Thromboembolic Disease in Pregnancy – The Silent Disorder

1. Thromboembolic Disease in Pregnancy – The Silent Disorder • Hassan Nasrat FRCS, RCOG • Professor of Obstetric and Gynecology • Fetal and Maternal Medicine • Faculty of Medicine • King Abdul Aziz university • Jeddah – Saudi Arabia

2. Thromboembolic Disease (VTE) Refer to • Deep Vein Thrombosis (DVT) • And Pulmonary Embolism (PE) Over 90 % Of Acute PE Are Emanating From Emboli Of The Lower Extremities. • Anticoagulation Is Highly Effective Therapy For Both Conditions • Tests Designed To Diagnose DVT Are Also Of Importance For The Diagnosis Of Acute PE.

3. Incidence And Epidemiology Pulmonary Embolism (PE) Is Responsible For Approximately 150,000 To 200,000 Deaths Per Year In The USA. PE Remains The Most Common Preventable Cause Of Hospital Death

4. Pregnancy and VTE • The Incidence: 4 To 50 Times Higher In Pregnant Versus Non-pregnant Women (Age-adjusted) • Absolute Incidence: 1 In 500 To 2000 Pregnancies (0.025 To 0.10 Percent)

5. VTE in Pregnancy: A Major Cause of Maternal Death VTE Is The Leading Direct Cause Of Maternal Death In Western Obstetric Practice (11 cases = 27% Of Cases) “Confidential enquiries into maternal death in UK”

6. VTE in Pregnancy: A Major CauseVenous Insufficiency and VTE in Young Women • 71 women (mean age 35.5 years) with VTE • Assessed about 4 years after event • 52 DVT & 19 PTE • 79% mild / moderate post thrombotic syndrome • Risk of VI after DVT: OR 10.9 (95% CI 4.2-28.0) • Risk of VI after PTE: OR 3.8 (95% CI 1.2-12.3) McColl, Ellison, Greer et al 1999

7. Thromboembolic Disease in Pregnancy – The Silent Disorder Part I PATHOGENESIS AND RISK FACTORS Part II Antithrombotic Strategies Part III Use of LMWHs in Pregnancy Part IV Summary and Recommendations

8. Thromboembolic Disease in Pregnancy – The Silent Disorder Part I PATHOGENESIS AND RISK FACTORS Part II Antithrombotic Strategies Part III Use of LMWHs in Pregnancy Part IV Summary and Recommendations

9. PATHOGENESIS AND Pregnancy Proper Blood Flow Balance between coagulation and anticoagulation mechanism: > 30% reduction by 15 weeks > 60% reduction by 36 weeks Increases coagulation Reduces fibrinolysis Vessel Wall Trauma At delivery Healthy Vessel walls

10. Circulatory stasis • A longitudinal Follow Up of 24 pregnant women with monthly Doppler ultrasound examinations found: • Progressive dilation of the deep veins of the legs. • Decreased flow velocity in the left common femoral vein and inferior vena cava that was most severe in the supine position. • The left lateral decubitus position significantly increased the velocity in both lower extremities An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Macklon NS; BrJOG1997, 104]

11. Features of DVT in Pregnancy • The Incidence Of Is Nearly Twice As Many Postpartum Than Antepartum Events. • Antepartum VTE Is Roughly Equally Distributed Across Trimester’s. • More Common In The Left Than The Right Leg.   • Pelvic Vein DVT Is More Likely In Pregnancy.

12. Among 5451 Patients With Ultrasound-confirmed DVT. • 1 % Had DVT Confined To The Pelvis. • While 12 % Of Pregnant And 11 % Of Post-partum Women Had Isolated Pelvic DVT

13. Conclusion - Part I VTE • A Serious Disease • High Mortality Rate • Serious Morbidities • Appropriate Prophylactic Measures • Appropriate Diagnosis • Appropriate Treatement

14. Thromboembolic Disease in Pregnancy – The Silent Disorder Part I PATHOGENESIS AND RISK FACTORS Part II Antithrombotic Strategies Part III Use of LMWHs in Pregnancy Part IV Summary and Recommendations

15. Antithrombotic Strategies • Vitamin K Antagonists • Un-Fractionated Heparin • Low-Molecular-Weight Heparins • Physical methods • Vena Cava Filter

16. Mechanical Thromboprophylaxis

17. Antithrombotic • Safety (Maternal and Fetal) • Effectiveness • Compliance • Cost

18. Safety (Maternal and Fetal) • Two potential fetal complications of maternal anticoagulant therapy: • Teratogenicity • Bleeding

19. Vitamin K Antagonists • Cross the placenta • Risk of maternal and fetal bleeding throughout gestation • Embryopathy: 6-12 wks of gestation - 4-5% • Chondrodysplasia punctata • Nasal (midface) hypoplasia • Stippled epiphyses, short proximal limbs, short phalanges, scoliosis • Central nervous system abnormalities • Adverse fetal outcomes if Warfarin > 5 mg/day

20. Warfarin Embryopathy • Embryopathy • chondrodysplasia punctata • midface hypoplasia • short proximal limbs • short phalanges • scoliosis • Increased risk of low IQ and neurological dysfunction (RR 7.6 for 2 or more defects)1 • Maternal and foetal haemorrhage 1Wesseling J, et al. Thromb Haemost. 2001;85:609-13. X-ray: Wellesley D, et al. Br J Obstet Gynecol. 1998;105:805.

21. UFH in pregnancy:no placental transfer but… Heparin-induced thrombocytopenia Osteoporosis Allergy Skin Necrosis Frequent monitoring

22. UF-Heparin Induced Osteoporosis • >30% of women on prolonged UFH therapy will lose ≥10% of bone mass • 2% symptomatic vertebral fractures on UFH thromboprophylaxis (Dahlman 1993)

23. Potential Advantages of LMWH over UFH • Like UFH: • Do not cross the placenta • Safe in nursing mother • less monitoring • Ease of administration • Efficacy comparable • Greater safety: allergy and HIT, bleeding, and osteoporosis But Also

24. 81 reports 2931 2777 11reports heart valve Pul hypertension 2 reports duplicate 3 reports methodological Safety & Effectiveness of LMWHSystematic Review of LMWH in Pregnancy Most Common: Enoxaparin 1287, Dalteparin 789 Least Common: Rivaparin 40, Tinzaparin 3. Greer & Nelson Piercy Blood 2005

25. Complications

26. Conclusion - Part II • The Two Major Concerns with Pharmacologic Antithrombotic Agents Are (1) Teratogenicity And (2) Bleeding. • Currently The evidence that LMWH Is The Antithrombotic Agent Of Choice. It Confer: Safety (Maternal And Fetal) And Efficacy.

27. Thromboembolic Disease in Pregnancy – The Silent Disorder Part I PATHOGENESIS AND RISK FACTORS Part II Antithrombotic Strategies Part III Use of LMWHs in Pregnancy Part IV Summary and Recommendations

28. Use of LMWHs in Pregnancy • Thromboprophylaxis • Treatment of VTE • Women with artificial heart valves • Fetal survival

29. Pregnancy and VTE • 8/13 (62%) women with Fatal Antenatal PTE died in the first Trimester. • 8/14 (71%) of postpartum deaths followed vaginal delivery. • There is a need for guideline on thromboprophylaxis after normal delivery “Confidential enquiries into maternal death in UK”

30. Risk Assessment In Pregnancy • All women should undergo an assessment of risk factors for VTE in early pregnancy or before pregnancy. • It should be repeated if the woman is admitted to hospital or develops other intercurrent problems (Grade C) • Women with VTE should be screened for inherited and acquired Thrombophilia ideally before pregnancy (Grade B) Royal College of Obstetricians and Gynecologists Guidelines No 37 (January 2004)

31. Risk Factors for VTE in pregnancy and the Puerperium RCOG guidelines

32. Risk Factors in Pregnancy • Pregnancy: 10 fold increase in risk of VTE beginning from 1st trimester • Obesity And Advanced Age: • All women dying from PTE following vaginal delivery were either obese or > 35 years of age. Only 1/10 deaths followed operative delivery. • Immobilization • Surgery-CS • Thrombophilia (Congenital and acquired) • Prior VTE

33. Vaginal delivery Elective CS Emergency CS Role of Age and Delivery in the Incidence of Postpartum VTE Macklon et al. Scott Med J 1996;41:83-6. Rate per 1,000 events Age (years)

34. Obesity and DVT

35. Prior VTE and pregnancy Women with a history of VTE (with or without thrombophilia) are believed to have a higher risk of recurrence in subsequent pregnancies.) • A retrospective cohort study of 159 women who had at least one pregnancy after an episode of VTE • 6% VTE among women who did not receive antepartum thromboprophylaxis. • 50 to 100 times higher than the overall incidence of antepartum VTE (0.6 to 1.3 of every 1000 deliveries)

36. Thrombophilia Higher Risk Thrombophilia • Antithrombin Deficiency. • Persistent Antiphospholipid Antibodies. • compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions Low Risk Thrombophilia • e.g. Protein C, Protein S Deficiency, And Hyperhomocysteinemia

37. Pharmacologic Thromboprophylaxis Timing Antepartum Intrapartum- Cesarean Section Postpartum

38. Antepartum Thromboprophylaxis Should be Administered • Single prior episode of VTE plus a higher risk thrombophilia • Single idiopathic episode of VTE who are not receiving long-term anticoagulants • Multiple prior episodes of VTE Antithrombin deficiency • Single prior episode of VTE that was related to pregnancy or estrogen use (e.g., contraceptives) Thromboprophylaxis on Case by Case Basis: • Single episode of VTE associated with a transient risk factor that is no longer present • Single prior episode of VTE in a patient with thrombophilia that is not considered higher risk The 2008 American College of Chest Physicians guidelines on VTE and pregnancy

39. Postpartum Postpartum Thromboprophylaxis Is Indicated For Women Who Have Had One Or More Episodes Of VTE Or Who Have Any Type Of Thrombophilia, Even Those That Are Not Considered Higher Risk Women who receive Epidural: LMWH may be initiated 4-6 hours after insertion or removal of the catheter In High Risk women Postpartum Thromboprophylaxis should be continued for at least 6 weeks The 2008 American College of Chest Physicians guidelines on VTE and pregnancy

40. For most postpartum women who are willing to receive subcutaneous injections, a LMWH-based regimen, rather than an UFH- or Warfarin-based regimen (Grade 2B). thromboprophylaxis be continued for four to six weeks For most postpartum women who are unwilling to receive subcutaneous injections, a Warfarin-based regimen, rather than no pharmacologic thromboprophylaxis (Grade 2B).

41. Intrapartum – Cesarean Section Thromboprophylaxis Is NOT Recommended For Women Whose Only Risk Factors For VTE Are The Pregnancy And CS. Women Who Have Only One Additional Risk Factor For VTE Should Receive Either Pharmacological or Mechanical Thromboprophylaxis Women who have multiple additional risk factors should receive Pharmacological Plus Mechanical Thromboprophylaxis The 2008 American College of Chest Physicians guidelines on VTE and pregnancy

42. Antenatal throboprophylaxis should begin as early in pregnancy as practical. • Postpartum prophylaxis should begin as soon as possible after delivery. (Grade B) • Low Molecular Weight Heparins are the agents of choice for antenatal thromboprophylaxis. They are as effective as and safer than Unfractionated heparin in pregnancy. (Grade B) Royal College of Obstetricians and Gynecologists Guidelines No 37 (January 2004)

43. RCOG guidelines

44. Antenatal Prophylactic and Therapeutic Doses of LMWH BMI > 30 in early pregnancy RCOG guidelines

45. Use of LMWHs in Pregnancy • Thromboprophylaxis • Treatment of VTE • Women with artificial heart valves • Fetal survival

46. Two Ways to Reduce Maternal mortality from PE: • by investigating women aggressively when they present with a clinical suspicion of deep vein thrombosis (DVT) or PE, and treating those with a diagnosis of venous thromboembolism (VTE) • by prophylaxis of those who have an increased risk for DVT and/or PE. • Both approaches are problematic

47. Dilemmas in Clinical Diagnosis of DVT in pregnancy • The S&S Compatible With DVT And PE Are Common and Usually Nonthrombotic In Origin During Pregnancy. • The compressive effects of the gravid alter the interpretation and sensitivity of the tests. • Concern about performing procedures that expose the fetus to radiation • The Significance of Identifiable Laboratory Abnormality Associated With Thrombophilia And Its Management Remain Controversial. • Prophylaxis of DVT and PE is problematic because it involves long-term parenteral unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Both are expensive, inconvenient, and painful to administer, and are associated with risks for bleeding, osteoporosis, and heparin-induced thrombocytopenia (HIT), although these complications, particularly HIT, are very uncommon with LMWH.

48. Diagnosis Of DVT in Pregnancy Pregnant Non-Pregnant > 25% Clinical DVT < 10% Diagnosis Of PE in Pregnancy 113 Patients suspected PE Ventilation Perfusion Lung Scan High Probability 2 (1.8%) Normal 83 (73%) Non Diagnostic 28 (25%) Pregnant Non-Pregnant High Probability 10 - 30% Hull et al Ann Int Med 1990, 112 chan et Arch Int. Med. 2002, 162l

49. Diagnosis of VTE – Importance of Confirming the Diagnosis • Long Term Treatment • Implication on Future pregnancy • Implications on Hormonal OC • Implications on HRT

50. Diagnosis of VTE - Clinical Examination Clinical Symptoms and signs Risk Factors For DVT Serum D-Dimer: Invasive Test: Contrast Venography Non Invasive Tests