Thromboembolic Disease in Pregnancy: Peeling back the layers

1. Thromboembolic Disease in Pregnancy: Peeling back the layers Rachel Johnson MS4 OHSU

2. Observation & Question: Over a 9 year period, Dr. Gosselin has observed that none of the “eval for PE” CTs have been positive in pregnant or postpartum patients. Is there any evidence in the literature to support this observation?

3. Basic Definitions • Venous thromboembolism (VTE) • any thromboembolic event in the venous system • Deep Venous Thrombosis (DVT) • radiologically confirmed occlusion of the deep venous system of the legs sufficient to produce symptoms of pain or swelling • Pulmonary embolism (PE) • radiologically confirmed occlusion of pulmonary arteries, sufficient to cause symptoms of breathlessness, chest pain, or both Fitzmaurice et al, www.vascularweb.org

4. An example of misused mortality data An example of a recent population based study Is there too much suspicion? Diagnosis Incidence The tests and their risks Thromboembolic Disease in Pregnancy and the Postpartum Period – Can we trust the information we are given? An example of misused population studies to estimate incidence Virchow’s Triad Endothelial damage – didn’t get to this one Do we have proof of hypercoagulability? What proof do we have of venostasis?

5. Maternal Mortality After reading about 50 articles and several textbooks, the first sentence usually goes like the following: Thromboembolic disease is a leading cause of maternal mortality. A few of them are quoting information from the following MMWR, but most of them are just quoting each other. Laros

6. MMWR Note: This says embolism, not pulmonary embolism Chang et al

7. Williams Obstetrics • It was great to see the authors go to some original information, but… • the authors concluded from this table without other data that, “[thrombotic]pulmonary embolism still remains a prominent cause of maternal death in the U.S.” • Perhaps a minor point, but since when did the term embolism refer to pulmonary embolism alone? • It may be likely that most emboli are pulmonary, but emboli is a broad term • Also, considering that Gosselin says he has seen more amniotic emboli than thrombotic ones, then maybe it is important to differentiate between types of emboli Cunningham et al

8. An example of misused mortality data An example of a recent population based study Is there too much suspicion? Diagnosis Incidence The tests and their risks Thromboembolic Disease in Pregnancy and the Postpartum Period – Can we trust the information we are given? An example of misused population studies to estimate incidence Virchow’s Triad Endothelial damage – didn’t get to this one Do we have proof of hypercoagulability? What proof do we have of venostasis?

9. Incidence based on population based studies “…the incidence of pulmonary embolism has decreased over time, [while] the incidence of DVT remains unchanged…” “We found a distinct upward trend for pregnancy-associated DVT…” “…this downard trend [in the overall incidence of fatal pulmonary thromboembolism] has been reversed…” Let’s look at the first of these studies (the one Gosselin has been quoting all month) Conclusion: There is little agreement about what is happening Heit et al, Stein et al, Greer

10. Trends in the Incidence of VTE during Preg or Postpartum: A 30-yr Pop-based Study Sounds very reputable, doesn’t it? • Journal: Annals of Internal Medicine • Authors: from the Mayo Clinic • Design: Cohort study out of Rochester Epidemiology Project in Minnesota • Patients: Women with DVT or PE 1st diagnosed 1966-1995, including those in pregnancy or postpartum period. Seems like a great idea to use 30 years of data from such a big project! Heit et al

11. Let’s look further • Which patients were included for DVT? • Tests: Venography, CT, MRI, impedance plethysmography, Doppler, Compression US, Radionuclide venography, Radiolabeled fibrinogen leg scan, Pathology • Medical record: Physician diagnosis, signs and symptoms, anticoagulant therapy, surgical procedure • Which Patients were included for PE? • Tests: Pulmonary angiography, CT, MRI, perfusion lung scan showing high prob, V/Q lung scan showing high probability, Pathology • Medical record: Physician diagnosis, signs and symptoms, anticoagulant therapy, surgical procedure ??? Remember the definitions for DVT and PE? There has to be radiologic evidence to make these diagnoses! Heit et al

12. The interesting thing about this study… “…the incidence of pulmonary embolism decreased dramatically during the last 10 years of the study...This observation is unlikely to have occurred by chance.” Heit et al

13. Theories as to why there were no PEs observed in the last decade • The authors suggest • earlier mobilization, associated with shorter hospitalizations • However: • OB patients are being treated more and more like surgical patients – get up and moving before leaving the hospital! • Perhaps that original “mistake” of using signs and symptoms for inclusion criteria was made less in the last decade. We suspect the diagnostic methods in the last decade were based on more accurate tests and fewer diagnoses were based on signs and symptoms or old hospital records alone. Heit et al

14. An example of misused mortality data An example of a recent population based study Is there too much suspicion? Diagnosis Incidence The tests and their risks Thromboembolic Disease in Pregnancy and the Postpartum Period – Can we trust the information we are given? An example of misused population studies to estimate incidence Virchow’s Triad Endothelial damage – didn’t get to this one Do we have proof of hypercoagulability? What proof do we have of venostasis?

15. I just want to show another example of misuse of data Guess what Williams Obstetrics did? They just took a bunch of different studies, did some addition and division and came up “incidences.” Please note: this is not a meta-analysis!! It is bad form to pass off this sort of practice as legitimate. Cunningham et al

16. An example of misused mortality data An example of a recent population based study Is there too much suspicion? Diagnosis Incidence The tests and their risks Thromboembolic Disease in Pregnancy and the Postpartum Period – Can we trust the information we are given? An example of misused population studies to estimate incidence Virchow’s Triad Endothelial damage – didn’t get to this one Do we have proof of hypercoagulability? What proof do we have of venostasis?

17. Virchow’s Triad Cotran et al

18. More questions: • Why would it be evolutionarily advantageous to be in a hypercoagulable state during pregnancy or the postpartum period? • Wouldn’t it be an evolutionary disadvantageous if the mother died from a thromboembolic event before being able to care for a child or to reproduce again?

19. Hypercoagulability • Blood volume expands in pregnancy • There is a greater plasma:erythrocytes ratio in pregnancy • Fibrinogen levels raise from 200-400 mg/dL to 300-600 mg/dL • Clotting factors are increased • The fibrinolytic activity is reduced in normal pregnancy 2/2 ↑ plasminogen-activator inhibitors • I felt hopeless, until I read this… Cunningham et al

20. Hypercoagulability • “Studies of the fibrinolytic system in pregnancy have produced conflictingresults…” • There is literature that says that the “overall fibrinolytic activity is not affected by pregnancy,” even though there are numerous changes in the system!!! Cunningham et al, Kruithof et al

21. Hypercoagulability • Perhaps in normal pregnancy, homeostasis is maintained • The bleeding time in pregnant and nonpregnant women are not significantly different! • There is likely a difference between in vitro and in vivo studies Berge et al

22. Hypercoagulability • “[Thrombophilias] are responsible for more than 50 percent of all thromboembolic events during pregnancy” • one author thought that all VTEs during pregnancy might someday be associated with a thrombophilia • Perhaps VTE is not inherent in pregnancy unless there is a predisposition Cunningham et al

23. The rest of the triad • Endothelial Damage • Venostasis/Venous distensibility – I’d guess this that this might be the most important part of the triad

24. An example of misused mortality data An example of a recent population based study Is there too much suspicion? Diagnosis Incidence The tests and their risks Thromboembolic Disease in Pregnancy and the Postpartum Period – Can we trust the information we are given? An example of misused population studies to estimate incidence Virchow’s Triad Endothelial damage – didn’t get to this one Do we have proof of hypercoagulability? What proof do we have of venostasis?

25. Clinical Suspicion • So in rethinking Gosselin’s original observation of not seeing any positive CTs, I thought perhaps clinical suspicion is too high. • Typical Signs of VTE are also common during pregnancy • Leg swelling and pain • Dyspnea • Chest pain

26. Clinical Suspicion “the prevalence of VTE in clinically suspected cases is significantly lower in pregnant women when compared to the nonpregnant population” Moores et al

27. Clinical Suspicio “The high percentage of normal scans in the pregnant population probably reflects the youth and fewer comorbid lung conditions.” “The lower percentage of high prob scans in the pregnant population probably reflects the lower prevalence of PE in those presenting with clinical suspicion of PE.” Moores et al

28. An example of misused mortality data An example of a recent population based study Is there too much suspicion? Diagnosis Incidence The tests and their risks Thromboembolic Disease in Pregnancy and the Postpartum Period – Can we trust the information we are given? An example of misused population studies to estimate incidence Virchow’s Triad Endothelial damage – didn’t get to this one Do we have proof of hypercoagulability? What proof do we have of venostasis?

29. Diagnosis • There is limited evidence for a best approach • Have to rely on studies in the nonpregnant population

30. Diagnosis of DVT Should probably begin with Compression Ultrasonagraphy Negative Positive Low clinical suspicion High clinical suspicion Consider anticoagulation therapy Venography, Magnetic Resonance Venography, Impedance Plethysmography, or serial CUS No further workup or Serial CUS over 7 days

31. Compression Ultrasonography www.nlm.nih.gov E:\Radiology 3\uhrad_com Nuclear and SPECT Teaching Files3.htm

32. Venography www.nlm.nih.gov www.healthopedia.com

33. MR Venography Superficial vein thrombosis MR venography compared with venography Hauge et al

34. Impedance Plethysmography www.nlm.nih.gov ultramedco.home

35. Diagnosis of PE Take your pick: V/Q scan Helical CT Pulmonary Angiography Of course, you could always get a CXR first

36. V/Q scan uniform distribution of Xenon gas <0.01 mGy to fetus Perfusion (Tc-99m) scan with significant areas that are not perfused 0.9 mGy to fetus www.vh.org, Huda

37. Helical CT A CT scan of the female thorax (20–80 sections, average of 30 sections) will give a dose of 100–250 CXRs to the lungs and 30-100 mammograms to the breasts 0.14 mGy to fetus Patel et al, Huda, Milne

38. Pulmonary Angiography Reid et al

39. References

40. “The one generalization about venous thromboembolism that is free from controversy is that many aspects of this disorder remain controversial” Fedullo et al