Venous thromboembolic disease in pregnancy and the early postnatal period

Venous thromboembolism (VTE) is a condition in which the blood clots inappropriately, and which is associated with considerable morbidity and mortality. The term VTE encompasses a continuum, including both deep vein thrombosis (DVT) (the formation of clots in the deep veins of the body ‐ predominately in the legs), and pulmonary embolism (PE) (which occurs when a clot in a deep vein breaks free and is carried to the arteries of the lungs) (Goldhaber 2012). Two of the most common initial symptoms of DVT are pain and swelling in an extremity (such as the lower leg), while symptoms and signs of PE include dyspnoea (shortness of breath), tachypnoea (rapid breathing), chest pain and haemoptysis (coughing up blood). Severe cases of PE can include signs of cyanosis (blue discolouration, particularly of the lips and fingers), and may results in collapse and sudden death (ACOG 2011; Greer 2012).

Pregnancy is associated with a number of physiological and anatomic changes that can increase the risk of VTE (ACOG 2011; Lussana 2012). During pregnancy there is a switch in the global haemostatic balance towards a hypercoagulable state (plasma levels of coagulation factors, fibrinogen, Von Willebrand factor and other markers of thrombin generation are increased in pregnancy) (Andersson 1996); a mechanism which protects the mother against excessive bleeding during birth. Other factors contributing to the higher risk of VTE in pregnancy include increased venous stasis, decreased venous outflow (Gordon 2007; Macklon 1997), compression of the inferior vena cava and pelvic veins by the enlarging uterus, and decreased mobility (Kovacevich 2000).

VTE is one of the most common causes of maternal mortality in high‐income countries (Atrash 1990; Bauersachs 2009; CMACE 2011; Dept of Health 1998; Högberg 1994; Lewis 2004; Sultan 2011), with most of the maternal deaths being due to PE. As well as directly causing maternal mortality, VTE can also lead to serious long‐term maternal morbidity (Lindhagen 1986), including venous insufficiency, often manifesting as a painful and sometimes ulcerating leg, due to the compromised blood flow to the limb.

Epidemiology

The risk of VTE in women during pregnancy and the immediate postnatal period is substantially higher than in non‐pregnant women of the same age. A case‐ control study (of 285 patients and 857 control participants) reported that compared with non‐pregnant women, the risk of VTE was increased five‐fold during pregnancy, and by 60‐fold during the first three months after birth (Pomp 2008). While the relative risk of VTE is greatly increased for women during pregnancy, the absolute risk remains low, estimated at around one to two in 1000 pregnancies (Arya 2011; Greer 2012; Heit 2005; James 2006; Lindqvist 1999; Lussana 2012). Although much evidence has suggested that the incidence of VTE is roughly similar across the three trimesters, a recent study has suggested that the risk may in fact increase exponentially across the duration of the pregnancy (Virkus 2011).

One of the best estimates of the incidence of VTE is believed to have come from the Lindqvist 1999 study, conducted in Sweden, which linked maternity and hospital admission data, thus avoiding problems of underestimation (of events not recorded as pregnancy‐related) faced by earlier studies. The incidence in this study was 0.13% (Lindqvist 1999), compared with other figures of 0.11% (Macklon 1996), 0.09% (Andersen 1998), 0.06% (Gherman 1999) and 0.06% (Rutherford 1991). Each of these estimates related to all pregnant women rather than to any particular group of women at risk; and much of their variation may be accounted for by differences between populations in their risk factors for VTE, along with differences in use of preventative measures.

In pregnancy, acute DVT is believed to be three to four times more common than acute PE in the antepartum period, with approximately 80% of pregnancy‐associated VTE being DVT and 20% to 25% being PE (James 2006; Simpson 2001). The incidence of VTE, especially PE, however is believed to be much higher during the immediate postpartum period (Heit 2005) (strongly associated with caesarean birth) (with between 40% and 60% of all acute PE cases reported to occur postpartum; and an estimated 15‐fold increased risk of PE postpartum, compared with antepartum) (Gherman 1999; Heit 2005).

A study examining trends over time suggested that the incidence of VTE during pregnancy remained fairly constant between 1966 and 1995, while the incidence in PE during the postnatal period decreased (Heit 2005). The most recent report from the United Kingdom Centre for Maternal and Child Enquiries (reviewing maternal deaths in the United Kingdom) encouragingly supported a decline overall in deaths associated with VTE in recent years; with a maternal mortality rate (for VTE) of 0.79 per 100,000 pregnancies (CMACE 2011).

Risk factors

Some groups of women have a higher risk of developing VTE. The most important individual risk factor for VTE in pregnancy is a personal history of thrombosis (ACOG 2011). For women who have had a previous thrombosis in pregnancy, the risk of VTE increases considerably in subsequent pregnancies if antenatal thromboprophylaxis is not used (Brill‐Edwards 2000; De Stefano 2006), with an estimated increased risk of recurrence of three‐ to four‐fold (Pabinger 2002). Another important individual risk factor for VTE in pregnancy is the presence of an inherited or acquired thrombophilia (a condition that predisposes individuals to developing thromboses) (ACOG 2011; Alfirevic 2002; James 2006; Larciprete 2007; Robertson 2006). The risk of a thromboembolic event occurring during pregnancy has been shown to differ according to the nature of the thrombophilia, with estimates of risk varying from 5% to 33% (Conard 1990; Friederich 1996; Pomp 2008).

Other pregnancy‐related factors shown to increase the risk of pregnancy‐related VTE include multiple gestation, pre‐eclampsia, prolonged labour and caesarean section (especially in the emergency setting). In a case‐control study conducted in the United Kingdom, the overall risk of VTE was 0.09%, but there was a much higher risk of events in the postnatal period following caesarean birth. In this study, the risk in the antenatal period was estimated as 0.18% following caesarean section compared with 0.03% without caesarean section (Simpson 2001). Obesity, smoking, advanced maternal age, heart disease, family history of VTE, and prolonged immobilisation are other commonly reported risk factors (James 2006; Knight 2008; Lindqvist 1999; Simpson 2001).

Thromboprophyaxis

While the evidence correlating risk factors and the occurrence of pregnancy‐related VTE has to date been imprecise, there is currently broad agreement (as shown in one recent review of guidelines from the United States and from other international organisations (Okoroh 2012)) that women should be assessed for VTE risk preconception and again during pregnancy in order to guide VTE thromboprophylaxis (any measures taken in order to prevent thrombosis).

A recent review of international guidelines acknowledged the uncertainties surrounding recommendations for thromboprophylaxis globally (Wu 2013), highlighting differences both within current United Kingdom recommendations (between the recent guidance from the National Institute for Health and Clinical Excellence (NICE) (Hill 2010) and from the Royal College of Obstetricians and Gynaecologists (RCOG) (RCOG 2009), and between the United Kingdom guidelines and a variety of international guidelines. Inconsistencies in international guidelines include advice regarding which groups of women to offer thromboprophylaxis to, and which options should be offered to pregnant women. Recommendations for the duration of prophylaxis also vary. Women who have had a previous episode of VTE may, for example, be recommended long‐term antenatal prophylaxis as well as prolonged postnatal prophylaxis, while women undergoing caesarean section may, for example, only be recommended postnatal prophylaxis for a few days.

Options for VTE thromboprophylaxis include both pharmacologic agents and nonpharmacologic methods (NHMRC 2009).

Pharmacologic agents that have been used include:

• unfractionated heparin (UFH) or low molecular weight heparin (LMWH);

• aspirin, a platelet aggregation inhibitor;

• warfarin, a vitamin K antagonist;

• hydroxyethyl starch (HES), a nonionic starch derivative;

• fondaparinux, a selective inhibitor of activated Factor X;

• danaparoid, a heparinoid.

Mechanical methods that have been used include:

• graduated compression stockings;

• intermittent pneumatic compression;

• venous foot pumps;

• early mobilisation;

• surveillance.

Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period

Pharmacological agents, such as heparin, warfarin and aspirin have been used in VTE prevention due to their anticoagulant properties. Thrombin has a key role in haemostasis and thrombosis, and thus anticoagulant strategies to inhibit thrombogenesis focus on either inhibiting thrombin or its generation. UFH, LMWH and coumarin derivatives (such as warfarin) prevent the generation of thrombin through a variety of mechanisms (Ansell 2004). Heparins (such as UFH and LMWH) exert their anticoagulant activity by activating antithrombin, which subsequently inhibits thrombin (and Factor Xa). Coumarin derivatives (such as warfarin) however, produce their anticoagulant effect by interfering with the cyclic conversion of vitamin K (which is required as a co‐factor for the 'carboxylation' of vitamin K dependent proteins, which include a number of coagulation factors); by blocking this process, the coagulation factors that are produced have no/little biological activity. Selective inhibitors of activated Factor Xa (such as fondaparinux), exert their antithrombotic activity by neutralisation of Factor Xa, which interrupts the blood coagulation cascade, inhibiting thrombin formation and thrombus development (Ansell 2004).

Non‐pharmacological methods, such as graduated compression stockings, intermittent pneumatic compression or venous foot pumps have been used for their ability to reduce venous statis and blood stagnation by promoting venous blood flow through external compression (NHMRC 2009).

The pharmacologic agents and non‐pharmacologic methods of thromboprophylaxis discussed above have been used, and have been shown to be effective, in reducing the risk of VTE in a variety of non‐pregnant patient groups, such as those with chronic illness and in individuals following surgery. The effectiveness of these agents/methods have been demonstrated in a number of Cochrane reviews, for example: the Alikhan 2010 review supported the use of heparin thromboprophylaxis in medical patients presenting with acute medical illness (with a significant risk reduction in DVT and PE shown); the Testroote 2008 review supported the use of LMWH in outpatients to significantly reduce VTE when immobilisation of the lower leg is required; and the Kakkos 2008 review revealed that compared with compression alone, and compared with pharmacologic prophylaxis, combined prophylactic modalities can significantly decrease the incidence of VTE and DVT respectively.

Despite previously established benefits of these methods of thromboprophylaxis for VTE in non‐pregnant patient groups, there is ongoing debate about whether thromboprophylaxis for VTE in pregnancy is cost‐effective and beneficial (with particular concern as to whether benefits outweigh the potential harms); routine screening of all pregnant women to identify women with thrombophilias, for example, has not been recommended (Okoroh 2012), and antenatal prophylaxis for all women with known thrombophilias remains controversial (Brenner 2003; Middeldorp 2003; Okoroh 2012; Wu 2005).

Pharmacological methods may cause adverse effects that could be sufficiently severe or common to outweigh the benefits of thromboprophylaxis. Heparin does not cross the placenta and is believed to be safe for the fetus, and therefore, has generally been used for antenatal therapy. However, it can cause adverse effects for the mother (Nelson‐Piercy 1997); there is a risk of thrombocytopenia (low platelets), bleeding and allergic reactions and symptomatic osteoporosis (loss of bone density, leading to fractures) in the longer term. When used after caesarean section, heparin may increase the frequency of bleeding and wound complications. Originally, UFH was used, but this now appears to have been largely superseded, at least for use in pregnancy and postnatally, by LMWH. The advantages of LMWH over UFH include a longer half‐life (allowing once or twice‐daily subcutaneous dosing), high bioavailability, and predictable anticoagulant response; avoiding the need for dose adjustment, or laboratory monitoring in most patients. In addition, LMWHs are thought to be associated with a lower risk of adverse effects (e.g. osteoporosis, and thrombocytopenia) (Bauersachs 2009). Warfarin is known to cause congenital abnormalities (Hall 1980) and it has, therefore, rarely been used in the first trimester or in the last few weeks of pregnancy (Bauersachs 2009). Both heparin and warfarin have been used for postnatal thromboprophylaxis, as they have been considered as safe for mothers who are breastfeeding (Bauersachs 2009; Letsky 1997; Orme 1977).

Low‐dose (e.g. 60 mg to 75 mg) aspirin has been widely used in pregnancy in an attempt to prevent the development of pre‐eclampsia (Knight 2001). Aspirin is usually well‐tolerated and has few adverse effects, and its use for thromboprophylaxis in orthopaedic surgery (PEP Trial 2000) suggests that it may have a role to play in the prevention of VTE in pregnancy (Bauersachs 2009). Hydroxyethyl starch (HES) has been used for thromboprophylaxis in the past however, it is believed to be no longer in use because of the risk of anaphylaxis (Paull 1987).