Obesity increases the risk of venous thromboembolism, and pregnancy also increases the risk, particularly around delivery and in the puerperium. Pregnancy complications, which often involve bed rest in hospital, increase the risk still further. This chapter reviews recent studies aimed at quantifying these risks and discusses the mechanisms linking obesity, pregnancy and thromboembolism. It is now apparent that obesity is a proinflammatory condition that creates a prothrombotic milieu, but as yet little is known about how this interacts with pregnancy. Awareness of interacting risk factors has led to guidelines for risk assessment in pregnancy, and implementation of thromboprophylaxis guidelines has been followed by a dramatic fall in deaths from thromboembolism, which was for many years the leading cause of direct maternal deaths in the UK. This chapter summarises the guidelines on the prevention, diagnosis and treatment of thromboembolism in pregnancy and discusses the next steps to further reduce mortality.
Highlights
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Obesity is a risk factor for venous thromboembolism in pregnancy and the puerperium.
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Guidelines on prophylaxis have reduced maternal mortality from thromboembolism.
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The dosages of heparin for both prophylaxis and treatment are weight related.
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More lives could be saved in the future by better adherence to guidelines.
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Research is needed on the links between pregnancy, obesity and thromboembolism.
Epidemiology
Both obesity and pregnancy increase the risk of venous thromboembolism (VTE) and the combination is sometimes fatal. Between 1991 and 2005, VTE was the leading cause of direct maternal deaths in the UK. During that 15-year period, the link between maternal mortality from VTE and risk factors including obesity became increasingly clear , and in 2004 the Royal College of Obstetricians and Gynaecologists (RCOG) published guidelines on thromboprophylaxis for women at risk. By 2008, a dramatic reduction in maternal deaths from VTE had been achieved in the UK , but preventable deaths are still occurring .
Incidence of VTE
The background incidence of VTE in non-pregnant, non-puerperal women of reproductive age is 2.4 or 4.6/10,000 woman-years, according to studies in Sweden and the USA respectively, and a recent systematic review . In pregnancy, the risk is increased fourfold, and in the post-partum period it is increased 20-fold to a rate of 99/10,000 woman-years . The period of highest risk is around delivery (from 2 days before to 1 day after parturition), when according to the Swedish study the risks of deep venous thrombosis (DVT) and pulmonary embolism (PE) are, respectively, 115 and 81 times higher than in the non-pregnant state .
The incidence of pregnancy-associated VTE has risen in the past few years. A US study of eight million birth records found a steady increase from 1999 to 2008. Overall, during that 10-year period, the estimated incidence of VTE was 167.7/100,000 births (i.e., just under one in 600 births) with an average case fatality rate of 0.41% (i.e., one in 250 cases of VTE). The resulting overall mortality rate of one in 150,000 births is very similar to that reported by the Confidential Enquiries into Maternal Deaths (CEMD) in the UK in 2006–2008, when there were 18 deaths from VTE among 2,291,493 ‘maternities’ (i.e., births and miscarriages), giving a fatality rate of one in 127,305 pregnancies .
A study based on the National Inpatient Sample in the USA identified an estimated 64,413,973 admissions for pregnancy-related complications between 1994 and 2009. Over that period, there was a 14% increase in the rate of overall VTE-associated pregnancy hospitalisations: the rate among delivery hospitalisations remained fairly constant but antepartum and post-partum hospitalisations increased by 17% and 47%, respectively. Obesity was identified as a factor in this increase, with the prevalence of hypertension and obesity being increased twofold among VTE-associated admissions. The authors recommended that clinicians should have a heightened awareness of the risk of VTE among pregnant women, “particularly those with comorbid conditions” .
The increased risk of VTE continues for at least 6 weeks after delivery, but in 2011 a systematic review commented that “when this risk returns to baseline is not clear from current data” . A recent study concluded that a measurable increase persists for at least 12 weeks after delivery, although beyond 6 weeks the absolute increase in risk is low. This study was based on 1,687,930 women with a first recorded hospital delivery in California between 2005 and 2010. In the 18 months after delivery, there were 720 cases of VTE, 248 cases of stroke, and 47 cases of myocardial infarction. All three types of thrombosis showed the same pattern – a markedly increased risk in the first 6 weeks post partum, a measurably increased risk for the next 6 weeks, and no increased risk thereafter. This indicates that the pregnancy-associated risk affects the arterial as well as the venous system. The authors suggested that research is needed into the risk/benefit ratio of continuing thromboprophylaxis beyond 6 weeks post delivery.
The rise in obesity
The recent increase in the incidence of VTE may be largely due to the rising prevalence of obesity. It has been calculated that almost one-third of all VTE events could be prevented by weight loss . In the UK, the proportion of women with obesity, defined as a body mass index (BMI) of >30 kg/m 2 , increased from 16% in 1993 to 24% in 2009, and obesity now affects >25% of women in the UK . A recent report based on the Million Women Study looked at almost three million UK hospital admissions over a 9-year period and estimated that one in eight admissions were likely to be due to overweight or obesity . In the USA, more than one-third of women are obese and 8% of reproductive-age women are extremely obese (BMI >40 kg/m 2 ), with the problem being most severe among non-Hispanic black women .
This increase has affected the obstetric population. Between 1990 and 2004, the proportion of UK women who were obese at the start of pregnancy rose from 9.9% to 16%, and the rate of increase was seen to accelerate during this period . Recent estimates put the prevalence of obesity among the UK obstetric population at between 17.7% and 21% . A 2009 survey by the Centre for Maternal and Child Enquiries (CMACE) found that 5% of women giving birth in the UK had a BMI of >35 kg/m 2 . The UK Obstetric Surveillance System (UKOSS) reported that in 2007–2008 about one in 1000 women had extreme obesity (BMI > 50 kg/m 2 ) and that it was associated with poor pregnancy outcomes including pre-eclampsia and diabetes .
Risk factors for VTE
Obesity is only one of several VTE risk factors, the most important of which are thrombophilia and a past history of VTE. Estimates of the exact degree of risk have varied among recent large studies. The US Nationwide Inpatient Sample was used to study 9,058,162 pregnancy admissions and 73,834 puerperal admissions in 2000–2001 . There were 14,335 VTE events (79% DVT and 21% PE or both), of which 50% occurred during pregnancy and 50% in the puerperium. The overall risk of VTE was 1.72 per 1000 deliveries. The most striking risk factors were thrombophilia (odds ratio (OR) 51.8), history of thrombosis (OR 24.8) and antiphospholipid syndrome (OR 15.8). Lupus, heart disease and sickle cell disease had ORs of 8.7, 7.1 and 6.7, respectively. For obesity, the OR was 4.4. Smaller but significant increases in risk were seen with the other risk factors – smoking (OR 1.7), age >35 (OR 1.4) and Black ethnicity (OR 1.4).
In another large study , all births in Denmark from 2003 to 2010 were linked to national registers for hospital admissions and drug dispensing from pharmacies. The study identified 337 cases of VTE among 299,810 pregnancies. Being underweight (BMI < 18.5) halved the risk and being overweight (BMI >25 but <30) increased it by a factor of 1.3, but neither obesity nor age had any significant effect in this study. A history of previous VTE, by contrast, increased the risk very considerably, with a hazard ratio of 72.65.
Another Danish study identified 748 cases of VTE among 1,297,037 pregnancies between 1995 and 2009 . Women with a history of previous VTE were excluded from this study. The risk of VTE during pregnancy was increased by hyperemesis, multiple pregnancy and infection, and the risk of VTE during the puerperium was increased by obesity, caesarean section, post-partum haemorrhage and infection. An important finding was that hospitalisation was the most important risk factor during both pregnancy and the puerperium. The condition necessitating hospitalisation (e.g., hyperemesis) may explain this, but it is also possible that admission to hospital is in itself a risk factor. In an English study, the risk of first VTE in pregnant women increased during admissions to hospital not related to delivery and remained significantly higher in the 28 days after discharge . These findings underline the fact that some although risk factors are present from the start of pregnancy, others are transient, requiring reassessment of risk as pregnancy progresses.
In the UK in 2005–2006, UKOSS carried out a case–control study of antenatal PE, comparing 143 patients with 259 matched control women. It found that 70% of the patients with PE had identifiable classical risk factors for VTE. The main ones were multiparity, with an adjusted odds ratio (aOR) of 4.03, and BMI >30 kg/m 2 , with an aOR of 2.65. A French study also highlighted the effect of obesity: it found that the apparent significance of insulin resistance as a risk factor disappeared once adjustment was made for obesity .
Pathophysiology
Physical effects such as reduced mobility and increased venous stasis are part of the link between obesity and VTE. Venous blood flow velocity in the legs is reduced by approximately 50% in the third trimester of pregnancy . Outside pregnancy, VTE is slightly more common in the left leg than the right, probably due to compression of the left iliac vein by the overlying right iliac artery, but in pregnancy this effect is increased, with 85% of DVTs affecting the left leg. In obese women, the physical effects of body fat may add to this physical limitation of venous return, but another major factor is the proinflammatory, prothrombotic and hypofibrinolytic milieu that results from obesity .
Once regarded as an inert energy store, fat is now recognised to be metabolically active, producing hormones, cytokines and chemokines . Around half the cells in adipose tissue are leukocytes, immune cells, endothelial cells and other non-adipocytes. The process of adipose tissue remodelling involves angiogenesis, infiltration by inflammatory cells and the secretion of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and transforming growth factor. Aberrant expression of adipose tissue-derived cytokines (‘adipokines’) modulates proinflammatory and prothrombotic pathways in obesity. Increased BMI is associated with elevated circulating levels of fibrinogen and Factor VII, and chronic inflammation and impaired fibrinolysis are mediators of obesity-associated VTE .
One of the most extensively studied adipokines is leptin, circulating levels of which are increased in obesity. Leptin receptors in the hypothalamus are involved in the transmission of satiety signals, but receptors also exist on vascular cell types, and leptin appears to exert direct thrombotic effects. In vitro stimulation of human platelets with leptin increases platelet adhesion to fibrinogen, and leptin may also promote the generation of active tissue factor (formerly known as thromboplastin), the primary initiator of the extrinsic coagulation cascade . Another adipokine, adiponectin, has anti-inflammatory properties and has been shown to exert anti-thrombotic effects by modulating the function of endothelial cells and platelets: reduced plasma levels of adiponectin have been reported in obese individuals .
Intra-abdominal adipose tissue is thought to be particularly active. Central obesity, a condition in which there is a decrease in subcutaneous adipose tissue and an increase in intra-abdominal and visceral fat, is a key feature of the metabolic syndrome (metS), which is a risk factor for cardiovascular disease. MetS is slightly commoner in men but affects both sexes. It is associated with platelet hyperactivity, hypercoagulability, reduced fibrinolysis and endothelial dysfunction. Non-obese individuals can have metS and not all obese subjects develop it, but its prevalence is higher in obesity .
The increased plasma levels of tissue factor in obesity are probably due to a variety of factors in addition to leptin. The chronic low-grade inflammatory process associated with obesity is also reflected by increased circulating levels of C-reactive protein, which may affect platelet adhesion and the production of procoagulant factors within the vascular wall. Obesity also upregulates the expression of plasminogen activator inhibitor 1 (PAI-1) in visceral fat: studies in mice have linked over-expression of PAI-1 to venous thrombosis, and elevated plasma levels of PAI-1 have been reported in humans . Research on these mechanisms is likely to continue and increase, as they are related not only to VTE but also to coronary artery disease and cancer, which are also more common in obesity .
Current studies are deepening our knowledge of mechanisms underlying the classic model of ‘Virchow’s triad’ (venous stasis, endothelial damage and hypercoagulability) but much remains to be clarified. In particular, we still know little about the interaction between the endocrine and paracrine changes of obesity and those of pregnancy. Already, however, researchers are cautioning that they are unlikely to produce a ‘magic bullet’ to counteract obesity. Rather, research is providing a more persuasive basis for existing health advice. As one review commented: “A better understanding of the interactions of the adipose tissue with circulating and vascular cells can only support (and by no means replace) the urgent need for education of the population and lifestyle modification in order to achieve and maintain a ‘healthy’ bodyweight” .
Pathophysiology
Physical effects such as reduced mobility and increased venous stasis are part of the link between obesity and VTE. Venous blood flow velocity in the legs is reduced by approximately 50% in the third trimester of pregnancy . Outside pregnancy, VTE is slightly more common in the left leg than the right, probably due to compression of the left iliac vein by the overlying right iliac artery, but in pregnancy this effect is increased, with 85% of DVTs affecting the left leg. In obese women, the physical effects of body fat may add to this physical limitation of venous return, but another major factor is the proinflammatory, prothrombotic and hypofibrinolytic milieu that results from obesity .
Once regarded as an inert energy store, fat is now recognised to be metabolically active, producing hormones, cytokines and chemokines . Around half the cells in adipose tissue are leukocytes, immune cells, endothelial cells and other non-adipocytes. The process of adipose tissue remodelling involves angiogenesis, infiltration by inflammatory cells and the secretion of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and transforming growth factor. Aberrant expression of adipose tissue-derived cytokines (‘adipokines’) modulates proinflammatory and prothrombotic pathways in obesity. Increased BMI is associated with elevated circulating levels of fibrinogen and Factor VII, and chronic inflammation and impaired fibrinolysis are mediators of obesity-associated VTE .
One of the most extensively studied adipokines is leptin, circulating levels of which are increased in obesity. Leptin receptors in the hypothalamus are involved in the transmission of satiety signals, but receptors also exist on vascular cell types, and leptin appears to exert direct thrombotic effects. In vitro stimulation of human platelets with leptin increases platelet adhesion to fibrinogen, and leptin may also promote the generation of active tissue factor (formerly known as thromboplastin), the primary initiator of the extrinsic coagulation cascade . Another adipokine, adiponectin, has anti-inflammatory properties and has been shown to exert anti-thrombotic effects by modulating the function of endothelial cells and platelets: reduced plasma levels of adiponectin have been reported in obese individuals .
Intra-abdominal adipose tissue is thought to be particularly active. Central obesity, a condition in which there is a decrease in subcutaneous adipose tissue and an increase in intra-abdominal and visceral fat, is a key feature of the metabolic syndrome (metS), which is a risk factor for cardiovascular disease. MetS is slightly commoner in men but affects both sexes. It is associated with platelet hyperactivity, hypercoagulability, reduced fibrinolysis and endothelial dysfunction. Non-obese individuals can have metS and not all obese subjects develop it, but its prevalence is higher in obesity .
The increased plasma levels of tissue factor in obesity are probably due to a variety of factors in addition to leptin. The chronic low-grade inflammatory process associated with obesity is also reflected by increased circulating levels of C-reactive protein, which may affect platelet adhesion and the production of procoagulant factors within the vascular wall. Obesity also upregulates the expression of plasminogen activator inhibitor 1 (PAI-1) in visceral fat: studies in mice have linked over-expression of PAI-1 to venous thrombosis, and elevated plasma levels of PAI-1 have been reported in humans . Research on these mechanisms is likely to continue and increase, as they are related not only to VTE but also to coronary artery disease and cancer, which are also more common in obesity .
Current studies are deepening our knowledge of mechanisms underlying the classic model of ‘Virchow’s triad’ (venous stasis, endothelial damage and hypercoagulability) but much remains to be clarified. In particular, we still know little about the interaction between the endocrine and paracrine changes of obesity and those of pregnancy. Already, however, researchers are cautioning that they are unlikely to produce a ‘magic bullet’ to counteract obesity. Rather, research is providing a more persuasive basis for existing health advice. As one review commented: “A better understanding of the interactions of the adipose tissue with circulating and vascular cells can only support (and by no means replace) the urgent need for education of the population and lifestyle modification in order to achieve and maintain a ‘healthy’ bodyweight” .
Prevention of VTE
History
The first important step in reducing maternal mortality from VTE came 50 years ago when attitudes changed towards the need for bed rest (‘lying in’) after childbirth. In the 1950s and early 1960s, most maternal deaths from VTE occurred after spontaneous vaginal delivery, but as the benefits of early postnatal ambulation were recognised this total fell dramatically . Avoidance of unnecessary bed rest is still important, particularly for obese pregnant women, but this lesson is still sometimes forgotten .
The next step was recognition that some pregnant women are at an increased risk of VTE. The UK CEMD played a leading role in drawing attention to risk factors. The role of obesity was first mentioned in the 1973–1975 report and the need for prophylactic anticoagulant therapy for high-risk women – those with previous proven DVT or PE – was first recommended in the 1979–1981 report. The 1988–1990 report called for wider use of prophylaxis in high-risk cases, and the 1991–1993 report repeated this call, pointing out that the National Confidential Enquiry into Perioperative Deaths (NCEPOD) had highlighted the need for thromboprophylaxis in gynaecological surgery .
Nevertheless, surgeons and obstetricians were initially cautious about anticoagulant prophylaxis, fearing that it would worsen the risk of surgical bleeding or post-partum haemorrhage (PPH). The breakthrough came in 1995, when the RCOG published a report on prophylaxis against thromboembolism in major gynaecological surgery and caesarean section . It contained a simple risk assessment profile for caesarean section, which included obesity (weight >80 kg) and age >35 years among the ‘moderate’ risk factors ( Table 1 ). The report not only focussed on surgical procedures but also recommended thromboprophylaxis for women with previous pregnancy-related VTE and those who had had multiple episodes of VTE.
LOW RISK – Early mobilisation and hydration
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MODERATE RISK – Consider one of a variety of prophylactic measures
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HIGH RISK – Heparin prophylaxis ± leg stockings
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