Marc Carrier, MD, MSc, FRCP(C) University of Ottawa

Ottawa Hospital Research Institute

Venous Thromboembolism (VTE) Prevention

in Obstetrics

Objectives • Review the incidence and pathophysiology

of venous thromboembolism (VTE) during the ante and post-partum periods

• Review the risk factors for VTE • Previous VTE • Asymptomatic thrombophilia • Pre-pregnancy risk factors (IBD, etc) • Pregnancy-related risk factors

• Review the risk and benefit of pharmacological thromboprophylaxis to prevent VTE

• Ante-partum period • Postpartum period

Population Epidemiology

Retrospective cohort studies

– Antenatal VTE: ~0.5-1.0/1000 maternities1-3

• Daily antenatal risk 3-7.5x higher than non-pregnant women4

– Postpartum VTE: ~0.5/1000 maternities

• Daily postpartum risk 15-35x higher than non-pregnant women4

1-Andersen BS, Acta Obstet Gynecol Scand,1998; 2-Simpson EL, BJOG 2001; 3-Treffers PE, Int J Gynaecol Obstet 1983; 4-Anderson FA, Arch Intern Med 1991

Bourjeily G, Rodger M, Lancet, 2009

Hypercoagulable Blood ↑Procoagulant Factors:↑ Fibrinogen, ↑V, IX, X, XII and VIII ↓Anticoagulant Activity: ↓ Protein S,↑ act. Protein C resistance ↓ Fibrinolytic Activity: ↑ PAI-1 and PAI-2, ↓ t-PA activity = more thrombin generation and less clot dissolution

Stasis Iliac Vein Compression: Right iliac artery compresses left iliac vein Gravid Uterus Venodilation: Hormonally Mediated Bed Rest Immobilization

Pelvic

Calf

Pregnant

DVT1

Non-Pregnant

DVT2

Right Left Right Left

Total 12% 88% 44% 56%

Pregnant1 Non-Pregnant3

Isolated Pelvic

17% 0%

Proximal Without Calf

71% 1%

Proximal with Calf

29% 99%

Total 100% 100%

1- Chan, CMAJ, 2010 2- Ouriel, J Vasc Surg, 2000 3- Cogo, Arch Int Med, 1993

Ante-partum Thromboprophylaxis

Case 1 • 30 yo woman

– 8 weeks GA – Known Factor V Leiden (FLV) found

on family screening

• ? Ante-partum thromboprophylaxis

• She also had a DVT post trauma 5 years ago…? Thromboprophylaxis

When should we consider thromboprophylaxis?

• Assess risk benefit ratio • Risks associated with prophylactic LMWH

• Ante-partum bleeding: 0.42% • Postpartum bleeding: 0.95% • Wound hematoma, HIT: 0% • Major skin reaction/allergy: 0.96% • Osteoporosis: 0.26%

Greer IA, Blood 2005;106:401-407

When should we consider thromboprophylaxis?

• Benefits of prophylactic LMWH – Risk of VTE > 10% - Thromboprophylaxis – Risk of VTE < 1% - No thromboprophylaxis – Risk ≥1 but ≤ 10% - Controversial (preferences, etc)

• SOGC panel consensus Risk of VTE ≥1 %= consider thromboprophylaxis

Ante-Partum Risk Factors Previous VTE

Risk of VTE < 1% ≥1 to ≤ 10% > 10% •Provoked VTE (Not OCP or pregnancy related)

•Unprovoked VTE •Pregnancy related VTE •OCP related VTE

•OCP related VTE

Brill-Edwards P et al. NEJM 2000;343:1439-1444; Pabinger I et al. J Thromb Heamost 2005;3: 949-954; De Stephano V, Br J Haematol 2006;135:386-391.

Ante-Partum Risk Factors Aymptomatic thrombophilia

Risk of VTE < 1% ≥1 to ≤ 10% > 10% •Hetero FVL •Hetero PTG •PC deficiency •PS deficiency

•Combined hetero FVL + PTG

•AT III •Homo FVL •Homo PTG

Pabinger I et al. Hematol J 2000;1:37-41; van Boven HH et al. Blood 1999;94:2590-2594; Tormene D et al. Haematologica 2001;86: 1305-1309; Middeldorp S et al. Ann Intern Med 1998;128:15-20. Zotz RB et al. Clinical Haemotalogy 2003; 16:243-259; McColl MD et al. Thromb Haemost 1997;78:1183-8; Gerhardt A et al. NEJM 2000; 342:374-80;

Ante-Partum Risk Factors Pre-pregnancy risk factors

Risk of VTE < 1% ≥1 to ≤ 10% > 10% •Diabetes •IBD •Cancer •Varicose veins •Weight/BMI •Age •Smoking

Sultan AA et al. Blood 2013;121:3953-3961; Simpson EL et al. BJOG 2001;108:56-60; Larsen TB et al. Thromb Res 2007;120:505-509; Knight M BJOG 2008;115:453-461; Jacobsen AF et al. J Thromb Haemost 2008;6:905-912.

Ante-Partum Risk Factors Pregnancy-related risk factors

Risk of VTE < 1% ≥1 to ≤ 10% > 10% •IUGR •Gestational diabetes •Multiple pregnancy •Bed rest (3 days to 3 weeks)

Sultan AA et al. Blood 2013;121:3953-3961; Knight M BJOG 2008;115:453-461; Jacobsen AF et al. J Thromb Haemost 2008;6:905-912.Blanco-Molina A. Thromb Haemost 2007;97:186-190.

Ante-Partum Risk Factors Multiple pregnancy-related risk factors

Risk of VTE < 1% ≥1 to ≤ 10% > 10% •IUGR + preeclampsia

•Bed rest (≥ 7 days) and BMI (≥ 25 Kg/m2)

Jacobsen AF et al. J Thromb Haemost 2008;6:905-912.

Dosing of thromboprophylaxis

• Unfractionated heparin: 5000 IU sc BID • Dalteparin 5000 IU sc daily • Enoxaparin 40 mg sc daily • Tinzaparin 4500 IU sc daily • Nadroparin 2850 IU sc daily • Consider decreasing dose if < 50 kg • Consider increasing dose if > 100 kg

Neuraxial anesthesia

• Hold anticoagulation at the onset of labor – or day prior of planned delivery

• UFH: – Neuraxial anesthesia: No delay up to 4 hours

• LMWH: – Neuraxial anesthesia: Min of 10 to 12 hours – ? Switch from LMWH to UFH at 37 weeks

• Depends on local practices and logistics

Take Home Message • Individual risk assessment

– If higher risk: Discuss signs and symptoms of VTE

• Consider prophylactic doses of LMWH: – Previous unprovoked or OCP or pregnancy

related VTE – Asymptomatic homo FVL or PTG, ATIII – Asymptomatic combined thrombophilia – In presence of multiple risk factors where the

overall absolute risk > 1% • e.g. Previous provoked VTE and thrombophilia

Take Home Message • Routine thromboprophylaxis is not

recommended for single pregnancy-related risk factors

• Any indication for intermediate or therapeutic doses of LMWH? – If already on long-term anticoagulation – Multiple previous VTE – Previous VTE with high risk thrombophilia

(ATIII, APLA, etc)

Post-partum Thromboprophylaxis

Case 1 • 30 yo woman

– 8 weeks GA – Known Factor V Leiden (FLV) found

on family screening – Uncomplicated vaginal delivery – No placeta-mediated complications

• Postpartum thromboprophylaxis

• She also add a DVT post trauma 5

years ago…? Thromboprophylaxis

Postpartum VTE

• Leading cause of death in Canada • 17 maternal deaths per year • 15 to 35 fold increase in the 6 weeks following the

delivery (highest during the first 3 weeks)

• Different risk factors for postpartum vs. ante-partum VTE

• Again: – Consensus: Risk of VTE ≥1 =

Thromboprophylaxis

Postpartum Risk Factors Pre-pregnancy risk factors

Risk of VTE < 1% ≥1 to ≤ 10% > 10% •Sickle cell disease •IBD •Cancer •Parity (≥ 2) •Smoking •Age •BMI

•Previous VTE •APLA •ATIII •Homo FVL or PTG

Sultan AA et al. Blood 2013;121:3953-3961; Jacobsen AF et al. J Thromb Haemost 2008;6:905-912; James AH et al. Am J Obstet Gynecol 1995;173:1042-1048; Blanco-Molina A et al. Thromb Haemost 2007;98:1237-1245; Danilenko-Dixon DR et al. Am J Gynecol 2001;184:104-110.

Postpartum Risk Factors Pregnancy-related risk factors

Risk of VTE < 1% ≥1 to ≤ 10%

•Gestational DM •IUGR •Placenta previa •Abruption •PROM •Preterm birth •Stillbirth

•Any C-section •Elective C-section •ER C-section

Sultan AA et al. Blood 2013;121:3953-3961; Jacobsen AF et al. J Thromb Haemost 2008;6:905-912; Jacobsen AF et al. Obstet Gynecolo 2008;198:233. e1-233; Blanco-Molina A et al. Thromb Haemost 2007;98:1237-1245; Danilenko-Dixon DR et al. Am J Obstet Gynecol 2001; 2001;184:104-110.

Postpartum Risk Factors Multiple risk factors

Risk of VTE < 1% ≥1 to ≤ 10% > 10% •IUGR + preeclampsia •C-section with infection postpartum

•> 1 liter hemorrhage + post-partum surgery •Vaginal delivery + infection postpartum •Bed rest (> 7days) + BMI ≥ 25 kg/m2

Jacobsen AF et al. J Thromb Haemost 2008;6:905-912.

Duration of thromboprophylaxis

• Persistent risk factors – Prior VTE (highest), high risk thrombophilia, etc – 6 weeks post-partum

• Transient risk factors

– Until discharged from hospital or up to 2 weeks

Neuraxial anesthesia

• Removal of neuraxial anesthesia: – UFH:

• 4 hours after last dose – LMWH:

• 10 to 12 hours after last dose (or before next dose) • May resume LMWH 2 hours post removal

Take Home Message • Individual risk assessment

– If higher risk: Discuss signs and symptoms of VTE – Close clinical follow-up

• Consider prophylactic doses of LMWH:

– Previous VTE – ATIII def, Homo FVL or PTG, combined

thrombophilia, APLA – Strict bed rest prior to delivery (> 7 days)

• >90% of the time in bed – Peri or postpartum blood loss (> 1L) or transfusion

and concurrent postpartum surgery – Vaginal delivery and peripartum sepsis

Take Home Message • Consider prophylactic doses of LMWH if 2 or

more of the following: – Any C-section – Smoking (> 10 cigarettes/day antepartum) – BMI ≥30 kg/m2 at first antepartum visit – IUGR – Preeclampsia – Placenta previa or abruption – Peri or postpartum infection (vaginal or c-section) – Low risk thrombophilia (PC, PS, hetero FV or PT) – IBD, DM, sickle cell disease – Multiple pregnancy – Pre-term delivery

Take Home Messages

• DVT in pregnancy is likely a north (proximal) to south (distal) disease

• Individual risk assessment – If higher risk: Discuss signs and symptoms of

VTE + Close follow-up

• Consider ante and/or postpartum thromboprophylaxis in patients with risk of VTE ≥1%

Diagnosis of DVT and PE in Pregnancy

Case 1

• 30 yo woman presents at 8 weeks GA with a tender swollen left leg/buttock

Exam: left thigh/calf are >5 cm bigger than her right leg

Case 1

How would you exclude DVT? 1. Negative D-dimer alone 2. Low Wells model and negative D-Dimer 3. Single negative compression US (CUS) 4. Negative serial compression US (CUS) on

Day 1 and day 7 5. Negative compression ultrasound (CUS)

and negative MRV

Wells Clinical Model for DVT Wells P, et al. Value of Assessment of Pre-test Probability of Deep-Vein Thrombosis in Clinical Management. Lancet Vol. 350, Dec 1997, 1795-1798.

Active cancer (treatment ongoing or within past 6 months or palliative) 1

Recent paresis, paralysis or cast immobilization of lower limb (within past 4 weeks) 1

Recently bedridden for more than 3 days or major surgery within the past four weeks 1

Localized tenderness of the deep venous system 1

Oedema of entire leg 1

Calf swelling > 3 cm when compared with contralateral calf (measured 10 cm under the tibial tuberosity) 1

Pitting oedema more marked on suspected side 1

Collateral vein network (non-varicose) (replaced by previous VTE in recent versions) 1

Another diagnosis as likely or more likely than DVT -2

Total Score:

Probability is: High Intermediate Low

if total is equal to or greater than 3 if total is 1 or 2 if total is 0

Probability is: Likely Unlikely

if total is >1 if total is ≤1

LEFt Clinical Decision Rule looks good …but needs validation • Multi-center cohort • 194 pregnant women with ?DVT

– Collect potential predictors • Gold standard: Serial CUS and 90d F/U

– 17 (8.8%) had DVT • 12, DVT initial CUS • 4 (24%), on d+3 or d+7 week CUS • 1, during 90d F/U • (serial CUS has NPV = 99.5% (95% CI 97.2-99.9%))

• Left leg presentation, Extremity swelling (calf circumference ≥ 2cm) and First trimester strong multivariate predictors (OR 27-53)

1- Chan, Ann Int Med, 2009

D-Dimer alone to exclude DVT in pregnancy looks good …but needs validation • Multi-center cohort • 149 pregnant women with ?DVT

– SimpliRED D-Dimer • Gold standard: Serial CUS and 90d F/U

– 13 (8.7%) had DVT

WS Chan, S Chunilal, A Lee, M. Rodger and JS Ginsberg. Annals Int Med 2007

100% Sensitivity

Specificity

Negative predictive

value …40

50

60 70 80 90 0…

100

Normal D-Dimer to exclude DVT in pregnancy

95% CI: 75-100%

60% 95%CI: 52-68%

95-100% 100%

WS Chan, S Chunilal, A Lee, M. Rodger and JS Ginsberg. Annals Int Med 2007

Case 1

How would you exclude DVT? 1. Negative D-dimer alone 2. Low Wells model and negative D-Dimer 3. Single negative compression US (CUS) 4. Negative serial compression US (CUS) on

Day 1 and day 7 5. Negative compression ultrasound (CUS)

and negative MRV

Case 2

35 yo women 30 wks GA presents with pleuritic CP and SOB and positive D-Dimer.

How would you exclude PE? 1. Low Wells model and negative D-

Dimer 2. Compression US first then if normal do

a V/Q; normal perfusion excludes PE 3. V/Q: normal perfusion excludes PE 4. Negative CT pulmonary angiogram

alone

Wells Clinical Model for PE Points

• Clinical symptoms of DVT 3

• No alternative diagnosis more likely than PE 3

• Heart rate over 100 1.5 • History of immobilization or surgery in previous 4 weeks

1.5

• Previous DVT/PE 1.5

• Hemoptysis 1.0

• Cancer

1.0

Total Score ≤4 = negative, >4 = positive

Return to Question 5

D-Dimer looks good …but needs validation

• Multi-center cohort • 149 pregnant women with ?DVT

– SimpliRed D-Dimer

• Gold standard: Serial CUS and 90d F/U – 13 (8.7%) had DVT

WS Chan, S Chunilal, A Lee, M. Rodger and JS Ginsberg. Annals Int Med 2007

V/Q CXR All 3

CT

0.016

0.032

0.05

0

0.066

0.082

0.1

0.000001 Gy

Radiation Exposure to Fetus G

ray

(Gy)

0.00051 Gy

0.000013 Gy

0.00054 Gy

Possible Teratogenic Threshold 0.1Gy

Possible Oncogenic Threshold 0.01Gy

V/Q Test of Choice in Pregnancy: Disadvantages of CT over V/Q • Higher proportion of inadequate CTs in

pregnancy (up to 1/3rd)1

– Contrast timing/ IVC dilution

• V/Q normal in >70% of patients in pregnancy with ?PE2,3

1- Ridge et al, AJR, 2009; 2- Chan et al, Arch Int Med, 2002; 3-Cahill, Obstet Gynecol, 2009;

V/Q Test of Choice in Pregnancy: Disadvantages of CT over V/Q • Non-Pregnant: High “false positive” rate

with CT in an RCT1 which may worsen with ↑slices in MDCT2

• Increase lifetime risk of malignancy from radiation exposure – 150X ↑ breast radiation than V/Q – 1 in 143 in 20 y.o. non-pregnant ♀3

1- Anderson, JAMA, 2007; 2- Carrier, JTH, 2010; 3-Einstein, JAMA 2007

Case 2

30 wks GA presents with pleuritic CP and SOB and positive D-Dimer.

How would you exclude PE? 1. Low Wells model and Negative D-Dimer

2. Compression US first then if normal do a V/Q; normal excludes PE

3. V/Q: normal excludes PE 4. Negative CT pulmonary angiogram alone

Take Home Messages

• DVT in pregnancy is likely a north (proximal) to south (distal) disease

• Serial ultrasounds are required to exclude DVT in pregnancy

• V/Q scan remains test of choice for ?PE