1. Venous thromboembolism (VTE) in obstetrics Dr. Yasir Katib MBBS, FRCSC, Perinatologist

2. Objectives Incidence Pathogenesis Predisposing factors Prophylaxis Management choices –Antepartum –Postpartum

3. Incidence Deep venous thrombosis –antepartum: 0.5-3 per 1000 pregnancies –postpartum: 0.5-18 per 1000 pregnancies High recurrent risk: 7-13% pulmonary embolus –untreated DVT: 24% have PE, 15% mortality –treated DVT: 5% have PE, 1-2% mortality

4. Number of pregnancy deaths from 1982- 1992 in Canada

5. Postpartum weekAntenatal trimester Data from CEMACH Maternal deaths enquiries, UK. Slide courtesy Peter MacCallum

6. Pathogenesis of VTE in pregnancy StasisHypercoagulation Vessel wall abnormality

7. Predisposing factors associated with pregnancy

8. Risk factor for VTEOR95% CI Previous VTE 1 24.817.1-36 Age > 35 4 1.31.0-1.7 BMI > 30 2 1 5.3 4.4 2.1-13.5 3.4-5.7 Smoking 3 2.71.5-4.9 Parity >3 4 2.41.8-3.1 Medical Conditions 1 Sickle cell disease, SLE, Heart disease, anaemia, infection, Hyperemesis 2.0 – 8.7 2.512.0-3.2 Immobility 3 7.7 (an) 10.8 (pn) 3.2-19 4-28.8 Pre-eclampsia 3 +Fetal Growth Restriction 3.1 5.8 1.8-5.3 2.1-16 Assisted reproductive therapy4.32.0-9.4 Twins 3 2.61.1-6.2 APH 1 2.31.8-2.8 Post partum haemorrhage4.12.3-7.3 Caesarean section 4 3.63.0-4.3 Varicose veins2.41.04-5.4 Transfusion 1 7.66.2-9.4 1.James et al 2006; 2.Larsen et al 2007; 3.Jacobsen et al 2008; 4.Lindqvist et al 1999

9. Thrombophilias Congenital: –resistance to activated protein C (factor V leiden) –hyperhomocysteinemia (controversial) –protein S, C deficiency: 2-4% risk, 18-20% risk during postpartum –antithrombin III deficiency: 25-55% risk Acquired: –antiphospholipid syndrome (APLS): role to cause VTE is uncertain

10. Prevalence in population General populationThrombosis Factor V leiden5-9%20-40% Prothrombin G20210A 3%6-15% Protein C def0.3%1-2% Protein S0.2%1-2% ATIII def0.07%<1% Hyperhomocystin- emia 5%5-10%

11. Obstetrical complications of thrombophilia There is growing evidence to suggest that the incidence of thrombophilias is also increased in women with 1. Late fetal loss (abortions) 2. Gestational hypertension 3. Intrauterine growth restriction 4. IUFD

12. Recommendations for thromboprophylaxis  Antepartum all pregnant women who had previous VTE should be tested for thrombophilia factors; for single episode of prior VTE with transient risk factors: surveillance (1C) for single episode of idiopathic VTE: surveillance or UFH or prophylactic LMWH dose (1C) for single episode of VTE and thrombophilia (except protein S): surveillance (except decreased antithrombin) or UFH or prophylactic LMWH dose (1C)

13. Recommendations for thromboprophylaxis Women with asymptomatic inherited or acquired thrombophilia may be managed with close surveillance antenatally. Exceptions are women with antithrombin deficiency, those with more than one thrombophilic defect (including homozygosity for factor V Leiden) or those with additional risk factors where advice of a local expert should be sought and antenatal prophylaxis considered

14. Antepartum continues: Antepartum continues: known thrombophilia: surveillance (except decreased antithrombin) or UFH or prophylactic LMWH dose(1C) recurrent episodes of VTE: adjusted dose of UFH or adjusted dose of LMWH(1C) > 3 moderate risk factors: surveillance or UFH or prophylactic LMWH dose(1C)

15. Postpartum thromboprophylaxis All women with class 3 obesity (BMI > 40kg/m2) should be considered for thromboprophylaxis with LMWH for 7 days after delivery. GPP All women with asymptomatic heritable or acquired thrombophilia should be considered for LMWH for at least seven days following delivery, even if they were not receiving antenatal thromboprophylaxis. This should be extended to 6 weeks if there is a family history or other risk factors present. Grade C

16. Summary of protocol for thromboprophylaxis in women with previous VTE and/or thrombophilia These women require joint specialist management by obstetricians and experts in haemostasis and pregnancy Very High Risk Previous VTE (+/- thrombophilia) on long term warfarin Antithrombin deficiency Antiphospholipid syndrome Antenatal high prophylactic or therapeutic dose LMWH and at least six weeks postnatal warfarin. High Risk Previous recurrent or unprovoked VTE Previous estrogen (pill / pregnancy) associated VTE Previous VTE + thrombophiliaAntenatal and six weeks postnatal prophylactic LMWH Previous VTE + family history of VTE Asymptomatic thrombophilia (combined defects, homozygous FVL or prothrombin gene defect) Moderate Risk Single previous provoked VTE associated with transient risk factor no longer present without thrombophilia, family history or other risk factors Six weeks postnatal prophylactic LMWH Seven days postnatal LMWH extended to six weeks if family history +ve, other risk factors Asymptomatic thrombophilia (except AT deficiency, combined defects, homozygous FVL or prothrombin gene defect)

17. Prophylactic doses of UFH and LMWH UFH 5000 IU sc bid Prophylactic LMWH: Enoxaparin 40 mg sc q24h, Dalteparin 5000 IU sc q24h. Anti–factor Xa assay: 0.2 and 0.6 U/mL 4 hours after the injection

18. IV Heparin –inhibits thrombin by activating AT-III, prevents conversion of fibrinogen to fibrin –need baseline CBC, INR PTT –initial 5000 IU bolus, then 1000-1500 IU/hr, INR & PTT q6hr PTT therapeutic level 1.5- 2.5, then INR/PTT q24h Advantages: –doesn’t cross placenta –not excreted in breast milk

19. IV Heparin –rapidly reversible (protamine sulfate 1mg/100units) –no increase in Perinatal mortality or morbidity over control Disadvantages: –bleeding in 4-8% –osteoporosis (15,000U/d > 5 months) –thrombocytopenia (by day 4) –Cost and compliance

20. Low molecular weight heparin Adjusted dose LMWH: Enoxaparin 1 mg/kg sc q12h, Dalteparin 200 IU/kg sc q24h Advantages: possibly less risk of –thrombocytopenia –osteoporosis more predictable therapeutic effect monitor anti-Xa levels in third trimester

21. Disadvantages: more difficult to reverse drug cost higher but no need for hospitalization Low molecular weight heparin

22. Coumadin easily crosses placenta up to 70% fetal complications if in 1st trimester –IUGR, chondrodysplasia punctata –multiple congenital anomalies 20-30% complication rate in 2nd-3rd trimester Long half life

23. Management during peripartum Therapy throughout pregnancy and 8-12 weeks post partum IV Heparin and LMWH should be held once labor is established in order to use local anesthesia If therapeutic PTT is required in labor, patient should be switched to IV heparin, and local anesthesia is contraindicated therapeutic PTT may increase the incidence of hematomas but not PPH

24. Avoid trauma or C/S at delivery – midline episiotomy if necessary – avoid tears Resume heparin 6 hrs postpartum Start coumadin when oral intake tolerated Avoid OCP, estrogen Consult! Management during peripartum

25. Take home message Thromboprophylaxis is recommended for previous VTE hx and a known thrombophilia; idiopathic VTE, recurrent VTE, and more than 3 major risk factors for VTE (II B) Diagnosis of VTE is clinical suspicion + lab tests, never hesitate to order V/Q scan or angiography if the result will change management Treatment is long term: till postpartum 8-12 weeks. Considering side effects of different drugs, cost, local anesthesia, avoiding instrument delivery

26. Take home message Extended use of LMWH –Increased number of risk factors –Focus on admitted patients Importance of estrogen related prior events Extended duration of LMWH post partum from 3-5 days to 7 days