood transfusions. An emergency exchange transfusion should be performed if there is severe hypoxia. Pulmonary embolism may have a similar pres­entation and should be considered as an alternative diagnosis, specifically if the chest X-ray is normal.

• Other acute complications: acute neurological complications such as haemorrhagic or ischaemic stroke are increased in patients with SCD (183). Urgent brain imaging and assessment should be performed in women presenting with symptoms, with urgent in­volvement of the haematology and neurology teams. Emergency exchange transfusion is imperative and can reduce long-t erm neurological disability.