maternal obesity and venous thromboembolism

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REVIEW ARTICLE Maternal obesity and venous thromboembolism E.S. Morgan, a E. Wilson, b T. Watkins, b F. Gao, b B.J. Hunt c a Department of Anaesthesia, Royal Gwent Hospital, Newport, UK b Academic Department of Anaesthesia, Critical Care and Pain, Heart of England NHS Foundation Trust, Birmingham, UK c Departments of Haematology, Pathology and Rheumatology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK ABSTRACT The incidence of obesity in pregnancy has increased rapidly in the last decade. Obesity is a risk factor for venous thromboembolism outside of pregnancy and previous studies of maternal death in the UK have identified obesity as a risk factor in pregnancy. As a result the Royal College of Obstetricians and Gynaecologists have targeted obesity as a risk factor in evaluation of the need for thromboprophylaxis in pregnancy. This article highlights the evidence that obesity increases the risk of venous thromboembolism in pregnancy and the puerperium, discusses thromboprophylaxis and appropriate dosing in obese parturients and details the anaesthetic implications of the 2009 Royal College of Obstetricians and Gynaecologists’ guidelines. More clinical studies are required to clarify the appropriate dose of low-molecular-weight heparin in an obese parturient. c 2012 Elsevier Ltd. All rights reserved. Keywords: Pregnancy; Obesity; Thromboembolism; Thromboprophylaxis Introduction Venous thromboembolism (VTE) is a major cause of maternal mortality, and was the leading direct cause of pregnancy-related mortality in the UK from 1985 to 2005. 1 The risk of VTE in pregnancy and the postpar- tum period is increased 4–5-fold with an overall risk of 1.72 per 1000 deliveries and an associated mortality of 1.1 per 100 000 deliveries. 2–4 Obesity is characterised by excess body fat and is most often quantified using body mass index (BMI = weight/ height 2 ), although this is an imperfect measure as it fails to account for variations such as muscle bulk and ethnic- ity. BMI does, however, correlate with percentage body fat in most clinical situations. The World Health Organi- sation (WHO) and National Institute for Health and Clinical Excellence (NICE) consider patients to be over- weight if they have a BMI >25. When BMI is >30, patients are classified as obese. This obese group is fur- ther subdivided into Grade 1 (BMI 30–34.9), Grade 2 (BMI 35–39.9) and Grade 3 (BMI >40). 5,6 Further terminology is used for higher grades of obesity, with a BMI >40 referred to as morbid obesity, and a BMI >50, termed extreme or super-morbid obesity. The 2006–2008 report from the Centre for Maternal and Child Enquiries (CMACE) has recently been pub- lished. 7 For the first time since 1985 VTE was not the leading direct cause of maternal death and a statistically significant reduction in deaths from VTE was shown. This is thought to be due to better recognition of at-risk women and more widespread use of national thrombo- prophylaxis guidelines. 7 Although the number of deaths fell, these are still preventable deaths and obesity re- mained the most important risk factor with 12 of the 16 women who died from pulmonary embolism being over- weight, obese or morbidly obese. A positive correlation between obesity and VTE is further supported by data from the UK Obstetric Surveillance System (UKOSS), which identified the major risk factors for non-fatal pulmonary embolism as obesity and multiparity. 8 Currently it is not known whether the risk of VTE in- creases with increasing obesity or whether morbid obes- ity as a single risk factor warrants thromboprophylaxis. With the positive correlation between obesity and VTE, however, the Royal College of Obstetricians and Gynae- cologists (RCOG) thromboprophylaxis guidelines were updated in 2009 stating that all women with morbid obesity should be considered for thromboprophylaxis with low-molecular-weight heparin (LMWH), continued for seven days following delivery. The level of evidence for this recommendation is best practice, based on the clinical experience of the guideline development group. 9 Accepted January 2012 Correspondence to: E.S. Morgan, Department of Anaesthesia, Royal Gwent Hospital, Cardiff Road, Newport NP20 2UB, UK. E-mail address: [email protected] International Journal of Obstetric Anesthesia (2012) 21, 253–263 0959-289X/$ - see front matter c 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijoa.2012.01.002 www.obstetanesthesia.com

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Page 1: Maternal obesity and venous thromboembolism

International Journal of Obstetric Anesthesia (2012) 21, 253–2630959-289X/$ - see front matter �c 2012 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.ijoa.2012.01.002

REVIEW ARTICLE

www.obstetanesthesia.com

Maternal obesity and venous thromboembolism

E.S. Morgan,a E. Wilson,b T. Watkins,b F. Gao,b B.J. Huntc

a Department of Anaesthesia, Royal Gwent Hospital, Newport, UKb Academic Department of Anaesthesia, Critical Care and Pain, Heart of England NHS Foundation Trust,

Birmingham, UKc Departments of Haematology, Pathology and Rheumatology, Guy’s and St Thomas’ NHS Foundation Trust,

London, UK

ABSTRACT

The incidence of obesity in pregnancy has increased rapidly in the last decade. Obesity is a risk factor for venous thromboembolismoutside of pregnancy and previous studies of maternal death in the UK have identified obesity as a risk factor in pregnancy. As aresult the Royal College of Obstetricians and Gynaecologists have targeted obesity as a risk factor in evaluation of the need forthromboprophylaxis in pregnancy. This article highlights the evidence that obesity increases the risk of venous thromboembolismin pregnancy and the puerperium, discusses thromboprophylaxis and appropriate dosing in obese parturients and details theanaesthetic implications of the 2009 Royal College of Obstetricians and Gynaecologists’ guidelines. More clinical studies arerequired to clarify the appropriate dose of low-molecular-weight heparin in an obese parturient.

�c 2012 Elsevier Ltd. All rights reserved.

Keywords: Pregnancy; Obesity; Thromboembolism; Thromboprophylaxis

Introduction

Venous thromboembolism (VTE) is a major cause ofmaternal mortality, and was the leading direct cause ofpregnancy-related mortality in the UK from 1985 to2005.1 The risk of VTE in pregnancy and the postpar-tum period is increased 4–5-fold with an overall risk of1.72 per 1000 deliveries and an associated mortality of1.1 per 100000 deliveries.2–4

Obesity is characterised by excess body fat and is mostoften quantified using body mass index (BMI = weight/height2), although this is an imperfect measure as it failsto account for variations such as muscle bulk and ethnic-ity. BMI does, however, correlate with percentage bodyfat in most clinical situations. The World Health Organi-sation (WHO) and National Institute for Health andClinical Excellence (NICE) consider patients to be over-weight if they have a BMI >25. When BMI is >30,patients are classified as obese. This obese group is fur-ther subdivided into Grade 1 (BMI 30–34.9), Grade 2(BMI 35–39.9) and Grade 3 (BMI >40).5,6 Furtherterminology is used for higher grades of obesity, with aBMI >40 referred to as morbid obesity, and aBMI >50, termed extreme or super-morbid obesity.

Accepted January 2012

Correspondence to: E.S. Morgan, Department of Anaesthesia, RoyalGwent Hospital, Cardiff Road, Newport NP20 2UB, UK.E-mail address: [email protected]

The 2006–2008 report from the Centre for Maternaland Child Enquiries (CMACE) has recently been pub-lished.7 For the first time since 1985 VTE was not theleading direct cause of maternal death and a statisticallysignificant reduction in deaths from VTE was shown.This is thought to be due to better recognition of at-riskwomen and more widespread use of national thrombo-prophylaxis guidelines.7 Although the number of deathsfell, these are still preventable deaths and obesity re-mained the most important risk factor with 12 of the 16women who died from pulmonary embolism being over-weight, obese or morbidly obese. A positive correlationbetween obesity and VTE is further supported by datafrom the UK Obstetric Surveillance System (UKOSS),which identified the major risk factors for non-fatalpulmonary embolism as obesity and multiparity.8

Currently it is not known whether the risk of VTE in-creases with increasing obesity or whether morbid obes-ity as a single risk factor warrants thromboprophylaxis.With the positive correlation between obesity and VTE,however, the Royal College of Obstetricians and Gynae-cologists (RCOG) thromboprophylaxis guidelines wereupdated in 2009 stating that all women with morbidobesity should be considered for thromboprophylaxiswith low-molecular-weight heparin (LMWH), continuedfor seven days following delivery. The level of evidencefor this recommendation is best practice, based on theclinical experience of the guideline development group.9

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254 Obesity and thromboembolism

It is important to note that the maternal deaths reportedin the 2006–2008 CMACE report occurred before pub-lication of this guideline.

Prevalence and implications of maternal obesity

In the 1990s the WHO declared obesity a global epi-demic and since then the prevalence of adult and child-hood obesity has continued to rise. The 2008 projectionsestimate there are 1.5 billion overweight adults glob-ally.6 Data from the International Obesity Task Forceshow that in the European 27 member states, 60% ofadults are overweight or obese.10 The Health Surveyfor England showed that the proportion of obese wo-men (BMI >30) increased from 16% in 1993 to 24% in2009 and recent figures from the WHO estimate thatin the UK 26.3% of women have a BMI P30.6,11

Heslehurst et al. traced the proportion of obese wo-men at the start of pregnancy from 1990 to 2004 andfound that the incidence increased significantly overtime from 9.9% to 16%. The results demonstrated thatby 2010, if the trend continued, the rate would increaseto 22%.12 Heslehurst’s projections have born true withcurrent evidence suggesting obesity has an estimatedprevalence of between 17.7% and 21% within the UKobstetric population.13,14 CMACE recently investigatedthe prevalence of the more severe grades of obesity aspart of their three-year wide obesity in pregnancy pro-ject: A two-month national cohort study in 2009 demon-strated the following prevalence of maternal obesity:BMI P35, 4.99%; BMI P40, 2.01%; and BMI P50,0.19%.15 Data collected by UKOSS suggest a calculatedprevalence of ‘‘extreme obesity’’ (BMI P50 or weight>140 kg) within the UK obstetric population of 8.7per 10 000 deliveries.16

Maternal obesity is not restricted to the UK. InAustralia, Callaway et al. reviewed data from 11252pregnant women from 1998 to 2002. They found 34%were overweight, obese or morbidly obese.17 In nineUSA states, Kim et al. found the prevalence of pre-preg-nancy obesity increased from 13% in 1993 to 22% in2002–2003.18 Maternal obesity is less of a problem inparts of Asia. A retrospective study of Chinese womenfrom 1995 to 2005 showed a prevalence of 2.3% and13.5% for maternal obesity and being overweight.19

The consequences of maternal obesity are multiplewith an increased risk of pregnancy-related complica-tions and adverse outcomes such as hypertensive disor-ders, gestational diabetes, induction of labour,caesarean section, postpartum haemorrhage, fetalabnormalities, neonatal unit admissions and stillbirth.15

In the 2006–2008 CMACE report, BMI values wereavailable for 87% of mothers who died from direct orindirect causes. Of those who died from direct causes47% were overweight or obese, as were 50% who diedfrom indirect causes.7

Pregnancy and venous thromboembolism

The risk of VTE is increased 4–5-fold in pregnancy andthe puerperium.2,3 James et al. obtained data on 14 335VTE events from the Nationwide Inpatient Sample fromthe Healthcare Cost and Utilization Project of theAgency for Healthcare Research and Quality in theUSA. They found an overall risk of 1.72 per 1000 deliv-eries.4 The risk of deep vein thrombosis (DVT) was 1.36per 1000 deliveries and that of pulmonary embolism 0.36per 1000 deliveries with a risk of mortality of 1.1 per100000 deliveries.4 The 2006–2008 CMACE report dem-onstrated a pulmonary embolism associated mortality of0.7 per 100000 maternities:7 a decrease from the 1.56 per100000 maternities reported in the previous triennium.1

The risk of VTE is evident from early in the first tri-mester, which continues through the second and third,and increases in the postpartum period.20,21 This washighlighted in the 2006–2008 CEMACE report whichstated that women are at risk from the beginning of preg-nancy to the end of the puerperium; one of the keyrecommendations being that risk assessment in earlypregnancy continues to be an important factor in reduc-ing mortality from thromboembolism.7 Heit et al. dem-onstrated the annual incidence of VTE to be five timeshigher in postpartum than pregnant women (511 vs.95.8 per 100000).2 Pomp et al. found the risk of VTEto be increased five-fold during pregnancy (OR 4.6,95% CI 2.7–7.8) and increased 60-fold during the firstthree months after delivery compared with non-pregnantwomen, (OR 60.1, 95% CI 26.5–136).3 The postpartumrisk decreases with time; Jacobsen et al. studied 559 preg-nant women with objectively verified VTE and found50% of postpartum VTE were in the first two weeks,88% within four weeks and 97% within six weeks.22

Deep vein thrombosis in pregnancy is more likely tobe left-sided and proximal probably because of compres-sion of the left ilio-femoral vein by the right commoniliac artery.20,21,23 If compression is severe it producesMay-Thurner syndrome, a left-sided iliac outflowobstruction with localised adventitial fibrosis and inti-mal proliferation.

Although there are multiple factors associated withan increased risk of VTE in pregnancy and the puerpe-rium, the factors associated with the strongest risk arethrombophilia (OR 51.8, 95% CI 38.7–69.2) and historyof thrombosis (OR 24.8, 95% CI 17.1–36.0).24 However,due to its prevalence in the population, obesity is one ofthe most common risk factors.

Obesity and pregnancy and the risk of venousthromboembolism

The National Library of Medicine literature database,accessed via PubMed and the internet search engine

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E.S. Morgan et al. 255

Google Scholar were searched using the terms ‘‘obes-ity’’, ‘‘pregnancy’’ and ‘‘venous thromboembolism’’in English only. Relevant articles and websites werehand-searched for further references. Twelve studiespublished from 2001 to 2009 were identified thatinvestigated obesity as a risk factor for VTE in preg-nancy or postpartum (Table 1).4,8,22,25–33 Nine out of12 studies demonstrated increased odds of VTE inobese pregnant or postpartum women.4,8,22,26,28,30–33

Two further studies with very small numbers showedan association between obesity and VTE but did notcalculate odds ratios.27,29 Only Danilenko-Dixonet al. found no increased risk of VTE with obesityin a study with several limitations including smallnumbers, low percentage of objectively diagnosedVTE, and a failure to identify other well-known riskfactors for VTE for example maternal age suggestinginadequate power.25 Unfortunately there was inconsis-tency between the studies demonstrating increasedodds ratios with regards to VTE complications andthe definition of obesity leading to difficulty calculat-ing an overall odds ratio although it probably lies inthe region of 1.4–5.3.

Two studies investigated the odds ratios for VTE forobesity in combination with other risk factors. Jacob-sen et al. and Simpson et al. investigated the risk ofante- and postpartum VTE in obese women. Bothfound increased risk of postpartum compared withantepartum VTE, consistent with studies where BMIwas not specified.2,22,26 Interestingly, the magnitudeof this difference, was less in the obese population.Jacobsen et al. also investigated odds ratios for VTEif obesity and immobilisation were combined. Theyfound the odds ratio of antepartum VTE to be 62.3although confidence intervals (CI) were wide (95% CI11.5–337.6). It is important to note that the 16% ofVTE cases where BMI data were missing were includedin the BMI >25 group.22

Unfortunately, only four studies have investigated agradient of VTE risk with increasing obesity.8,26,28,30

Knight et al. suggested a potential gradient of increasingrisk for antepartum pulmonary embolism with higherBMI. However, because of the small number of womenwith BMI >30 the authors were not able to investigatefurther.8 Robinson et al. found an almost two-fold in-creased risk of antepartum VTE in the severely obesegroup (weight >120 kg) compared with the moderatelyobese group (90–120 kg).28 Larsen et al. also demon-strated a potential gradient of risk with the odds ratiosincreasing from 1.4 in the BMI 25–30 group to 5.3 witha BMI >30.30 Simpson et al. demonstrated similar oddsratios for BMI 25–30 and BMI >30.26 The limitation ofall of these studies was the low number of VTE and evenlower number when separated into BMI groups. There-fore it is difficult to demonstrate a gradient of risk withincreasing obesity.

Pathophysiology of venous thromboembolism inmaternal obesity

The pathogenesis of VTE is based on Virchow’s triad ofhypercoagulability, venous stasis and endothelial injury.Although the exact pathogenesis of VTE in maternalobesity is unclear, possible mechanisms can be linkedto these three risk factors. Pregnancy results in a hyper-coagulable state due to increases in coagulation factorsand platelet activation as well as a reduction in naturalanticoagulant and fibrinolytic activity (Table 2). Adi-pose tissue secretes a variety of bioactive peptides calledadipokines such as plasminogen activator inhibitor 1(PAI-1), leptin and interleukin 6 (IL-6). These influencemany physiological processes, including haemostasis.34

PAI-1 results in impaired fibrinolysis and leptin, whichis predominantly produced and secreted by adipose tis-sue and promotes platelet aggregation.35 Obesity isrecognised as a state of chronic inflammation due tothe associated increases in inflammatory markers suchas C-reactive protein (CRP) and IL-6. The latter in-creases the acute phase response thereby stimulatingthe liver to produce coagulation factors. Thus fibrino-gen, factor VII, factor VIII and von Willebrand factorare all increased in obese compared to non-obese sub-jects.36 Elevated CRP levels have been found in obesewomen and associated with platelet activation.37 Adipo-nectin levels are decreased in obesity leading to a reduc-tion of its protective actions against angiogenesis.38

Lastly, there is evidence from animal studies that tissuefactor, the principal initiator of blood coagulation, maybe upregulated in obesity.39,40 Therefore it seems likelythat the hypercoagulable state in pregnancy may befurther exacerbated by obesity.

Relative venous stasis in pregnancy is thought to be amechanism in the pathogenesis of VTE. In an ultra-sound study of gestational and postural changes in thedeep venous system of the leg, an increase in vesseldiameter and a fall in flow velocity with increasing ges-tation was observed.41 This may be compounded byobesity as the resulting increased abdominal pressureleads to an increased ilio-femoral venous pressureincreasing the likelihood of venous stasis.42

Under physiological conditions the endothelium sup-ports an antithrombotic state by mediating vasodilata-tion, preventing platelet adhesion and activation, andinhibiting thrombin formation and adhesion of inflam-matory leucocytes. However, if the endothelium is acti-vated it becomes prothrombotic, characterised byvasoconstriction, platelet activation, thrombin produc-tion and leukocyte adhesion and migration.43 Endothe-lial activation is a recognised component in thepathogenesis of arterial thrombus and is now thoughtto be central to the pathogenesis of VTE.44–46 Arterialatherosclerotic disease is associated with a two-fold in-creased risk of VTE.47,48 Venous and arterial thrombosis

Page 4: Maternal obesity and venous thromboembolism

Table 1 Venous thromboembolism during and after pregnancy and effects of obesity

Data collection VTE (n) VTE diagnosis Study design Risk factor Oddsratio

AdjustedOdds ratio

95% confidenceinterval

Danilenko-Dixonet al.25

1966–1990 85 Objective 23 Case control Overweight 1.51 0.71–3.21Subjective 62 Obese 0.77 0.22–2.72

Simpson et al.26 1988–1997 336 Not reported Case control BMI <20 Antepartum 0.4 0.2–1.1Postpartum 1.3 0.8–2.1

BMI 20–24.9 Reference valueBMI 25–29.9 Antepartum 1.2 0.8–2.0

Postpartum 1.7 1.2–2.4BMI P30 Antepartum 1.4 0.7–2.6

Postpartum 1.7 1.1–2.6

Larsen et al.30 1980–2001 91 Objective Case control BMI <25 ReferenceBMI 25–30 1.4 0.7–2.8BMI >30 5.3 2.1–13.5

Robinson et al.28 1988–2002 105 Not reported Cohort Moderate obesity Antepartum 2.17 1.3–3.6(90–120 kg)Severe obesity Antepartum 4.13 1.26–13.54(>120 kg)

James et al.4 2000–2001 14 335 Not reported Retrospectivedatabase analysis

Obesity (BMIunspecified)

4.4 3.4–5.7

Knight8 2005–2006 141antenatalPE only

97% objective Case control BMI <20 0.69 0.18–2.59BMI <25 ReferenceBMI 25–29.9 2.51 1.02–6.19BMI P30 2.65 1.09–6.45

Jacobsen et al.22 2003 559 Objective Case control BMI P25 Antepartum 1.8 1.3–2.4Postpartum 2.4 1.7–3.3

BMI P25 +immobilisation

Antepartum 62.3 11.5–337.6

Postpartum 40.1 8.0–201.5

Lindqvist et al.31 1990–2005 37postpartumonly

Objective Case control BMI P28 2.3 1.05–4.8

Kobayashi et al.32 1991–2000 76 Objective Case control BMI >25 1.89 1.01–3.55BMI >27 3.47 1.75–6.91

Liu et al.33 1991–2006 DVT 4677 Not reported Cohort Obesity 1.8 1.2–2.6PE 2144 Obesity 2.7 1.6–4.4

Sharma and Monga29 1999–2006 8 Objective Case control BMI >29 12.5% of cases (no OR)BMI >35 75% of cases (no OR)

Chan et al.27 1998–2000 27 Objective Case control BMI at delivery VTE Mean 28.6 SD ± 4.1BMI at deliveryno VTE

Mean 26.7 SD ± 3.3

VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism; BMI: body mass index.

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Table 2 Hypercoagulability of pregnancy

Coagulation factors

Fibrinogen, Factors VII, VIII, IX, X, XII, von Willebrand factor ›Prothrombin and Factor V No changeFactors XIII and XI fl

Markers of thrombin production

Prothrombin fragment 1 + 2 and thrombin–antithrombin complex levels ›

Platelets

Platelet count mild thrombocytopenia in 10%Platelet activity ›

Physiological anticoagulants

Free protein S flActivated protein C › resistance

Fibrinolysis

Plasminogen activity ›PAI-1, PAI-2 ›Thrombin activable fibrinolysis inhibitor ›Tissue-type plasminogen activator › (net reduced activity due to › PAI-1 and PAI-2)

PAI-1: plasminogen activator inhibitor 1; PAI-2: plasminogen activator inhibitor 2.

E.S. Morgan et al. 257

may share risk factors and have a similar pathogenesisinvolving endothelial activation and inflammation. Inthe non-pregnant population, studies have demon-strated that obesity is associated with endothelial dys-function.49,50 In normal pregnancy the endotheliummaintains a state of vasodilatation associated with in-creased levels of nitric oxide production.51 Stewartet al. studied endothelial function in lean and obese(BMI P30) women at intervals through their pregnan-cies. In vivo endothelial-dependent and independentvascular function was measured using laser Dopplerimaging in each trimester and postnatal. They foundthat although endothelial function improved duringpregnancy in lean and obese women, endothelial-dependent vasodilation was significantly lower in theobese women in each trimester.52

Microparticles are membrane vesicles shed fromendothelial cells, macrophages and monocytes after acti-vation or apoptosis. It is thought that microparticlescarry exposed tissue factor and play an active role inthe thrombotic process.53 Healthy pregnancy is associ-ated with increased levels of microparticles comparedto healthy non-pregnant controls. In preeclampsiamicroparticles show proinflammatory properties in thevascular wall.54,55 Microparticle levels are also markedlyhigher in obese women compared to controls,56 and cir-culating endothelial and platelet derived microparticlesare higher in obese compared to lean women; levelsare negatively correlated with endothelial-dependentvasodilation.57

It is therefore likely that obesity and the associatedstate of chronic inflammation exacerbate the hypercoag-ulability and venous stasis of pregnancy. Maternal obes-ity may also result in an activated endothelium in

contrast to the antithrombotic, vasodilated endotheliumassociated with normal pregnancy.

Preventing antepartum and postpartum venousthromboembolism in obesity

There is a lack of high-level evidence to develop guide-lines for VTE prophylaxis in pregnancy and even lessconcerning thromboprophylaxis in the obese parturi-ent.58 The UK is unique in having detailed thrombopro-phylaxis guidelines, mentioning obesity as a risk factor,for pregnancy and postpartum VTE.9 The AustralianNational Health and Medical Research Council hasdeveloped guidelines for the prevention of VTE butstate, ‘‘there is a lack of high level formal evidence’’on which recommendations could be made for the pre-vention of VTE during pregnancy and the early postna-tal period.59 The American College of Chest Physicians(ACCP) thromboprophylaxis guidelines for pregnancyand postpartum do not mention obesity as a risk fac-tor.60 The Antithrombotic Therapy and Pregnancy Con-sensus Report identifies obesity as a risk factor for VTE,but offers no specific advice concerning thrombopro-phylaxis if obesity is a single risk factor. It states thatmore studies are needed to determine the impact onVTE risk and VTE prevention studies.61

The first step in preventing VTE is a risk assessmentearly in the antenatal period and this needs to be re-peated whenever there is a change in the woman’s con-dition or on admission to hospital. A range of optionscan then be used to reduce risk in the antepartum, intra-partum and postpartum periods. Data for most of theevidence behind such interventions, however, come fromthe non-obstetric population.

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258 Obesity and thromboembolism

Non-pharmacological methods

Reducing immobility and avoiding dehydration are usu-ally well tolerated, cheap and not associated with signif-icant risk to mother or baby, and so should be usedwhenever possible. Immobility should be minimisedand active exercises encouraged.59,62 Inadequate hydra-tion should be avoided, so as to prevent haemoconcen-tration and increased blood viscosity.63 More invasiveoptions should be implemented following an analysisof potential risks and benefits to both mother and baby.Mechanical methods of thromboprophylaxis such asgraduated compression stockings, intermittent pneu-matic compression (IPC) devices and venous foot pumpsaim to improve venous blood flow, thereby reducing ve-nous stasis. They are of particular use for patients withcontraindications to pharmacological agents, most com-monly, increased risk of haemorrhage.64 All three meth-ods are considered to reduce VTE risk in certain patientgroups, although clinical trials assessing their effect havebeen small or of poor quality. They are considered lessefficacious than pharmacological methods.65 Moreover,no form of mechanical prophylaxis has been shown toreduce the risk of death due to pulmonary embolism.64

Graduated compression stockings improve venousblood flow.66 Zaccoletti and Zardini found a reductionin postpartum VTE from 4.3% to 0.9% in >1000 moth-ers when using stockings and adding low-dose heparinin high-risk patients.67 However, evidence of their effi-cacy in the obese or obstetric patient is scant, and theweight of evidence to support their use is not from thesepatient populations.68,69 The use of stockings in strokepatients has been seriously questioned by the clots inlegs or stockings after stroke (CLOTS) trial collabora-tion.70,71 CLOT-1 randomised 2500 stroke patients tothigh length stockings vs. nothing and showed no reduc-tion in rate of VTE in those wearing stockings. Moreworryingly 5% of those with stockings suffered fromskin problems such as blistering, abrasions and evennecrosis.70 CLOT-2 compared the use of thigh lengthwith below knee stockings and found that thigh lengthappeared to confer a greater reduction in risk fromVTE.71 Recent NICE guidelines on thromboprophylaxisrecommended that stockings should not be used instroke patients.72

There are also limitations of compression stockings,which may be exacerbated by obesity. It has been sug-gested that 20% of patients will be intolerant or unableto wear them due to leg size or shape.65 Estimations sug-gest that they are worn by only 40% of women all thetime whilst hospital inpatients, and 38% do not wearthem at all.73 Typically, if thigh circumference is toolarge (>81 cm), due to sizing restraints, stockings arenot often used as they may be both uncomfortableand also impair venous flow by cutting into the thigh.

Intermittent pneumatic compression devices maycover the whole leg, just the calf, or just the foot. Theformer have been shown to improve blood flow and pre-vent venous stasis and are associated with a reduction inPAI-1 concentrations and a consequent increased fibri-nolytic activity.74–76 The use of such devices is not con-fined to the obstetric population; they have beenrecommended by the ACCP, both for patients at riskof bleeding and, in conjunction with standard anticoag-ulant prophylaxis, for patients with a high risk ofVTE.77 For patients with peripheral vascular disease,however, such devices are relatively contraindicated,although within the obstetric population this is uncom-mon. There is also concern about their use with thosewho may have pre-existing DVT, such as the immobilepatient, as there is a theoretical risk of dislodging clots.Compressive devices are associated with varying levelsof patient compliance.78 In some studies, rates of appro-priate and effective usage were as low as 36%.79 Lowrates of correct usage might be expected in the obese,where intermittently compressing possibly ill-fittingdressings might be uncomfortable. Moreover, in the ob-ese, as devices are typically used only below the knee,their clinical efficacy may be reduced. Lower rates mayalso be expected in the obstetric patient, for, while por-table devices are available, encouragement of earlymobilisation and discharge may reduce their use.

Within non-obstetric populations, meta-analysis hasshown that IPC devices are effective in reducing VTEin high-risk patients. It has also been shown that thecombined use of an IPC device along with pharmaco-logic agents is superior to the use of an IPC devicealone.80 Specific evidence for the effectiveness of IPCor venous foot pumps in the obese obstetric populationis, however, scant.

Pharmacological thromboprophylaxis

Until November 2009, RCOG guidelines for thrombo-prophylaxis recommended postnatal prophylaxis to wo-men with two or more risk factors and antenatalprophylaxis where three or more were present. Theguidelines also stated that, ‘‘one or two risk factorsmay be sufficient to justify antenatal thromboprophy-laxis’’.81 Evidence from the 2003–2005 Confidential En-quiry into Maternal and Child Health (CEMACH)report and UKOSS suggested that firmer recommenda-tions were needed.1,8 Based on the previous 2004 RCOGguideline, nearly 94% of women with antenatal pulmon-ary emboli in the UKOSS study would not have met thecriteria for thromboprophylaxis. There were also possi-ble inadequacies with the practical implementation ofthe guidelines. Of the morbidly obese women who diedfrom pulmonary embolism, 75% had received nothrombo-prophylaxis. The remaining 25% received an

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Table 3 RCOG thromboprophylaxis risk factors

Pre-existing Previous venous thromboembolismThrombophilia:Heritable:Antithrombin deficiencyProtein C deficiencyProtein S deficiencyFactor V LeidenProthrombin gene G20210AAcquired (antiphospholipid syndrome):Persistent lupus anticoagulantPersistent moderate/high-titre anticardiolipin antibodies or b2 glycoprotein 1 antibodiesMedical comorbidities (e.g. heart or lung disease, SLE, cancer, inflammatory conditions(inflammatory bowel disease or inflammatory polyarthropathy), nephrotic syndrome(proteinuria >3 g/day), sickle cell disease, intravenous drug userAge >35 yearsObesity (BMI >30 kg/m2) either prepregnancy or in early pregnancyParity P3SmokingGross varicose veins (symptomatic or above knee or with associated phlebitis,oedema/skin changes)Paraplegia

Obstetric Multiple pregnancy, assisted reproductive therapyPreeclampsiaCaesarean sectionProlonged labour, mid-cavity rotational operative deliveryPostpartum haemorrhage (>1000 mL) requiring transfusion

New-onset/transient Surgical procedure in pregnancy or puerperiumPotentially reversible (hyperemesis, dehydration)Ovarian hyperstimulation syndromeImmobility (P3 days ‘‘bed rest’’)Systemic infection (requiring antibiotics or admission to hospital)Postpartum wound infectionLong-distance travel (>4 h)

E.S. Morgan et al. 259

inadequate dose or the correct dose but too late. Ofthose women who met the criteria, only 33% actually re-ceived thromboprophylaxis, and half of these were givenlower than the recommended dose.8,81

One of the recommendations of the 2003–2005CEMACH report was the urgent need for a guidelineon the management of prevention of VTE in obese preg-nant women.1 In response, the latest RCOG guidelinesnow recommend seven days of postnatal thrombopro-phylaxis for any woman with morbid obesity(BMI P40) even as a single risk factor. The RCOG alsorecommend seven days of postnatal thromboprophy-laxis for women with a BMI P30 plus another VTE riskfactor. In agreement with the previous guideline, theyrecommend considering antenatal thromboprophylaxisfor any woman with three or more risk factors(Table 3).9

Thromboprophylaxis in pregnancy is complicated bythe associated pharmacokinetic changes of pregnancy,namely an increase in volume of distribution and clear-ance of renally-excreted drugs. LMWH is a polar mole-cule and predominantly cleared by the kidney. Peak

concentration is lower and the half-life shorter in preg-nancy compared with the non-pregnant population.82

Obesity further alters the pharmacokinetics.83 Clinicalstudies have shown that fixed-dose prophylaxis may re-sult in an unacceptably high rate of VTE in the non-obstetric obese population.84 There is also evidence thatfixed-dose LMWH results in a negative correlation be-tween weight and anti-factor Xa activity,85 suggestingthat higher doses are needed. Evidence also suggests thatweight-based dosing results in anti-factor Xa activity inthe correct region for prophylaxis although studies havebeen too small to demonstrate safety and clinical effi-cacy.84 Although total body weight is commonly usedfor calculation of weight-based dosing, this may not beaccurate. Obesity is associated with an increase involume of distribution and clearance of certain drugs,these are, however, non-linear relationships,86 and there-fore, drug-dose calculations based on total body weightmay lead to overdosing. Lean body weight (total bodyweight minus fat mass) has been advocated by some asa more useful metric when calculating drug doses inthe obese, especially for hydrophilic drugs.86 Clearance

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Table 4 Suggested thromboprophylactic doses for ante- and postnatal low-molecular-weight heparin

Weight (kg) Enoxaparin Dalteparin Tinzaparin

<50 20 mg daily 2500 units daily 3500 units daily50–90 40 mg daily 5000 units daily 4500 units daily91–130 60 mg daily 7500 units daily 7000 units daily131–170 80 mg daily 10 000 units daily 9000 units daily>170 0.6 mg/kg/day 75 units/kg/day 75 units/kg/day

High prophylactic (intermediate) dose for women weighing 50–90 kg

40 mg 12-hourly 5000 units 12-hourly 4500 units 12-hourly

Treatment dose

1 mg/kg/12 hourly antenatal 100 units/kg/12 hourly 175 units/kg daily1.5 mg/kg/daily postnatal 200 units/kg/daily postnatal (ante- and postnatal)

May be given in two divided doses.

260 Obesity and thromboembolism

of enoxaparin is increased in obese subjects, but whennormalised for total body weight clearance was reduced,demonstrating its non-linear relationship with clear-ance.87 Lean body weight is therefore the best descriptorfor clearance of enoxaparin in the obese population.88

Overall, it appears that higher doses of LMWH forthromboprophylaxis are required in the obese popula-tion but more evidence is needed with regards to whichmetric is used for weight-based dosing. Although theACCP guidelines for VTE prevention in pregnancy donot specifically address LMWH dosage in obesity, theguidelines for bariatric surgery highlight that higherdoses may be required in obese individuals.60,89

It may be expected that when pregnancy and obesityare combined, an even lower peak concentration ofLMWH and shorter elimination half-life results, necessi-tating increased and more frequent dosing. However, atpresent there is little supporting evidence and the opti-mum dose and dosing frequency of LMWH for ante-and postpartum thromboprophylaxis are not known.In an attempt to ensure appropriate dosing, increasingdoses of thromboprophylaxis with increasing weighthave been updated in the 2009 RCOG guidelines(Table 4).9 The recent NICE guideline on the preventionof venous thromboembolism in hospitalised patients isin line with the RCOG guideline.72 Due to the uncer-tainty in LMWH dosing, guidance states that anti-factorXa monitoring may be of value in the extremes of bodyweight.90

Anaesthetic implications

Implementation of RCOG and NICE guidelines to-gether with the obesity epidemic, have resulted in morewomen being treated with LMWH. Moreover, guide-lines recommend doses to be calculated according toweight. This will result in patients receiving higher dosesthan previously considered standard, although bloodlevels in obese women will be similar to those in thenon-obese population. The main anaesthetic concernsfrom increased use and dosing of LMWH are the

balance between VTE prevention and the potential in-creased risk of maternal haemorrhage, as well as the safedelivery of analgesia and anaesthesia for labour anddelivery. All departments should have clear writtenguidelines on VTE management during pregnancy andthe postnatal period with specific guidance on themanagement of obese patients. These guidelines shouldinclude recommendations for thomboprophylaxisregimens.

Risk assessment in early pregnancy is a key factor inreducing mortality from VTE. RCOG guidelines stratifyantenatal and postnatal VTE risk into high, intermedi-ate and lower risk. Those at high risk of VTE shouldbe offered antenatal prophylactic LMWH and formalreferral for expert obstetric thrombotic opinion. Thosewith more than three risk factors (two or more if admit-ted to hospital) are considered at intermediate risk. Suchwomen should be considered for antenatal LMWH pro-phylaxis, and advice, although not necessarily formalreferral, sought for expert obstetric thrombotic opinion.Those considered at lower risk should simply be coun-selled to avoid dehydration and immobility.

Although referral of patients to an antenatal high-risk anaesthetic clinic will depend on local guidelines,it is advisable that women receiving treatment-doseLMWH, and those with multiple risks for VTE are seenduring pregnancy. Women with a BMI >40 should auto-matically undergo full anaesthetic assessment regardlessof VTE risk. Clear anaesthetic plans for labour anddelivery should be made and documented on an individ-ualized basis. It is important to discuss the implicationsof treatment with LMWH. Patients should be told tostop thromboprophylaxis if labour commences, if thereare signs of bleeding, and at an appropriate time (see be-low) before planned elective delivery. When induction oflabour is planned for women receiving intermediate (be-tween non-pregnant thromboprophylactic and treat-ment doses) or therapeutic LMWH treatment, dosesshould be reduced to a standard thromboprophylacticdose on the day before induction. It is prudent to discussalternative methods of analgesia and anaesthesia when

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E.S. Morgan et al. 261

timings of administration of LMWH restrict the use ofneuraxial techniques.

A postnatal risk assessment should be made follow-ing delivery. Those at high risk should be offered sixweeks of thromboprophylaxis; for those at intermediaterisk this may be limited to seven days. Women at lowrisk are encouraged to mobilise and avoid dehydration.All women with a BMI P40 as a single risk factor areconsidered intermediate risk.

Pregnancy-associated prothrombotic changes aremaximal immediately following delivery. It is thereforeimperative that VTE prophylaxis and treatment areoptimized in the perinatal phase. The anaesthetic impli-cations of more widespread postnatal thromboprophy-laxis relate to the associated increased risk of maternalhaemorrhage and epidural haematoma. Kominiareket al. demonstrated in a large case-control study thatwomen receiving treatment or prophylactic doses ofLMWH were not at an increased risk of bleeding com-plications compared with a control group matched formode of delivery.91 Further to this, Voke et al. con-ducted a prospective multicentre observational surveyof management of antenatal venous thromboembolismin 126 women in the UK and Ireland. They found a5% incidence of primary postpartum haemorrhage inline with the incidence in other developed countries.23

The risk of postpartum haemorrhage is likely to be evenlower in cases of prophylaxis. Despite this evidence, cau-tion should be exercised. LMWH should not be used inthose actively bleeding, and only with caution in thoseconsidered at risk of bleeding such as those with throm-bocytopenia. Whilst the use of heparin may aggravatehaemorrhage, maternal haemorrhage itself is a risk fac-tor for VTE. In patients at high risk of haemorrhage,unfractionated heparin and non-pharmacological tech-niques may be more appropriate than LMWH. All hep-arins should be stopped in cases of active haemorrhage,with haematological advice being promptly sought.

The risk of epidural haematoma is thankfully veryrare. In a meta-analysis of one million women who re-ceived obstetric epidurals post 1990, the incidence ofvertebral canal haematoma was 1 in 168 000.92 Althoughthe authors restricted studies to post 1990, this figuremay not be representative of current practice as throm-boprophylaxis is now more widespread. More recentdata from the Third National Audit Project of the RoyalCollege of Anaesthetists looking at major complicationsof central neuraxial block in the UK showed an inci-dence of 0.85 per 100000. However out of the 320425obstetric patients studied, there were no cases of verte-bral canal haematoma.93

Current guidance states that there should be a 2–4 hwindow between epidural insertion or removal and theadministration of prophylactic LMWH. There shouldbe a 12 h window after prophylactic LMWH dose and24 h window after therapeutic LMWH dose before

epidural insertion or removal.90,94 These time periods re-main the same with weight-based dosing. Communica-tion between obstetricians and anaesthetists, mostimportantly following operative delivery, is vital to en-sure these guidelines are followed.

Venous thromboembolism remains an importantcause of maternal morbidity and mortality. Maternalobesity is increasing and is associated with an increasedrisk of developing VTE. Evidence is suggestive of agradient of risk with increasing levels of obesity. Moreevidence is urgently needed with regard to which indi-viduals warrant thromboprophylaxis and the dose andfrequency of thromboprophylaxis required in the obesepregnant and postpartum population, as the obesityepidemic shows no signs of halting.

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