Venous Thrombosis in Pregnancy

1. Venous Thrombosis in Pregnancy Vicky Tagalakis, MD MSC General Internal Medicine Academic Rounds September 8, 2009

2. Objectives • Facts about VTE in pregnancy • VTE diagnostic modalities in pregnancy • Treatment of VTE in pregnancy • Thrombophilia in pregnancy? • Thromboprophylaxis during pregnancy?

3. VTE in pregnancy • Pregnant women are at an increased risk for venous thromboembolic disease (VTE) • 1 in 1000 pregnancies • 2-4 fold increase compared to non-pregnant state • Cesarian delivery > vaginal delivery • 2/3 of DVT occur antepartum (equally distributed among all three trimesters) • 43-60% of PE occur 4-6 weeks after delivery • Daily risk of PE and DVT highest following delivery than antepartum • PE is the major non-obstetric cause of maternal mortality • 2/100 000 pregnancies

4. Case scenario #1 34 year old woman 24 weeks pregnant who reports non-productive cough, SOBOE, and pleuritic chest pain of 3 days duration. Sick 2 year old at home. She has had 2 prior uncomplicated pregnancies. She has a history of a prior DVT post surgery for an ankle fracture repair.

5. DVT facts 90% of DVT during pregnancy occurs on the left side. A significant proportion of DVT in pregnancy occurs in the pelvic veins and therefore, may not be picked up by routine testing. Ovarian vein thrombosis can also occur.

6. Why is the risk greater in pregnancy? • Pathopsysiology • Increased venous capacity (estrogen) • Increased plasma volume • Compression of IVC • Increased levels of coagulation factors (fibrinogen, factor VII) • Decreased levels of natural anticoagulants (protein S) • Acquired protein C resistance

7. Independent risk factors of a higher VTE risk in pregnancy? • Bed rest • Multiparity • Advanced maternal age (>35 yo) • Overweight • Personal or family history of VTE • Preeclampsia

8. Case scenario #1 34 year old woman 14 weeks pregnant who reports non-productive cough, SOBOE, and pleuritic chest pain. Sick 2 year old at home.She has a history of a prior DVT post surgery for an ankle fracture repair. Physical exam BP 105/80, HR 95, O2 Sat 91% on RA, T 37.8°C Mild bilateral leg swelling Decreased a/e at bases

9. VTE presentation in pregnancy Leg symptoms, chest pain, and dyspnea are common in pregnancy. Swelling, tenderness, skin discoloration, warm to touch, unusual firmness/hardness, cord, pain on dorsiflexion Tachycardia may be a normal physiologic response. ABG and A-a gradient are often normal.

10. Diagnosis of VTE in pregnancy: challenges • Clinical diagnosis by itself is unreliable. • In symptomatic pregnant patients, DVT and PE are less prevalent than in non-pregnant patients. • Anticoagulant treatment is highly effective but carries risks. • Untreated VTE can result in fatal and non fatal PE. • Hence, when VTE is suspected, it is essential to diagnose it when present and exclude it when absent.

11. Diagnosis of VTE in pregnancy: challenges • The common diagnostic tests have not been studied in pregnant women, and hence not appropriately validated for this population • D-dimer assays and DVT/PE clinical prediction rules have not been validated in the pregnant population • …..and what about the issue of both radiation exposure to the fetus with diagnostic testing???

12. Diagnosis of VTE in pregnancy: challenges • It is important to avoid ionizing radiation exposure whenever possible during pregnancy, but the risks of undiagnosed PE are much greater than any theoretical risk to the fetus from diagnostic testing

13. DVT and PE - Investigation • CUS, IPG, and venography can be done safely and with reliable results in pregnancy. • Ventilation perfusion scans and pulmonary angiograms can be done safely during pregnancy. • Pelvic vein ultrasound, CT scan and MRI are all tests that can be used to look for pelvic clot. • CT angiography can be done in pregnancy (risk of congenital hypothyroidism in first trimester) • IVC filters can be placed in pregnancy.

14. Risk of radiologic procedures to the fetus • Radiation exposure of up to 0.05 Gy (5 rad) in utero: • Oncogenicity • Relative risks of 1.2-2.4 • Absolute risk of malignancy (baseline) in fetus is estimated to be 0.1%. • Tetratogenicity • No increase in pregnancy loss, growth or mental retardation

15. CT angiography: 0.013- 0.0026 (rads)

16. Techniques to lower radiation exposure during • Circumferential screening of the abdomen and pelvis (CTPA) • Duration of scanning reduced (CTPA) • Half-dose (perfusion) techniques (VQ scan) • If perfusion is normal, then ventilation scan unnecessary (PE excluded) ***Please note that even if a pregnant woman underwent a CXR, followed by a VQ scan, then CTPA, and then pulmonary angiogram, the combined fetal radiation dose would still be less than that obtained via background radiation during the nine months of pregnancy!

17. Case scenario #1 WBC 14 with neutrophilia. Platelets are normal. CXR: RLL atelectatic changes ABG shows an increased aA gradient.

18. CTPA Fig. 2. Algorithm for clinically suspected pulmonary embolism in pregnancy. PE, pulmonary embolism; CT, computed tomography; PA, pulmonary angiography; HP, high probability; CUS, compression ultrasonography. *ND, non-diagnostic result. Non-diagnostic results are those that indicate an intermediate or low-probability of pulmonary embolism, or that do not indicate a high probability. Nijkeuter et al, JTH 2008

19. Scarsbrook et al, Clinical Radiology, 2007

20. Diagnosis of DVT: Algorithm

21. VTE Treatment

22. VTE treatment • LMWH preferred based on better safety profile, reliable pharmacokinetics, more practical, and as effective as UFH • Largely based on studies in non-pregnant population • Widespread use over the last 10-15 years in pregnant women have shown that LMWHs are as effective and safer than UFH (less HIT and less osteoporosis than UFH) • Does not cross placenta!

23. VTE treatments: other options • UFH • Initial IV UFH therapy followed by UFH bid sc dosing (adjusted weekly to achieve target PTT (60-80 sec) 6H after injection). Weekly surveillance • VKA • Teratogenicity (coumarin embryonopathy: nasal hypoplasia and/or stippled epiphyses); observed only duirng 6-12 weeks of gestation (Chan et al, studied 549 live births; VKA through out preg vs. UFH 6-12 weeks then VKA vs. UFH throughout pregnancy) • CNS abnormalities during any trimester (corpus callosum agenesis; midline cerebellar atrophy); very rare and questionable association • Fetal hemorrhagic complications especially at delivery due to prolonged anticoagulant effect of warfarin as a result of fetal liver being immature and hence fetal levels of vit K dependent coag factors are low. • ?role in pregnant women with mechanical prosthetic valves at high risk for embolization (i.e. previous CVA)

24. VTE treatments: other options • Fondaparinux • Anti Xa activity found in plasma umbilical cord of 6 women treated with fondaparinux • For now, avoid general use and reserve for pregnant women with HIT or a history of HIT who cannot receive danaproid • Danaproid • In vitro data shows placenta crossing but… • No detectable anti Xa activity in plasma umbilical cord of the few women wolr-wide that have been treated with danaproid. • DTIs • No human data!

25. DVT and PE – Treatment • CHEST 2008 recommendations: • Treatment of acute DVT/PE in pregnancy • Adjusted dose LMWH thru pregnancy OR (but less preferred) • weight-based intravenous UFH protocol for 5 days, then adjusted dose UFH (PTT mid-interval of 60-80 secs; weekly surveillance).

26. LMWH: adjust dose during pregnancy? • LMWH requirements may alter as pregnancy progresses ( volume of distribution of LMWH changes and GFR increases in second trimester) • Hence, some suggest that dose should change as weight changes (based on small studies that support dose escalation to achieve “therapeutic anti Xa levels”) • Adjusted dose LMWH thru pregnancy • adjust as weight , or adjust to anti Xa level 0.5-1.2 U/ml (every 1-3 months blood test, 4 hrs after last dose) (bid vs qd dosing) • Others have demonstrated that few women require dose adjustment when therapeutic LMWH doses are given Controversial; ACCP does not give any recommendations

27. At time of delivery • D/C LMWH (or UFH sc) 24 hrs. prior to elective induction • If very high risk of recurrence (eg, PE or DVT within 2-4 weeks of expected delivery), IV UFH can be initiated and d/c 4-6 hours prior to delivery; in addition, a temporary IVC filter can be inserted • If spontaneous labour occurs while receiving adjusted-dose SC UFH, monitor PTT and if prolonged give protamine • If spontaneous labor occurs while receiving LMWH, anticoagulant effect depends on timing of last dose. • Avoid epidural • Protamine can be considered

28. Postpartum management • Re-start anticoagulation within 8-12 hours of delivery (consult with obstetrician) • LMWH or coumadin for 6 weeks after delivery • For a minimum total duration of 6 months

29. Fetal complications during pregnancy • Heparins and LMWH • Heparins and UFH do not cross placenta • Uteroplacental bleeding possible but very rare • Warfarin • Risk of embryopathy (nasal hypoplasia) (6-12 weeks of gestation) • CNS abnormalities in any trimester • Anticoagulant effect in fetus (**at delivery)

30. Maternal complications of anticoagulant therapy • Bleeding • 2% risk with UFH • Very uncommon with LMWH • Heparin induced osteoporosis • 2.2% incidence of vertebral fracture with UFH (>1 month) • Uncommon with LMWH • HIT • 3% risk with UFH • suspect HIT if platelets <100 or 50% of baseline value 5-15 days after commencing UFH • Uncommon with LMWH

31. Nursing mother • Heparin and warfarin not secreted into breast milk. • LMWH: small amounts may be secreted into breast milk but not absorbed by infant and no anticoagulant effect in breast-fed infant • Danaproid: case reports +/- passage into breast milk; no anticoagulant effect in infant • Fondaparinux and DTIs: unknown

32. Prevention of VTE during pregnancy • How do we evaluate women with an increased risk of VTE? • Prior history of VTE • Thrombophilia without a prior history of VTE

33. Case scenario #2 28 year old woman who is 10 weeks pregnant is referred to you to assess the need for DVT prophylaxis. She has a history of a prior DVT. She is currently not on any anticoagulants. She feels well otherwise.

34. Thromboprophylaxis during pregnancy and postpartum

35. How we manage pregnant women who have a high risk of VTE • Women with a history of VTE have a higher risk of recurrence with subsequent pregnancy (1-13% risk of recurrence) • Risk dependent on nature of VTE risk factor, presence or absence of thrombophilia, and (number of previous VTEs). • N=125 women with a single previous VTE who only received prophylaxis in ppp for 4-6 weeks (Brill-Edwards, NEJM 2000) • 3/125 had antepartum recurrence (2.4%, 95% CI 0.2-6.9%) and 3/125 had ppp VTE recurrence • Post hoc analysis: women without thrombophilia and a VTE associated with a temporary risk factor were at low risk for recurrence (0%)

36. Single prior VTE • VTE associated with transient risk factor: clinical surveillance and pp prophylaxis for 6 weeks • VTE associated with pregnancy or estrogen-related or there are additional risk factors (eg. obesity) clinical surveillance and pp prophylaxis for 6 weeks OR antenatal with pp prophylaxis for 6 weeks • LMWH (dalteparin 5000u q24 hrs or enoxaparin 40mg sc q24hrs) • Mini-dose UFH SC (5000 U SC bid) vs intermediate dose UFH SC (10 000 sc bid)

37. Single prior VTE • Idiopathic VTE: antenatal and pp prophylaxis (4-6 weeks pp) OR clinical surveillance and pp prophylaxis • Prophylactic dose LMWH • Mini- or moderate-dose UFH SC • With thrombophilia: antenatal and pp prophylaxis (4-6 weeks pp) OR clinical surveillance and pp prophylaxis • Prophylactic dose LMWH (eg. dalteparin 5000u q12 hours) • Mini- or moderate-dose UFH SC

38. Single prior VTE • With “higher risk” thrombophilia: antenatal and pp prophylaxis (4-6 weeks pp) • Prophylactic dose LMWH (eg. dalteparin 5000u q12 hours) • Mini- or moderate-dose UFH SC APLA, ATIII deficiency, compound heterozygote PT/FVL, or homozygosity for FVL or PT

39. Multiple episodes of VTE (or those on long-term anticoagulation) • Prophylactic, vs. intermediate, vs. adjusted dose LMWH (or UFH) • PP prophylaxis for 6 weeks, consider long-term anticoagulants, or resumption of long-term anticoagulants

40. For all women with prior DVT.. • Consider compression stockings during pregnancy and ppp • reduce risk of PTS

41. Do you adjust LMWH prophylaxis dosing in pregnancy? • The need to adjust according to anti-Xa levels is very controversial • Appropriate “therapeutic range” for prophylaxis is not known • It has not been shown that dose adjustment to attain specific anti-Xa level increases safety or efficacy.

42. Thrombophilia with no history of prior VTE • 50% of gestational VTEs occur in women with an underlying thrombophilic disorder • AT 3 deficient: OR = 8-13.1 • FVL Homozygote: OR = 6.9-8.7 • PT Homozygote: OR 1.8-9.5 • Double FVL/PT mutations: OR=15 • Antenatal and pp prophylaxis is recommended in women without a prior VTE and with any of the above disorders. • For women without prior VTE and who have less thrombogenic thrombophilias, clinical surveillance and pp prophylaxis

43. Antiphospholipid Antibodies • Lupus anticoagulant/non-specific inhibitor • Anticardiolipin antibodies • Convincing evidence of an association with increased risk of thrombosis and pregnancy loss (less so with preeclampsia, abruptio, IUGR) • But how to manage during pregnancy…not clear? • Prednisone not useful • ASA with LMWH (UFH) is likely the best combination (outcomes: fetal loss, pregnancy complications, VTE)

44. Management of pregnant women with APLAs • Positive APLAs and hx of 2 or more early pregnancy losses or one or more late pregnancy losses, IUGR, preeclampsia, or abruptio • Antepartum ASA plus prophylactic LMWH • Antepartum ASA plus minidose or moderate dose UFH • Positive APLAs and hx of VTE are usually receiving long-term anticoagulation bc of high risk of recurrence • Antepartum adjusted dose LMWH (or UFH) plus ASA • Long-term oral anticoagulation postpartum • Positive APLAs and no hx of pregnancy complications or VTE • Clinical surveillance • Minidose UFH • Prophylactic LMWH and/or asa?

45. Prevention of pregnancy complications in women with non-APLA thrombophilia? • Data support weak associations between thrombophilias (FVL, PT mutation) and adverse pregnancy outcomes (early (recurrent) preg loss, preeclampsia, IUGR) • But, clinical studies with LMWH or UFH vs. placebo (no drug) in women with a history of adverse pregnancy outcomes and non-APLA thrombophilias do not show improved pregnancy outcomes.

46. C-section and the risk of VTE? • Risk 0.4/1000 (c-section) vs. 0.2/1000 (vaginal delivery) • Not standard of care to thromboprophylax • Thrombosis risk assessment to determine need for prophylaxis (grade 2C) • If no additional thrombosis risk factor, no prophylaxis • If additional risk factors (eg. prior VTE, lower limb paralysis, thrombophilia, extended surgery such as hysterectomy, preeclampsia, obesity, increased age, heart failure), then…

47. C-section and the risk of VTE? • Prophylaxis doses of LMWH or UFH +/- stockings while in hospital following delivery (grade 2C) and perhaps for 6 weeks pp if important risk factors persist (grade 2C).