Pathogenesis of thromboembolism in pregnancy

Pregnancy evokes a physiologically hypercoagulable state that is protective against haemorrhage at the time of delivery and placental separation. The hypercoagulable state of pregnancy is provoked by thrombin-mediated fibrin generation. The procoagulant changes of pregnancy include an increase in plasma concentration of coagulation factors and fibrinolysis inhibitors, reduced venous flow and increased venous dilatation. Physiological increases in all coagulation factors occur during pregnancy, with the exception of factors XI and XIII, which are frequently decreased. In addition, free protein S levels fall and acquired resistance to activated protein C develops during pregnancy. Risk for thromboembolism is further increased by compression of the inferior vena cava and iliac veins by the gravid uterus, promoting stasis. By 25–29 weeks’ gestation, venous flow velocity is reduced by approximately 50% in the legs and does not return to normal non-pregnancy flow velocity until around 6 weeks postpartum. During pregnancy, local damage to pelvic veins may occur during vaginal and especially caesarean delivery and this provides an increased risk for thrombosis. When these physiological coagulation changes combine with genetic predisposition conditions such as thrombophilias, socioenvironmental factors and other medical factors (obesity, inactivity and caesarean section), the risk for thromboembolism is increased.

Most deep venous thrombosis (DVT) occurs in the antepartum period, equally distributed across all trimesters, whereas most pulmonary embolism occurs in the postpartum period.

Thromboembolism in inherited and acquired anticoagulation deficiencies

Thrombophilias are disorders of homeostasis that predispose to thrombotic events. The prevalence of inherited thrombophilias depends on the population and/or ethnicity. Approximately 15% of the western population is affected by a thrombophilia. Approximately 50% of cases of venous thromboembolism in pregnancy are associated with inherited or acquired thrombophilias. The absolute risk of venous thromboembolism for pregnant women with antithrombin III deficiency is reported to be as high as 40–68% ( ; ). Protein C, in its active form, is responsible for inactivation of factors V and VIII and activation of fibrinolysis. Protein S is a vitamin K-dependent, naturally occurring inhibitor of haemostasis that is synthesised and released from the endothelium and shows autosomal dominant inheritance. It is a cofactor for protein C in the neutralisation of activated factor V and in fibrinolysis. The incidence of thromboembolism has been reported to be 2.5% per year for protein C-deficient individuals, and 3.5% per year for those with protein S deficiency ( ). Protein C deficiency is also autosomal dominant, and the heterozygous trait results in plasma protein C levels of 55–65% of normal. During pregnancy, an incidence of DVT up to 25% has been reported for heterozygote protein C-deficient individuals. The risk for stillbirth is also increased in women with these protein deficiencies ( ). Activated protein C resistance results from a point mutation in the factor V gene (the factor V Leiden mutation; FVL) and is the most frequent aetiology for thrombosis. The gene mutation is inherited as an autosomal dominant trait and is particularly prevalent in the white population. Heterozygosity for the FVL gene defect confers a five- to 10-fold increased risk for thrombosis.

Acquired thrombophilias include antiphospholipid antibodies and lupus anticoagulant. These conditions are typically diagnosed in women with recurrent pregnancy loss rather than thromboembolism. However, both disorders should be considered as risk factors for thromboembolism during pregnancy, and they may also increase the risk of thromboembolic disease in the fetus. For antiphospholipid antibody syndrome, the absolute risk for thrombosis has been reported to be as high as 30% ( ).

Clinical presentation and diagnosis of thromboembolic disease

During pregnancy, venous thromboembolism may present with symptoms of DVT, or pulmonary embolism. The most common symptoms of DVT are pain, tenderness and swelling of the lower extremity. In pregnancy, 85% of DVT cases present in the left leg. This is due to the abrupt right-angle drainage of the left iliac vein that leads to more venous stasis in the left leg.

Clinical signs of a suspected DVT include heat, redness and swelling. The signs and symptoms result from obstructed venous return and/or in combination with vascular inflammation. The risk of pulmonary embolism is greater with femoral or iliac thrombosis and can occur without obvious swelling. Symptoms of pulmonary embolus include dyspnoea, pleuritic chest pain, cough and haemoptysis. Clinical signs include tachycardia, tachypnoea, crepitations, fever, pleuritic rub, cyanosis and the development of an accentuated second heart sound and gallop rhythm. Massive pulmonary embolism, defined as obstruction of more than 50% of the pulmonary circulation, may present with syncope, representing cardiovascular collapse, and recognised with hypotension.

Diagnostic evaluation test for thromboembolism

Doppler flow studies with compression sonography are the primary non-invasive tests used in the diagnosis of DVT. Compression ultrasonography has a sensitivity of 97% and a specificity of 94% for the diagnosis of symptomatic, proximal DVT in the general population. Doppler combined with real-time ultrasound and colour flow have become the diagnostic studies of choice in cases of suspected proximal vein thrombosis ( ). Imaging provides additional information about venous compressibility.

Magnetic resonance imaging (MRI) has a sensitivity for thrombi above the knee of nearly 100% and has a place in the evaluation of the patient suspected of having a pelvic thrombus with a negative Doppler/ultrasound examination. A chest X-ray to rule out other diagnoses is a first step in investigating the breathless pregnant patient. Computed tomography (CT) scanning, unlike ultrasonography and MRI, is associated with fetal as well as maternal radiation exposure.

D-dimer is a specific degradation product of cross-linked fibrin. Levels of D-dimer are increased in the presence of thrombi, but also increase with the progression of normal pregnancy and are therefore of little positive diagnostic value. Guidelines for the evaluation of pulmonary embolism in pregnancy attempt to balance diagnostic efficacy, decreasing maternal morbidity and mortality and minimisation of fetal exposure to ionising radiation. The most commonly used non-invasive study is the ventilation–perfusion scan (V/Q scan). Ventilation–perfusion lung scanning delivers a higher fetal dose of radiation (100–370 µGy) than does CT pulmonary angiography (PA) (3–131 µGy). Perfusion scanning alone in women with a normal chest X-ray reduces radiation exposure ( ). Although helical CT gives good diagnostic sensitivity for pulmonary embolus, there are concerns about the future risk of maternal breast cancer following helical CT to the chest. Pulmonary embolus is however a life-threatening condition and pregnancy must not interfere with the most appropriate investigations when a pulmonary embolism is suspected.

Management of thromboembolism during pregnancy

Management of women with a history of prior thromboembolism

Women with a history of DVT or pulmonary embolism during a prior pregnancy or while on oral contraceptives are at increased risk for recurrent thrombosis during subsequent pregnancies. Fifteen to 25% of thromboembolic events in pregnancy are recurrent events ( ). The risk of recurrent thromboembolism in women with a prior pregnancy-related event has been reported to be 4–12%.

The usual treatment regimen for women with a prior DVT includes thromboprophylaxis with LMWH throughout pregnancy until 6 weeks postpartum. Thromboprophylaxis should be considered for those with a history of unprovoked thrombosis, morbidly obese pregnant women (body mass index >40) and those confined to bed for prolonged periods (e.g. premature rupture of membranes, placenta praevia). The use of pneumatic compression devices for the prevention of pregnancy-related thrombosis has not been well studied and the risks are primarily extrapolated from perioperative data ( ). Pulmonary embolism after caesarean delivery is much higher than after vaginal delivery by a factor of 2.5–20 ( ). The duration of thromboprophylaxis after caesarean section for this high-risk group has not been studied. As the risk of peripartum DVT is highest during the first week or so postpartum, it is not unreasonable to continue mechanical means with a compression stocking or boot, or with low-dose LMWH for the first week after delivery.

Clinical presentation

Valve disease

In general, pregnant women tolerate valvular regurgitation better than stenosis. This is because the reduced systemic vascular resistance improves forward flow and limits the effects of regurgitation. Stenosis, in contrast, creates a fixed impediment to the increase in cardiac output that accompanies pregnancy and labour, possibly precipitating pulmonary oedema and arrhythmias. In the UK, calcific degeneration of congenital bicuspid aortic valves is the leading cause of stenosis encountered in pregnancy. Pregnancy in women with artificial heart valves is a major dilemma. Most cardiologists currently recommend a tissue valve for women wanting to have children as, unlike mechanical valves, they avoid the need for anticoagulation, but they wear out more quickly.

Peripartum cardiomyopathy

Peripartum cardiomyopathy is a poorly understood condition, with an incidence of 1 : 1500 to 1 : 4000 live births. It has been defined clinically as the onset of cardiac failure with no identifiable cause in the last month of pregnancy or within 5 months after delivery, in the absence of heart disease before the last month of pregnancy ( ). It is associated with older maternal age, greater parity, black race, pre-eclampsia and multiple gestations ( ). Diagnosis rests on the echocardiographic identification of new left ventricular systolic dysfunction during a limited period around parturition, in a woman with symptoms and signs of heart failure and when other causes of cardiomyopathy have been excluded. All patients usually exhibit cardiomegaly on chest X-ray. Endomyocardial biopsy demonstrates myocarditis in up to 76% of patients, and may be necessary where the diagnosis is unclear. Treatment of peripartum cardiomyopathy includes diuretics to decrease pulmonary congestion and volume overload and vasodilators to reduce afterload. Hydralazine is the drug of choice prepartum, in addition to nitrates ( ). ACE inhibitors are the mainstay of treatment postpartum, even in mothers who are breastfeeding. The beta-blocker carvedilol has been shown to improve overall survival in pregnant women with dilated cardiomyopathy. Atrial arrhythmias should be treated with digoxin, which may also be used for its positive inotropic effect ( ). The benefits of class 3 (amiodarone) and class 4 (verapamil) agents needs to be balanced against their side-effects: fetal hypothyroidism and premature delivery, fetal bradycardia, heart block and hypotension respectively. Patients with poor cardiac function, as evidenced by an ejection fraction <35%, are at risk of thromboembolism and anticoagulation may be considered ( ).

After stabilisation of the mother’s symptoms, in most cases induction and vaginal delivery can be attempted in consultation with consultant obstetrician and anaesthetic staff ( ). The advantages of vaginal delivery are minimal blood loss, greater haemodynamic stability, avoidance of surgical stress and less chance of postoperative infection and pulmonary complications. Effective pain management is a necessity to avoid further increases in cardiac output from pain and anxiety.

Myocardial infarction

Ischaemic heart disease in pregnancy is uncommon, occurring in an estimated 1 in 10 000 deliveries ( ). Myocardial infarction is more common during the third trimester or puerperium of either the first or second pregnancies. occurs within 2 weeks of labour or delivery, mortality may be as high as 45% ( ). Patients typically present with ischaemic chest pain in the presence of an abnormal electrocardiogram (ECG) and elevated cardiac enzymes. Symptoms may often be masked or unclear during labour and delivery, and the ECG and cardiac enzymes can be insensitive. Cardiac-specific troponin I is a more sensitive indicator of myocardial infarction than creatinine kinase muscle–bone serum concentrations, which increase during normal labour ( ).

Management of myocardial infarction must involve early coronary angiography. In the immediate postpartum period, spontaneous coronary artery dissection is the most common cause of myocardial infarction. The pathophysiological mechanisms responsible in the coronary arteries are similar to those responsible for aortic dissection, although the exact pathogenesis remains unclear. Most women with peripartum coronary artery dissection have no risk factors for coronary artery disease, but most affect the left anterior descending artery ( ). Treatments include coronary stenting and emergency coronary artery bypass grafting.

Intrauterine fetal death

Despite advances in antenatal monitoring, women with poorly controlled diabetes still have an increased incidence of intrauterine fetal death, especially beyond the due date. The underlying mechanism has not been elucidated, but relates to glucose control as reflected in the glycosylated haemoglobin.

Screening for gestational diabetes and impaired glucose tolerance

There are few conclusive data to support a screening programme for gestational diabetes in all age group mothers, as only small numbers of young and lean women will go on to develop gestational diabetes. What has been shown is that 75 g oral glucose loading is an appropriate mode of testing. If the screening test is abnormal, then the pregnant mother should go on to have an oral glucose tolerance test. The diagnostic criteria are shown in Figure 11.1 .

Revised World Health Organization criteria for 75 g oral glucose tolerance test during pregnancy.

Management of diabetic pregnancy

Just as outside pregnancy the aim is to keep to a normal blood glucose level, diet, insulin and oral hypoglycaemic agents are the key components of diabetic management. A meta-analysis into large randomised controlled trials comparing oral hypoglycaemic and insulin demonstrates that there were no differences in glycaemic control or pregnancy outcomes, including incidence of babies that were large for gestational age, caesarean sections and increased birthweight ( ).

Labour and the puerperium

Preterm delivery is more common in diabetic pregnancy, and, if steroids are given to promote fetal lung maturity, the hyperglycaemic effect requires extra monitoring, but not usually a sliding scale of insulin.

Women with well-controlled diabetes, no vascular disease and a normally grown fetus appear to be at no more risk than non-diabetic counterparts and may be allowed to carry at least to the due date. With a macrosomic fetus and poor glucose control, early delivery may be contemplated to reduce the risk of stillbirth.

During labour women with type 1 diabetes can be treated with an insulin sliding scale, 10% glucose solution and hourly blood glucose monitoring. Once the baby is delivered the rate of insulin infusion should be reduced, or stopped if the woman has insulin-requiring gestational diabetes or type 2 diabetes. Insulin requirements fall back to prepregnancy levels as soon as the placenta has been delivered.

Breastfeeding and effects on glycaemic control

Women with insulin-treated pre-existing diabetes are at increased risk of hypoglycaemia in the postnatal period, especially when breastfeeding. Women with gestational diabetes should discontinue hypoglycaemic treatment after birth. Women with pre-existing type 2 diabetes who are breastfeeding can resume or continue to take hypoglycaemic agents following birth.