Antiphospholipid syndrome in obstetrics

Definition

Antiphospholipid syndrome (APS) is an autoimmune condition characterized by recurrent arterial or venous thromboembolic episodes and adverse pregnancy outcomes such as recurrent mis­carriage, stillbirth, and severe pre-eclampsia/toxaemia (PET); in as­sociation with persistent antiphospholipid antibodies.

The antibodies associated with this condition are lupus anti­coagulant, anticardiolipin, and anti-beta-2 glycoprotein-1. APS and antiphospholipid antibodies can occur in isolation as primary APS or secondary, in association with other diseases such as systemic lupus erythematosus.

Background

Antiphospholipid antibodies can be found in up to 1-5% of healthy women, this rises to 15% in women with recurrent miscarriages and up to 20% in women having a stroke before the age of 50 (1). Recent studies reported a lower prevalence in women with re­current miscarriage, when current diagnostic criteria for positive antiphospholipid antibodies were followed (2).

Thrombosis may occur in 30% of patients with antiphospholipid antibodies, and 30% of women with severe early PET may have posi­tive antibodies (3).

The prevalence of APS in the general population is 0.5% (4); the female- to- male ratio is 3.5:1 in primary disease, and 7:1 in secondary disease related to systemic lupus erythematosus, with a mortality rate of 5% (5). Approximately 30-40% of patients with systemic lupus erythematosus have antiphospholipid antibodies.

Pathogenesis

The hallmarks of APS are thrombosis and inflammation in the venous and arterial beds and placental circulation leading to pla­cental insufficiency. Placental thrombosis is not exclusive to patients with APS, and may be seen in patients with PET. Conversely; inflam­mation rather than thrombosis may be found in some patients with APS and obstetric complications (6, 7).

Endothelial cells, neutrophils, monocytes, platelets, cytokines, and complement all contribute to thrombosis and fetal loss.

Antiphospholipid antibodies binding to negative phospho­lipids and protein-binding phospholipids may trigger endothelial activation, which in turn plays a role in abnormal placentation (8). Activated endothelial cells upregulate tissue factor produc­tion, which initiates a coagulation cascade and plays a key role in thrombosis and inflammation and the hypercoagulability state seen in APS (9). There is also trophoblast dysfunction and impaired transplacental exchange which leads to early miscarriage, PET, fetal growth restriction, and fetal death (10).

Effect of pregnancy on APS

The prothrombotic state in pregnancy increases the risk of new- onset, and recurrent venous (deep vein thrombosis and pulmonary embolism) and arterial (stroke and transient ischaemic attacks) thrombosis, which classically recur in the same region as previous thrombotic events (3).

There is also a risk ofworsening ofpre- existing thrombocytopenia.

Effect of APS on pregnancy

There is an increased risk of maternal and fetal complications (5, 11, 12), this risk is particularly raised in patients with lupus antibodies (13).

Maternal

• PET, which is usually of early onset and severe

• Eclampsia

• Haemolysis, elevated liver enzymes, and low platelets (HELLP) complete or partial syndrome

• Placental abruption

• Catastrophic APS—some studies have shown a 0.9% occur­rence of this rare life threatening cause of multiorgan failure in pregnancy (5).

Fetal

• Recurrent miscarriages

• Intrauterine fetal growth restriction

• Preterm labour

• Intrauterine fetal death.

Classification criteria and diagnosis

The presence of antiphospholipid antibodies alone does not con­stitute APS. The international classification criteria—Sapporo criteria—were introduced in 1998 and revised in 2008 (14). To fulfil

Table 15.1 Revised classification criteria for antiphospholipid syndrome

IgG, immunoglobulin G; IgM, immunoglobulin M.

^a In studies of populations of women who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of women according to a, b, c as listed.

Reproduced from Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306 with permission from John Wiley and Sons.

the criteria, there must be at least one clinical feature—thrombosis or pregnancy morbidity—in addition to at least one laboratory ab­normality including lupus anticoagulant, anticardiolipin, and anti­beta-2 glycoprotein-1 antibodies detected in medium or high titre on two occasions at least 12 weeks apart. Classification details are shown in Table 15.1.

Early recognition of APS helps prevent thrombosis and adverse obstetric outcomes. Situations (12, 15, 16) where patients should be tested for antiphospholipid antibodies are summarized in Box 15.1.

Management

Preconceptual care

Prepregnancy counselling is recommended to discuss the risk of po­tential complications and formulate a management plan (17):

• Women with a history of recurrent miscarriage, intrauterine fetal death, early-o nset PET, severe fetal growth restriction,

Box 15.1 Situations in which antiphospholipid antibodies should be tested

• Systemic autoimmune diseases carriers.

• Women who have a history of:

— recurrent miscarriages

— fetal loss after 10 weeks' gestation

— severe early intrauterine fetal growth restriction

— stillbirth

— early onset severe pre-eclampsia or eclampsia (treatment of APS in pregnancy

Antiphospholipid syndrome Antiphospholipid syndrome with with poor obstetric outcomes thrombosis

Recurrent early (pre-embryonic or embryonic) miscarriage: low dose aspirin alone or plus: low-molecular- weight heparin: usual thromboprophylactic doses (e.g. enoxaparin 40 mg/d sc. or dalteparin 5000 U/d sc. or tinzaparin 4500 U/day sc.)

Low-dose aspirin plus:

Low-molecular-weight heparin: full anticoagulation doses (e.g. enoxaparin

1 mg/kg sc. or dalteparin 100 U/kg, sc. every 12 h or enoxaparin 1.5 mg/kg/day sc.

In all cases associate supplementary: calcium 1000 mg/day

vitamin D 800 I U/day

Fetal death (>10 weeks' gestation) or prior early delivery (commonest inherited bleeding disorder is von Willebrand disease (vWD), followed by haemophilia A and haemophilia B.

Rarer types of bleeding disorders include fibrinogen, factor II, V, VIII, VII, X, XI, XIII deficiencies, and multiple deficiencies of vitamin K-dependent factors.

Physiological changes in pregnancy

Multiple haemostatic changes occur in normal pregnancy to prepare for the challenges of delivery. These changes also occur in women with bleeding disorders and may act to normalize their existing haemostatic abnormality. There is a large variation in this response however, even in women with the same condition. The various changes are summarized in Table 15.3.

Von Willebrand disease

This is the commonest inherited bleeding disorder, occurring in about 1% of the general population (38, 39). The mode of inherit­ance is usually autosomal dominant, and it is due to either a quan­titative or qualitative defect in von Willebrand factor (vWF) which acts as a carrier for factor VIII. There are three types of vWD: type 1, which is due to partial deficiency of vWF, is autosomal dom­inant, usually mild, and accounts for 70-80% of cases. Type 2, is due to a functional defect in the vWF protein, has four subtypes based on pathogenesis, and is also autosomal dominant. Type 3, due to a complete absence of vWF, is autosomal recessive and typ­ically severe.

Diagnosis

There is no single simple test to diagnose vWD; the diagnosis is made using a combination of specific investigations.

vWF and FVIII levels may be reduced and the activated partial thromboplastin time may be prolonged. Specific tests to measure vWF activity using ristocetin cofactor may be used in addition to a quantitative immunoassay assessment of vWf (vWf:Ag).

Due to the physiological increase in vWF levels in pregnancy, most women have uncomplicated pregnancies and usually do not have complications such as antepartum haemorrhage (40, 41).

Table 15.3 Haemostatic changes during normal pregnancy

F, factor; vWF, von Willebrand factor.

these women are at a significant risk of primary and secondary post­partum haemorrhage.

Haemophilia A and B

Haemophilia A is caused by a deficient or defective coagulation factor VIII and haemophilia B is caused by a deficient or defective coagulation factor IX. They are X-linked recessive conditions, therefore males are affected and females are obligate carriers. Haemophilia can cause significant complications such as bruising, muscle and joint bleeding, spontaneous bleeding, bleeding after sur­gery, and intracranial bleeding. Carriers of haemophilia usually have a clotting factor level of 50% of normal and are therefore also at risk of bleeding complications.

Some studies have shown an increased risk of miscarriage and bleeding in pregnancy in haemophilia carriers (42-44), but at pre­sent the evidence is not robust enough to support antenatal prophy­laxis to prevent early pregnancy loss. Replacement may be indicated, however, in some women with significant bleeding.

Preconceptual counselling

Preconceptual counselling is important in patients who are either affected or are carriers of a bleeding disorder to allow appropriate counselling and discuss the option of prenatal diagnosis, and make an appropriate plan for pregnancy and delivery, and perform a trial of desmopressin if indicated.

It is also an opportunity to discuss and arrange hepatitis immun­ization for women who are more likely to need blood transfusions during pregnancy.

Prenatal diagnosis

Prenatal diagnosis is a vital part of the management of patients with bleeding disorders, specifically in patients who are haemophilia car­riers, as they have a 50% chance of having an affected male fetus and a 50% chance of a carrier female. Invasive diagnostic tests such as chorionic villous sampling and amniocentesis are available, but they are associated with a risk of miscarriage of approximately 1%. The uptake of prenatal diagnosis and termination for patients with haemophilia remains generally low (45)—possibly due to the effect that improvement in management has made to the quality of life of most affected individuals.

Preimplantation genetic diagnosis using in vitro fertilization to selectively transfer unaffected embryos is another option. Table 15.4 summarizes the options for prenatal diagnosis.

Antenatal care

Patients with inherited bleeding disorders should be cared for in an obstetric medicine clinic, or by obstetricians who have experi­ence in managing high-risk pregnancies with close liaison with a haematologist:

• Clotting factors levels should be checked at booking if there are no recent prepregnancy readings, and they should ideally be repeated at 28 and 34 weeks' gestation, specifically in women with low levels prior to pregnancy.

• Desmopressin, fibrinogen concentrate, recombinant factor VIII, platelets, and plasma have all been used to manage bleeding disorders. These are all specialised treatments and should only be used by experienced clinicians and in conjunction with a

Table 15.4 Prenatal diagnosis options for haemophilia carriers

CVS, chorionic villus sampling; ffDNA, free fetal DNA in maternal blood; USS, ultrasound

haematologist. Recombinant products are preferable to reduce the risk of viral transmission. Treatment options are summarized in Table 15.5.

• A clear plan for delivery must be made and documented in the patient's notes; this plan should also include provisions for unex­pected early delivery. There is no evidence to suggest a caesarean section for all women; a careful assessment must be made ante- natally to highlight any additional risk factors that may affect the mode of delivery

Intrapartum care

• Intravenous access, full blood count, coagulation screen, and a sample for group and antibody screen should be taken upon ar­rival to the delivery suite.

• Clotting factor levels are generally not available in an emergency, so clinicians should be guided by third-trimester levels.

• Knowledge of fetal sex is useful, but since it is not always available, it is recommended to follow the same plan for all patients as there is a 50% chance of a male fetus.

• Fetal scalp electrode and fetal blood sampling should not be performed—a caesarean section should be carried out if there is a suspicion of fetal distress (46).

• Delivery by vacuum, mid-cavity, or rotational forceps should be avoided due to the high risk of cephalohaematoma and intracra­nial bleeding (47).

• Delivery by outlet forceps may be considered as it is safer than a caesarean section in advanced labour. This should be con­ducted by a senior practitioner to minimise the risk of potential complications.

• The majority of haemophilia A carriers do not need prophylactic cover during labour unless their levels are persistently low at term (48-50). Conversely, the majority of haemophilia B carriers will have persistently low levels and require treatment in labour to maintain factor levels greater than 50 IU/dL.

Table 15.5 Therapeutic options for women with inherited bleeding disorders in pregnancy.

F, factor; PCC, prothrombin complex concentrates, r, recombinant; SD plasma, fresh frozen plasma virally inactivated using a solvent detergent technique; VKCFD, hereditary combined deficiency of the vitamin K-dependent clotting factors; vWD, von Willebrand disease.

• Treatment is usually not required in patients with type1 vWD, type 2 patients usually require vWF concentrate and desmopressin especially if a caesarean section is required. Treatment is usually indicated for all types of delivery in patients with type 3 vWD.

• Intramuscular injections should be avoided in patients with un­treated coagulopathy due to the risk of haematoma.

• Spinal or epidural anaesthetic use is controversial in women with bleeding disorders. It is contraindicated in patients with a sig­nificant coagulopathy but studies have shown that it may be used safely in patients with normal or corrected factor levels (51). An assessment and decision should be made antenatally and a plan documented in the patient's records.

Postnatal care

There is a significant increased risk of primary and secondary post­partum haemorrhage in these patients. This risk is usually propor­tional to the factor levels. The key factor in the management of these patients is prevention; active management of the third stage of la­bour, careful haemostasis during caesarean section, operative va­ginal delivery, and perineal repair are all measures that reduce the incidence of bleeding following delivery (14, 15). Management of postpartum haemorrhage may be challenging and input from the haematologists and anaesthetists is required.

Prophylactic cover using desmopressin is required for patients with vWF, factor VIII, or factor IX levels less than 50 IU/dL and this level should be maintained for a minimum of 3 days following va­ginal delivery and 5 days following caesarean section (52, 53). There is an ongoing risk of bleeding (54) and women should be counselled and given follow-up advice prior to discharge from hospital (55).

Neonatal care

• Cord blood samples should be taken and tested for coagulation profile and clotting factor levels.

• A cranial ultrasound scan should be performed if there has been a traumatic delivery or ifthere are signs of intracranial bleeding (56).

• Intramuscular injections should be avoided and any surgical pro­cedures delayed until the coagulation status is known.

• It is important to be aware that clotting factor levels correlate with gestational age and some do not reach adult levels until 6 months after birth.

• Haemophilia A is the only bleeding disorder that can be reliably diagnosed at birth.