Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e12

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Deep venous thrombosis and pulmonary embolism in obese women James Drife, MD, FRCOG, FRCPE, FRCSE, FFSRH, FCOG(SA), Emeritus Professor of Obstetrics and Gynaecology, University of Leeds 25 Park Lane, Roundhay, Leeds LS8 2EX, UK

Keywords: obesity venous thromboembolism pregnancy thromboprophylaxis guidelines treatment

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. © 2014 Published by Elsevier Ltd.

Epidemiology Both obesity [1] and pregnancy [2e4] 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

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http://dx.doi.org/10.1016/j.bpobgyn.2014.08.012 1521-6934/© 2014 Published by Elsevier Ltd.

Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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deaths in the UK. During that 15-year period, the link between maternal mortality from VTE and risk factors including obesity became increasingly clear [5], 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 [6], but preventable deaths are still occurring [7]. 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 [8] and the USA [9] respectively, and a recent systematic review [10]. In pregnancy, the risk is increased fourfold, and in the post-partum period it is increased 20-fold [9] to a rate of 99/10,000 woman-years [10]. The period of highest risk is around delivery (from 2 days before to 1 day after parturition), when according to the Swedish study [8] the risks of deep venous thrombosis (DVT) and pulmonary embolism (PE) are, respectively, 115 and 81 times higher than in the non-pregnant state [10]. The incidence of pregnancy-associated VTE has risen in the past few years. A US study of eight million birth records [11] 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 2006e2008, 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 [6]. 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” [12]. 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” [9]. A recent study [13] 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 e 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 [14]. In the UK, the proportion of women with obesity, defined as a body mass index (BMI) of >30 kg/m2, increased from 16% in 1993 to 24% in 2009, and obesity now affects >25% of women in the UK [15]. 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 [16]. In the USA, more than one-third of women are obese and 8% of reproductive-age women are extremely obese (BMI >40 kg/m2), with the problem being most severe among nonHispanic black women [17]. Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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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 [18]. Recent estimates put the prevalence of obesity among the UK obstetric population at between 17.7% and 21% [15]. 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/m2 [19]. The UK Obstetric Surveillance System (UKOSS) reported that in 2007e2008 about one in 1000 women had extreme obesity (BMI > 50 kg/m2) and that it was associated with poor pregnancy outcomes including pre-eclampsia and diabetes [20]. 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 2000e2001 [21]. 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 e smoking (OR 1.7), age >35 (OR 1.4) and Black ethnicity (OR 1.4). In another large study [22], 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 kg/m2, 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 [25]. 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 [26]. 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. [26] 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 [27]. Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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Once regarded as an inert energy store, fat is now recognised to be metabolically active, producing hormones, cytokines and chemokines [28]. 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 [29]. 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 [30]. Another adipokine, adiponectin, has antiinflammatory 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 [28]. 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. Nonobese individuals can have metS and not all obese subjects develop it, but its prevalence is higher in obesity [31]. 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 [30]. 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 [28]. Current studies are deepening our knowledge of mechanisms underlying the classic model of ‘Virchow's triad’ (venous stasis, endothelial damage and hypercoagulability) [32] 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” [30].

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 [33]. Avoidance of unnecessary bed rest is still important, particularly for obese pregnant women, but this lesson is still sometimes forgotten [34]. Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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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 1973e1975 report and the need for prophylactic anticoagulant therapy for highrisk women e those with previous proven DVT or PE e was first recommended in the 1979e1981 report. The 1988e1990 report called for wider use of prophylaxis in high-risk cases, and the 1991e1993 report repeated this call, pointing out that the National Confidential Enquiry into Perioperative Deaths (NCEPOD) had highlighted the need for thromboprophylaxis in gynaecological surgery [35]. 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 [36]. 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.

Current guidelines Publication of the 1995 RCOG report was followed by a dramatic fall in deaths from VTE after caesarean section, which strongly suggested that RCOG guidelines could be effective in changing practice and saving lives [5]. Nevertheless, VTE remained the leading cause of maternal mortality in the UK for the rest of the 1990s and indeed until 2005. Guidelines for thromboprophylaxis in vaginal deliveries were included in the 1997e1999 CEMD report, and in 2004 the RCOG published a guideline on thromboprophylaxis during pregnancy, labour and after vaginal delivery [37]. Another dramatic fall in maternal deaths from VTE occurred in the first full triennium after publication of the RCOG guideline (Fig. 1). It was revised in 2009 [38] and similar guidelines were published in the USA [39], Scotland [40], Australia [41] and Italy [42]. With all such guidelines, the key to success is awareness among clinical staff that risk factors are important and that guidelines exist. Risk factors such as obesity and past history of VTE are present from the beginning of pregnancy but others, such as immobilisation or infection, may appear during pregnancy or the puerperium, and therefore risk assessment needs to be repeated by midwives and obstetricians. A major challenge is that clinicians in other specialties, including emergency medicine and general practice, should also know about the guidelines on thromboprophylaxis in pregnancy, but widespread awareness is hard to achieve. Table 1 Risk assessment profile for thromboembolism in caesarean section (1995) (from Ref. [36]). LOW RISK e Early mobilisation and hydration  Elective caesarean section e uncomplicated pregnancy and no other risk factors MODERATE RISK e Consider one of a variety of prophylactic measures  Age >35 years  Obesity (>80 kg)  Para 4 or more  Gross varicose veins  Current infection  Pre-eclampsia  Immobility prior to surgery (>4 days)  Major current illness, for example, heart or lung disease, cancer, inflammatory bowel disease, nephrotic syndrome  Emergency caesarean section in labour HIGH RISK e Heparin prophylaxis ± leg stockings  A patient with three or more moderate risk factors from above  Extended major pelvic or abdominal surgery, for example, caesarean hysterectomy  Patients with a personal or family history of deep vein thrombosis, pulmonary embolism or thrombophilia, paralysis of the lower limbs  Patients with antiphospholipid antibody (cardiolipin antibody or lupus anticoagulant)

Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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Fig. 1. Direct deaths from thrombosis and thromboembolism: UK 1985e2008 (adapted from Ref. [6]). Arrow A: Publication of RCOG Working Party Report [36]. Arrow B. Publication of RCOG Green-top Guideline on thromboprophylaxis [37].

Guidelines and obesity The most recent RCOG guideline [38] recommends that two risk assessments be made e one at booking (to be repeated if circumstances change during the pregnancy) and the second at delivery. If obesity (BMI >30 kg/m2) is noted at the first risk assessment, two other risk factors must also be present (such as age >35 or parity >3) for thromboprophylaxis with low-molecular-weight heparin (LMWH) to be considered. If the woman is hospitalised during pregnancy, only one other risk factor is necessary for consideration of thromboprophylaxis. The second risk assessment is made at delivery, when a distinction is made between BMI >30 and BMI >40 kg/m2. The latter by itself is an indication to consider LMWH prophylaxis for at least 7 days after delivery. If the BMI is >30 kg/m2, only one other risk factor is necessary for consideration of LMWH for at least 7 days, but if two other risk factors are present more prolonged thromboprophylaxis may be considered. The safety and effectiveness of LMWH are now well established [43], and because of its safety profile both the RCOG guideline and the American College of Chest Physicians (ACCP) guideline [39] recommend LMWH over unfractionated heparin (UFH) for thromboprophylaxis. Graduated compression stockings are widely recommended for women at risk but this recommendation is based on studies in hospitalised non-pregnant populations, and stockings may be of less value in the ambulant population [38]. Evidence of their effectiveness in obese patients is scant, and their limitations may be exacerbated by obesity. If thigh circumference is too large (>81 cm), stockings are often not used because of discomfort and they may also impair venous flow by cutting into the thigh. There are similar problems with intermittent pneumatic compression devices in obese women [15]. Body weight is important with regard to the dosage of any drug, including heparin, and the significance of obesity in relation to therapeutic heparin dosage was recognised many years ago [44]. Nevertheless, successive CEMD reports have commented that in some fatal cases the dosage of prophylactic or therapeutic heparin was inadequate [6,35]. Morbidly obese women are recommended to have a higher dose of LMWH, and detailed recommendations on LMWH dosage in relation to body weight are given in the RCOG guideline (Table 2) [38]. In the USA, the ACCP guideline on thromboprophylaxis in pregnancy [39] and the accompanying guideline on general hospital (particularly surgical) patients [45] have surprisingly little to say about obesity as a risk factor, with only brief mention of the relation between BMI and LMWH dosage. In response to this (and pointing out that 33% of the US population is obese), Willett et al. [46] reviewed the literature on heparin dosage in relation to body weight. Only three small studies were identified, in Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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Table 2 Suggested thromboprophylactic doses for antenatal and postnatal LMWH (from Ref. [38]). Weight (kg)

Enoxaparin

Dalteparin

Tinzaparin (75 mg/kg/day)

170 High prophylactic (intermediate) dose for women weighing 50e90 kg Treatment dose

20 mg daily 40 mg daily 60 mg dailya 80 mg dailya 0.6 mg/kg/daya 40 mg 12 hourly

2500 units daily 5000 units daily 7500 units daily 10 000 units daily 75 units/kg/day 5000 units 12 hourly

3500 units daily 4500 units daily 7000 units daily 9000 units daily 75 u/kg/day 4500 units 12 hourly

Antenatal: 1 mg/kg/12 hourly Postnatal: 1.5 mg/kg/daily

100 units/kg/12 hourly or 200 units/kg/daily postnatal

175 u/kg/daily (antenatal and postnatal)

a

May be given in divided doses.

which different dosage schedules were used, and the end point was serum anti-Xa levels rather than the incidence of VTE or bleeding episodes. Willett et al. commented that more studies are needed to establish a standard of care with regard to the most safe and effective enoxaparin dose in obese patients. Effectiveness of thromboprophylaxis Another recent report from the USA summarised the rationale for high-dose heparin thromboprophylaxis in morbidly obese non-pregnant inpatients, pointing out that pneumatic compression devices have limited effectiveness in such patients [47]. The authors reviewed 9241 patients with weight >100 kg discharged between 2010 and 2012 in a health-care system that included three hospitals. They compared hospital-acquired VTE and bleeding episodes in those treated with high-dose thromboprophylaxis and those who received standard doses of heparin or enoxaparin. Among the 3928 morbidly obese patients (BMI >40), high-dose thromboprophylaxis halved the risk of symptomatic VTE, without altering the incidence of bleeding episodes. Arya [48], however, has drawn attention to a high incidence of PPH in obese women in the CMACE report into maternal obesity [19]. Among women with BMI >35, PPH defined as >500 ml was four times higher than in the general obstetric population, and women receiving antenatal LMWH were nine times more likely to have a major PPH (>1000 ml) than those not on LMWH. This is contrary to clinical experience and other evidence suggesting that LMWH is associated with a low risk of PPH, and the interaction between LMWH use and obesity with regard to PPH risk needs further investigation [48]. In the UK, the main evidence for the effectiveness of thromboprophylaxis comes from the maternal mortality reports [6]. Studies of morbidity are now being conducted by UKOSS. In 2005e2006, a national matched caseecontrol study identified 143 women who had had an antenatal PE, and compared them with 259 matched control women. The estimated incidence of PE was 1.3 per 10,000 maternities and 70% of the women had classical risk factors e the main ones being multiparity and BMI >30. Nine women should have received LMWH prophylaxis according to current national guidelines but only three of them did. Six women had a PE after LMWH prophylaxis and three of these were receiving lower-than-recommended doses. Five women died, giving a case fatality rate of 3.5% [7]. The authors commented that “there may be scope for further work on guideline implementation”. Implementation of guidelines The CMACE report on obesity [19] also found that only half of women with a BMI >40 were offered post-partum thromboprophylaxis. Similar evidence of failure to implement guidelines has come from Ireland. Cregan et al. [49] reviewed 364 charts in a university unit and found that, of the 145 women at a risk of VTE, 69% received thromboprophylaxis but only 54% received the correct weight-adjusted Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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dose. Of the four morbidly obese women in the study, three received thromboprophylaxis but none at the recommended dose. Only 67% of the 364 women in the study had had their BMI recorded, and the authors commented that awareness of the importance of increased BMI needs to be improved. Some clinicians have questioned the reliability of current pregnancy guidelines. Few of the recommendations are ‘Grade A’ e based on evidence from meta-analyses or randomised controlled trials. Most of the recommendations in the RCOG and other guidelines are ‘Grade C’, that is, based on evidence “including studies rated as 2þ directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2þþ” [38]. Studies rated as ‘2þ’ are “well-conducted case-control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal”. This lack of Grade A evidence has caused concern that the widespread use of LMWH may have unintended consequences, and has led to an urgent call for large-scale and well-designed studies [50]. Guideline compilers themselves are well aware of the preponderance of Grade C recommendations and have called for appropriate clinical studies to be carried out to address the inadequacy of present evidence [41]. The cost-effectiveness of LMWH prophylaxis has also been questioned. One hospital estimated that 19% of women delivering had a BMI >30 kg/m2, and that when other risk factors such as age and parity were taken into account, over 50% of women would be at an intermediate or high risk of VTE at some point during pregnancy. These authors questioned the strategy of attributing risk by accumulating factors that individually have a low risk of VTE, in the absence of data indicating that this approach improves clinical outcome [51]. It might be argued, however, that the CEMD has already provided evidence of improved outcome after the implementation of this approach [6]. There are also concerns that recent guidelines, which are more complicated than earlier versions, may not be as easy to implement as their predecessors. Touqmatchi et al. [52] surveyed the implementation of the 2004 RCOG guideline in a single maternity unit in England, prior to updating the local risk assessment protocol in line with the 2010 RCOG guideline. They found that only 60% of patients were adequately assessed and managed antenatally, and 68% postnatally. The authors revised their local protocol in the hope that this would improve risk assessment, and recommend that other units do the same. Diagnosis and treatment Diagnosis VTE rarely causes sudden death without warning. Clinical suspicion is vital for the diagnosis of PE in pregnancy [53], and prompt diagnosis is essential to reduce mortality. The common presentation of DVT is pain and swelling of the leg (particularly the left leg), and there may be tenderness, increased temperature, lower abdominal pain or a raised white cell count [5]. A history of immobilisation is particularly important [54]. With PE, breathlessness is the main feature, usually with chest pain, and there may be faintness or collapse, haemoptysis, focal chest signs, raised jugular venous pulse and signs or symptoms of DVT [5]. Clinical diagnosis of VTE, however, is very unreliable [55], particularly in pregnancy. Many of the signs and symptoms e such as shortness of breath, tachycardia and swollen legs e are present in normal pregnancy, and especially in pregnant obese women. Studies have shown that morbid obesity is associated with delayed diagnosis of PE in the emergency department [56], and that obese patients are more likely than normal-weight patients to suffer from post-thrombotic syndrome after DVT [57]. In the most recent UK CEMD report [6], in which nine of the 16 women who died were obese, seven women had reported chest symptoms to a doctor or midwife in the weeks before they died, without appropriate action being taken. The RCOG guideline on acute management of VTE during pregnancy and the puerperium [58] stresses the importance of recognising signs and symptoms suggestive of VTE. Treatment with LMWH should be given until the diagnosis has been excluded by objective testing, unless treatment is strongly contraindicated [58,59]. Prompt treatment is essential even though many women will be treated unnecessarily. Among non-pregnant women, PE is confirmed in 25% of the patients in whom the diagnosis is suspected, but in pregnancy this proportion drops to 10% [53,59]. Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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It should be borne in mind, too, that the risk factors for VTE (including obesity) also apply to cerebral vein thrombosis, which accounted for eight maternal deaths in 2003e2005 in the UK. This total fell to only two in 2006-2008 after the publication of the RCOG guideline on thromboprophylaxis [38]. In women with headaches and unusual neurological symptoms, clinicians must be vigilant and consider VTE. In all cases of suspected VTE, a multidisciplinary approach to diagnosis is important [48,58]. The gold standard for diagnosis of acute lower-limb DVT used to be contrast venography, but this is invasive and is no longer recommended. Compression duplex ultrasound (CUS) should be undertaken when there is clinical suspicion of DVT [48,53,58e62]. If ultrasound is negative and there is a low level of clinical suspicion, anticoagulant treatment can be discontinued. In pregnancy, however, most DVTs arise proximally rather than in the calf veins, and if clinical suspicion of VTE remains when CUS is negative, further testing in the form of magnetic resonance imaging or venography (MRI/MRV) should be done [48]. When PE is suspected, bilateral CUS, if positive, makes further testing unnecessary. If CUS is negative, the next step is a chest X-ray (which is safe in pregnancy [53,58]) and then, depending on the result and on local availability, a ventilation/perfusion (V/Q) scan or computerised tomographic pulmonary angiography [48,58]. These tests carry maternal and fetal risks, which are very small but should be discussed with the woman beforehand so that she can give informed consent [58]. D-dimer testing is not recommended in pregnancy [48,58e61]. The diagnostic pathway is summarised in Fig. 2. Treatment The treatment of VTE, like the diagnosis, should be multidisciplinary [48,58e60]. Detailed recommendations are given in the RCOG guideline [58] and the recent Canadian guideline [60]. Treatment consists of LMWH given daily in subcutaneous divided doses, with doses titrated against the woman's booking or most recent weight. The RCOG guideline [58] gives a calculation of the initial doses of LMWH drugs for various weight groups (90 kg). Warfarin is not recommended for treatment during pregnancy but can be used in the puerperium. In therapeutic doses, LMWH is preferred over UFH because of strong evidence that LMWHs are more effective and associated with lower mortality and lower risks of haemorrhagic complications than UFH in the initial treatment of DVT in non-pregnant women. There is substantial evidence that they are safe in pregnancy, and other advantages are reduced risks of bleeding and of heparin-induced

Fig. 2. Diagnostic algorithm for suspected VTE in pregnancy (from Ref. [48]). Abbreviations: DVT, deep venous thrombosis; CUS, compression ultrasonography; CXR, chest X-ray; CTPA, computerised tomography pulmonary angiography; LMWH, low-molecularweight heparin; MRI, magnetic resonance imaging; V/Q: ventilation/perfusion scan.

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osteoporosis [58]. The exception is in the acute treatment of massive life-threatening PE, when UFH should be used because of its rapidity of action. The loading dose of UFH is also weight related [58]. When massive PE occurs, the consultant obstetrician and the on-call medical team should be called immediately. Management may involve thrombolytic therapy or surgical embolectomy and requires a multidisciplinary resuscitation team including senior physicians, obstetricians and radiologists. Postnatal anticoagulant therapy should be continued for at least 6 months and until at least 6 weeks post partum [58,62]. Summary A gratifying reduction in the mortality from VTE in pregnancy has been achieved in recent years by observing the risk factors present in fatal cases and applying guidelines for thromboprophylaxis based on risk factors. Nevertheless, we still lack a full understanding of the pathophysiological mechanisms underlying the risks. Research on the endocrine and paracrine effects of obesity is still in its infancy, and almost nothing is yet known about how these effects interact with the more familiar endocrine changes of pregnancy. Epidemiological studies have clarified the times of highest risk for VTE in pregnancy, revealing a high risk around the time of delivery and a possible extension of the at-risk period beyond 6 weeks after delivery. All this research is taking place against a background of increasing prevalence of obesity in the UK, where 5% of women giving birth now have severe obesity, with the associated increased chance of caesarean section, itself a risk factor for VTE. Despite the success of guidelines in reducing the adverse sequelae of this trend, there is wide awareness that the guidelines are not yet based on Grade A evidence. Large and well-designed clinical studies to support them are still urgently needed. Studies show that implementation of the existing guidelines is patchy, and awareness of the importance of thromboprophylaxis needs to be extended, not only to all midwives and obstetricians but also to other specialties. Research on the most effective ways of increasing such awareness is sadly lacking.

Practice points  All women must have their weight and height measured at booking.  Risk assessment for VTE must be carried out at the beginning of pregnancy, at the time of delivery and at any point when the risk profile changes (e.g., hospitalisation).  Both prophylactic and therapeutic dosages of LMWH are weight dependent. Local protocols should be produced based on national guidelines.  Obese women are at particular risk of their signs and symptoms of possible VTE not being taken seriously. Symptoms must always be interpreted in the light of existing risk factors such as severe obesity.  Suspected VTE should be treated with therapeutic doses of LMWH before full investigation to confirm or rule out the diagnosis.

Research agenda  The benefits and risks of continuing thromboprophylaxis beyond 6 weeks after delivery.  Basic science research into how the endocrine and paracrine effects of obesity interact with similar changes in pregnancy.  Large, well-designed clinical studies to provide Grade A evidence to underpin the existing guidelines.  Clarification of the rate of PPH in severely obese women taking prophylactic LMWH.  Better ways of ensuring that all clinicians are aware of professional guidelines.

Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

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Conflict of interest statement The author has no conflict of interest to declare. References [1] Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005;118:978e80. [2] Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374e80. [3] Pomp ER, Lenselink AM, Rosendaal FR, et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008;6:632e7. [4] Armstrong EM, Bellone JM, Hornsby LB, et al. Pregnancy-related venous thromboembolism. J Pharm Pract 2014;27: 243e52. [5] Drife J, Thromboembolism. Br Med Bull 2003;67:177e90. *[6] Lewis G. Saving Mothers' Lives: Reviewing maternal deaths to make motherhood safer: 2006e2008. The eighth report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG 2011;118(Suppl. 1):1e203. [7] Knight M. Antenatal pulmonary embolism: risk factors, management and outcomes. BJOG 2008;115:453e61. [8] Salonen Ros H, Lichtenstein P, Bellocco R, et al. Increased risks of circulatory diseases in late pregnancy and the puerperium. Epidemiology 2001;12:456e60. [9] Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697e706. [10] Jackson E, Curtis KM, Gaffield ME. Risk of venous thromboembolism during the postpartum period: a systematic review. Obstet Gynecol 2011;117:691e703. [11] Abbasi N, Balayla J, Laporta DP, et al. Trends, risk factors and mortality among women with venous thromboembolism during labour and delivery: a population-based study of 8 million births. Arch Gynecol Obstet 2014;289:275e84. [12] Ghaji N, Boulet SL, Tepper N, et al. Trends in venous thromboembolism among pregnancy-related hospitalizations, United States, 1994e2009. Am J Obstet Gynecol 2013;209:433.e1e8. [13] Kamel H, Navi BB, Sriram N, et al. Risk of a thrombotic event after the 6-week postnatal period. N Engl J Med 2014;370: 1307e14. [14] Pomp ER, le Cessie S, Lenselink AM, et al. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007;139:289e96. [15] Morgan ES, Wilson E, Watkins T, et al. Maternal obesity and venous thromboembolism. Int J Obstet Anaesth 2012;21: 253e63. [16] Reeves GK, Balkwill A, Cairns BJ, et al., Million Women Study Collaborators. Hospital admissions in relation to body mass index in UK women: a prospective cohort study. BMC Med 2014;12:45. [17] American College of Obstetricians and Gynecologists. Obesity in pregnancy. Committee opinion no. 549. Obstet Gynecol 2013;121:213e7. [18] Heslehurst N, Ells LJ, Simpson H, et al. Trends in maternal obesity incidence rates, demographic predictors, and health inequalities in 36 821 women over a 15-year period. BJOG 2007;114:187e94. [19] CMACE. Maternal obesity in the UK: findings from a national project. London: Centre for Maternal and Child Enquiries; 2010. [20] Knight M, Kurinczuk JJ, Spark P, et al. Extreme obesity in pregnancy in the United Kingdom. Obstet Gynecol 2010;115: 989e97. [21] James AH, Jamison MG, Brancazio LR, et al. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006;194:1311e5. [22] Jensen TB, Gerds TA, Gron R, et al. Risk factors for venous thrombosis during pregnancy. Pharmacoepidemiol Drug Saf 2013;22:1283e91. [23] Virkus RA, Lekkegaard E, Lidegaard O, et al. Risk factors for venous thromboembolism in 1.3 million pregnancies: a nationwide prospective cohort. PLoS One 2014;9:e99495. [24] Sultan AA, West J, Tata LJ, et al. Risk of first venous thromboembolism in pregnant women in hospital: population based cohort study from England. BMJ 2013;347:f6099. [25] Delluc A, De Moreuil C, Kerspem H, et al. Body mass index, a major confounder to insulin resistance association with unprovoked venous thromboembolism. Results from the EDITH case-control study. Thromb Haemost 2013;110:593e7. [26] Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep venous system of the legs in pregnancy. BJOG 1997;101:191e7. [27] Allman-Farinelli MA. Obesity and venous thrombosis: a review. Semin Thromb Hemost 2011;37:903e7. [28] Lorenzet R, Napoleone E, Cutrone A, et al. Thrombosis and obesity: cellular bases. Thromb Res 2012;129:285e9. [29] Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol 2013;20:437e44. [30] Schafer K, Konstantinides S. Adipokines and thrombosis. Clin Exp Pharmacol Physiol 2011;38:864e71. [31] Morange PE, Alessi MC. Thrombosis in central obesity and metabolic syndrome: mechanisms and epidemiology. Thromb Haemost 2013;110:669e80. *[32] Bourjeilly G, Paidas M, Khalil H, et al. Pulmonary embolism in pregnancy. Lancet 2010;375:500e12. [33] Greer IA, Thomson AJ. Management of venous thromboembolism in pregnancy. Best Pract Res Clin Obstet Gynaeol 2001; 15:583e603. [34] Liston F, Davies GA. Thromboembolism in the obese pregnant woman. Semin Perinatol 2011;35:330e4. [35] Drife J on behalf of the Editorial Board. Thrombosis and thromboembolism. In: CEMACH. Why mothers die 2000e2002: the sixth report of the confidential enquiries into maternal deaths in the United Kingdom. London: RCOG Press; 2004. [36] Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on prophylaxis against thromboembolism in gynaecology and obstetrics. London: RCOG; 1995.

Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

12

J. Drife / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e12

[37] Royal College of Obstetricians and Gynaecologists. Thromboprophylaxis during pregnancy, labour and after vaginal delivery. Green-top Guideline No. 37. London: RCOG; 2004. *[38] Royal College of Obstetricians and Gynaecologists. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top Guideline No. 37a. London: RCOG; 2009. [39] Bates SM, Greer IA, Pabinger J, et al., American College of Chest Physicians. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133(6 Suppl.):844Se86S. [40] Scottish Intercollegiate Guidelines Network (SIGN). Prevention and management of venous thromboembolism. (SIGN publication no. 122). Edinburgh: SIGN; 2010. Available from: URL: http://www.sign.ac.uk. *[41] McLintock C, Brighton T, Chunilal S, et al. Recommendations for the prevention of pregnancy-associated thromboembolism. Aust NZ J Obstet Gynecol 2012;52:3e13. [42] Lussana F, Coppens M, Cattaneo M, et al. Pregnancy-related venous thromboembolism: risk and the effect of thromboprophylaxis. Thromb Res 2012;129:673e80. [43] Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401e7. [44] Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med 1993;119:874e81. [45] Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American college of chest physicians evidence-based clinical practice guidelines. Chest 2008;133:381Se453S. [46] Willett KC, Alsharhan M, Durand C, et al. Dosing of enoxaparin for venous thromboembolism prophylaxis in obese patients. Ann Pharmacother 2013;47:1717e20. [47] Wang TF, Milligan PE, Wong CA, et al. Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients. Thromb Haemost 2014;111:88e93. *[48] Arya R. How I manage venous thrombosis in pregnancy. Br J Haematol 2011;153:698e708. [49] Cregan A, Higgins JR, O'Shea S. Implementation of thromboprophylaxis guidelines. Ir Med J 2013;106:80e2. [50] Wu P, Poole TC, Pickett JA, et al. Current obstetric guidelines on thromboprophylaxis in the United Kingdom: evidencebased medicine? Eur J Obstet Gynecol Reprod Biol 2013;168:7e11. [51] Hayes-Ryan D, Byrne BM. Prevention of thrombosis in pregnancy: how practical are consensus-derived guidelines? J Obstet Gynaecol 2012;32:740e2. [52] Touqmatchi D, Cotzias C, Girling J. Venous thromboembolism in pregnancy: the implications of changing to the 2010 RCOG guidelines. J Obstet Gynaecol 2012;32:743e6. [53] Donnelly JC, D'Alton ME. Pulmonary embolus in pregnancy. Semin Perinatol 2013;37:225e33. [54] Jacobsen AF, Skjeldestad FE, Sandset PM. Ante- and postnatal risk factors of venous thrombosis: a hospital-based casecontrol study. J Thromb Haemost 2008;6:905e12. [55] Kierkegaard A. Incidence and diagnosis of deep vein thrombosis associated with pregnancy. Acta Obstet Gynecol Scand 1983;62:239e43. [56] Smith SB, Geske JB, Morgenthaler TI. Risk factors associated with delayed diagnosis of acute pulmonary embolism. J Emerg Med 2012;42:1e6. [57] Tick LW, Kramer MH, Rosendaal FR, et al. Risk factors for post-thrombotic syndrome in patients with a first deep venous thrombosis. J Thromb Haemost 2008;6:2075e81. *[58] Royal College of Obstetricians and Gynaecologists. The acute management of thrombosis and embolism during pregnancy and the puerperium. Green-top Guideline No. 37b. London: RCOG; 2010. *[59] Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008;359:2025e33. *[60] Chan WS, Rey E, Kent NE, VTE in Pregnancy Guideline Working Group. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynecol Can 2014;36:527e53. *[61] American College of Obstetricians and Gynecologists. Thromboembolism in pregnancy. Committee opinion no. 123. Obstet Gynecol 2011;118:718e29. *[62] McLintock C, Brighton T, Chunilal S, et al. Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period. Aust NZ J Obstet Gynaecol 2012;52:14e22.

Please cite this article in press as: Drife J, Deep venous thrombosis and pulmonary embolism in obese women, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.08.012

Deep venous thrombosis and pulmonary embolism in obese women.

Obesity increases the risk of venous thromboembolism, and pregnancy also increases the risk, particularly around delivery and in the puerperium. Pregn...
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