Critical Care in

Obstetrics:

An Innovative and Integrated Model for Learning the Essentials

Pulmonary Embolus in Pregnancy

Mary E. D’Alton, M.D.

Willard C. Rappleye Professor and Chair, Department of Obstetrics & Gynecology

Columbia University College of Physicians & Surgeons

§  Learning Objectives

§  Risk Factors/ Signs & Symptoms

§  Diagnosis

§  Treatment

§  Additional Management Considerations

§  Summary

§  Evidence

Outline

Learning objectives

§ Discuss incidence of PE in pregnancy

§ Discuss methods used in diagnosis of PE in pregnancy

§ Discuss standard and emerging treatments for PE in pregnancy

Risk Factors/ Signs &

Symptoms

PE in Pregnancy

It’s so hard to breath sometimes…

Risk Factors for PE

§ Most important risk factor - history of VTE

§ All women should undergo a risk assessment for risks factors for VTE

§ High risk women - pre-pregnancy counseling to plan thromboprophylaxis

§  Risk should be risk stratified into low, moderate, and high (RCOG- UK)

RCOG, GTG 37a, 2010

Symptoms & Signs of PE

Symptoms Signs

•  Dyspnea •  Chest pain •  Hemoptysis •  Leg edema •  Collapse

•  Tachycardia •  Low grade pyrexia •  Raised JVP •  Low pO2

Mari & Plante N Engl J Med. 2008;359(19):2025–2033

Diagnosis

Diagnosis of PE § Maintain high index of

suspicion & low threshold for diagnostic testing

§  High mortality rate in untreated (30%) vs. treated (8%) PE in non-pregnant patients

§  PE confirmed in 25% nonpregnant women in whom diagnosis is suspected §  In pregnancy <10%

Marik & Plante N Engl J Med. 2008;359(19):2025–2033 Carson et al, NEJM, 1992; 326:1240-5

Diagnosis of PE – Wells Score §  Assignment of pre-test probability in non-

pregnant patients integral part of diagnostic management

§  Used to reduce false positive and false negative results in the investigation of PE

§ Not effective for pregnancy §  Substantial risks to mother & fetus of

overtreatment and under-diagnosis Wells et al, Ann Emerg Med 2001; 135 (2): 98-107

Carson et al, NEJM, 1992; 326:1240-5

Diagnosis of PE – DDx §  Cardiopulmonary

collapse

•  AFE

•  Aortic dissection

§  Chest pain

•  Pneumonia

•  MI/coronary artery dissection

•  Musculoskeletal

•  Sickle cell crisis

§  Physiologic changes of pregnancy

§  Shortness of breath •  Pneumothorax

•  Hyperventilation

Diagnosis of PE – Tests

§ ECG, ABG are of limited value in diagnosis

§ D-dimer testing widely used in non-pregnant population

§ Negative test safely exclude PE in low clinical probability

§ Poor utility in pregnancy Morse J Thromb Haemost 2004; 2: 1202–04.

Diagnosis of PE – D-Dimer

0

100

200

300

400

500

600

700

Control 16 weeks 26 weeks 34 weeks

ng ml-1

Morse J Thromb Haemost 2004; 2: 1202–04.

Diagnosis of PE – Doppler §  Not validated in

pregnancy (clear role in non-pregnant women)

§  Presence of DVT may indirectly confirm diagnosis of PE

§  Potentially limits radiation to mother and fetus

RCOG, GTG 37b, 2010 MacGillavry, Thrombosis Haemost, 2000 (6):973–976

Wells et al, NEJM, 2003;349(13):1227–1235

Diagnosis of PE – CXR §  Fetal risk from CXR negligible

at any stage of pregnancy

§  May identify other cause

§  pneumonia

§  pneumothorax

§  CXR features of PE (50%)

§  atelectasis

§  effusion

§  focal opacities

§  pulmonary edema Damilakis J, et al Eur Radiol. 2003;13 (2):406–412

Diagnosis of PE – CPTA §  Better sensitivity/

specificity in non-pregnant patients

§  Can identify other pathology

§  Higher radiation to breasts than VQ

§  Technical limitations in pregnancy

§  Over-diagnosis compared to V/Q

!

Anderson DR et al JAMA 2007; 298: 2743–53.

Diagnosis of PE – V/Q §  Advantages

§ Low radiation exposure to breast and fetus

§ Useful first test in pregnancy due to high NPV

§  Disadvantages

§ Interpretation strongly linked to pretest probability

§ 20% scans non-diagnostic

§ Doesn’t offer differential diagnosis

Chan WS et al Arch Intern Med 2002; 162: 1170–75.

Diagnostic Algorithm - CPTA Suspected PE in Pregnancy

CTPA

Negative

CUS

Positive

Segmental PE or larger

Isolated subsegmental PE

VTE

Positive

No VTE

Negative

Consider VQ VTE

Diagnostic Algorithm – V/Q Suspected PE in Pregnancy

Leg symptoms

Yes

CUS

No

V/Q

Negative Perfusion scan Positive

VTE

Ventilation scan

Segmental defects

No VTE

Normal/Near Normal

Diagnostic Algorithm – V/Q & CTPA Suspected PE in Pregnancy

Leg symptoms

CUS

VTE

Negative- STOP

CXR

CTPA

Treat CTPA, CUS Treat

Consider VQ VTE

+

+

+

-

-

VQ scan

Normal Abnormal

-

- + Technically Inadequate

Treatment - Anticoagulation

Anticoagulation - Heparin §  Large trials in non-pregnant patients-

LMWHs at least as safe/effective as UFH for treatment and prophylaxis of VTE

§  Systematic reviews and large series of cases have concluded

§ Treatment of acute PE with LMWH is a safe alternative to unfractionated heparin during pregnancy

Ensom MHH, Stephenson MD. Pharmacotherapy 1999;19:1013–25 Sanson BJ, Lensing AW, et al. Thromb Haemost 1999;81:668–72

Lepercq J, et al.. BJOG 2001;108:1134–40

Anticoagulation - Heparin

§  IV UFH preferred to LMWH for § Patients with renal failure

§ High risk of bleeding or imminent surgery (e.g. urgent reversal needed)

§ Activity monitored by APTT

Greer et al. Blood. 2005;106(2):401–407 Marik & Plante, NEJM 2008; 359 (19): 2025-33

Anticoagulation - LMWH §  Advantages of LMWH compared to UFH

§  fewer bleeding episodes §  lower risk of HIT §  more predictable pharmacokinetics §  lower incidence of osteoporosis

§  LMWH has longer half life than UFH §  may be an advantage or a disadvantage

§  Anti-Xa activity measurement not required for LMWH except for §  extremes of body weight §  renal impairment

Greer et al. Blood. 2005;106(2):401–407 Ni Ainle F et al. Blood Coagul Fibrinolysis. 2008;19 (7):689–692

Nelson-Piercy C et al, Eur J Obstet Gynecol Reprod Biol. 2011, Dec;159(2):293-9.

Anticoagulation - LMWH

Greer et al. Blood. 2005;106(2):401–407

Anticoagulation Regimens

LMWH Enoxaparin

  Dalteparin

  Tinzaparin

Unfractionated heparin

Warfarin (postpartum)

Antepartum 1mg/kg/12 hourly

100 units/kg/12 hourly

175 units/kg/day

10000 units or more 12 hourly adjusted to mid interval target aPTT (1.5-2.5)

-

Postpartum 1.5mg/kg/daily 200 units/kg/day

175 units/kg/day

 As above INR 2.0-3.0

Anticoagulation - UFH

GTG 37b, RCOG 2010

Anticoagulatin - Warfarin

§  Typically contraindicated in pregnancy

§  Known teratogen

§  Embryopathy in 5% of exposed fetuses before 6-9 weeks (mid-face hypoplasia, stippled chondral calcifications, short proximal limbs)

§  Fetal intracranial hemorrhage, schizencephaly later

§  Can be used postpartum

§  Safe in breastfeeding

Duhl AJ et al Am J Obstet Gynecol 2007;197(5): 457 Wesseling et al Thromb Haemost 2001;85:609-13

Relative Contraindications •  Hemophilia or other known bleeding disorder (e.g. von

Willebrands or acquired coagulopathy) •  Active or threatened antenatal bleeding (e.g. placenta

previa/placental abruption) •  Thrombocytopenia (platelet count <75 x109) •  Stroke in previous 4/52 (hemorrhagic/ischemic) •  Severe renal disease (GFR <30ml/min) •  Severe liver disease (prolonged PT) •  Uncontrolled hypertension (BP >200mmHg systolic or

>120mmHg diastolic)

Treatment - Other

Treatment-Embolectomy

•  Massive life-threatening PE −  Patients not suitable for thrombolysis

− Moribund patients •  Non-pregnant series (24 patients)

§ 12.5% mortality

§ 19 (79.2%) cardiogenic shock

§ 16 (66.7%) preoperative percutaneous cardiopulmonary support

§ 11 (45.8%) were in cardiac arrest te Raa GD et al Thromb Res. 2009 May;124(1):1-5 Takahashi et al Ann Thorac Surg. 2012;94(3):785-91. Taniguchi S, et al Surg Today. 2008;38(1):59-61.

Treatment-ECMO

§ Massive life-threatening PE §  Prior to/ alternative to embolectomy

§  Studies •  29 non-pregnant patients with PE

•  26/29 patients with surgical embolectomy

•  3/29 received ECMO as alternative, 1/29 delayed embolectomy following ECMO

§  Case report of ECMO in amniotic fluid embolus 20 minutes after CD for placenta previa •  Profound cardiorespiratory collapse, severe right ventricular

dysfunction, massive pulmonary vasoconstriction

Malekan et al, Ann Thorac Surg. 2012;94 (1):104–108 Ecker JL et al. N Engl J Med. 2012;367(26):2528–2536

Treatment- IVC Filter §  First report of IVC filter in pregnancy in 1981

§  Long term safety concerns with permanent filters

§  Peripartum insertion of retrievable filter becoming more widely reported

§  Case report §  mechanical fragmentation and optional retrievable inferior

vena cava (IVC) filter insertion in a 38-week pregnant woman

§  delayed pharmacological catheter-directed thrombolysis during the early postpartum period to successfully treat a massive PE

Ahearn et al . Arch Intern Med. 2002;162 (11):1221–1227 O’Keeffe et al J Matern Fetal Neonatal Med 2008;; 21(80; 591-4

Additional Management

Considerations

Late Pregnancy/Labor

§  Consider switching from LMWH to UFH at 36 weeks

§  LMWH heparin can be stopped and induction of labor started 24 hours later

§  UFH clearance can be verified by PTT

§  UFH can be reversed by protamine sulfate

§  SCDs in labor

Green Top Guideline no 37a. RCOG; 2010. ACOG. Thromboembolism in pregnancy. ACOG practice bulletin. 2011.

Anesthesia

Antepartum/Intrapartum  

UFH therapeutic Wait 6 hours post last therapeutic UFH dose

LMWH therapeutic Wait 24 hours post dose prior to neuraxial blockade

Postpartum  

UFH therapeutic Wait ≥ 1 hour after epidural catheter removal or spinal needle placement

LMWH therapeutic Avoid therapeutic dosing with epidural catheter in situ. Wait at least 24 hours after catheter removal or spinal needle

Horlocker TT et al, ASRA Guidelines, 2010

Postpartum Management

§  Treat for at least 6 weeks post partum, total 3-6 months from event

§  If using warfarin §  delay at least 3 days following delivery (longer if PPH risk)

§  use heparin until dose is stable >2 days

§  Thrombophilia testing NOT recommended during treatment (but done subsequently)

§  Counsel about contraception

§  Counsel regarding thromboprophylaxis in other high-risk situations including future pregnancies

Green Top Guideline no 37a. RCOG; 2010. ACOG. Thromboembolism in pregnancy. ACOG practice bulletin. 2011.

Summary

Summary – Acute VTE §  Maintain high index of suspicion

§  VQ is diagnostic modality of choice

§  Early aggressive treatment with UFH or LMWH

§  Alternative treatments, filters for those acute unstable

§  Transition to UFH at 36 weeks

§  Treat for remainder of pregnancy and 6 weeks postpartum, at least 3-6 months from event

§  Avoid Coumadin in pregnancy

Summary-Prevention § All women should have assessment of

risk factors

§  Prophylaxis should be discussed with high risk women

§  Prophylaxis recommended for pregnant women with prior VTE (high recurrence risk)

§  LWMH is prophylaxis of choice in pregnancy

Evidence

Evidence

LMWH first line in acute PE in pregnancy – ACCP and RCOG

Evidence level Ib, supported by levels II & III

q  Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and thrombolytic therapy. Chest 2004;163: 627S–44S.

q  Ensom MHH, Stephenson MD. Low molecular weight heparins in pregnancy. Pharmacotherapy 1999;19:1013–25.

q  Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E, et al. Safety of low molecular weight heparin in pregnancy: a systematic review. Thromb Haemost 1999;81:668–72.

q  Lepercq J, Conard J, Borel-Derlon A, Darmon JY, Boudignat O, Francoual C, et al. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG 2001;108:1134–40.

q  Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thrombo-embolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401–7.

Evidence Evidence level Ia (outside of pregnancy)

q  Dolovich L, Ginsberg JS. Low molecular weight heparin in the treatment of venous thromboembolism:an updated meta- analysis. Vessels 1997;3:4–11.

q  Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Low molecular weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130:800–9.

q  Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2004;140:175–83

Investigations for diagnosis of PE in Pregnancy

(CXR, CUS, CTPA, V/Q) - Evidence level IV q  Scarsbrook AF, Evans AL, Owen AR, Gleeson FV. Diagnosis of suspected venous thromboembolic

disease in pregnancy. Clin Radiol 2006;61:1–12.

q  Fidler JL, Patz Jr EF, Ravin CE. Cardiopulmonary complications of pregnancy: radiographic findings. Am J Roentgenol 1993: 161:937–42.

q  Leung AN, Bull TM, Jaeschke R, Lockwood CJ et al. An offical American Thoracic Socity/Society of Thoracic Radiology Clinical Practice Guideline: Evaluation of Suspected Pulmonary Embolism in Pregnancy. Am J Respir Crit Care Med 2011:184;1200-1208

Evidence

q  Damilakis J,Perisinakis K,Prassopoulos P,Dimovasili E,Varveris H, Gourtsoyiannis N. Conceptus radiation dose and risk from chest screen-film radiography. Eur Radiol. 2003;13:406–12.

q  Turkstra F, Kuijer PM, van Beek EJ, Brandjes DP, ten Cate JW, Buller HR. Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism. Ann Intern Med 1997;126:775–81. Daniel KR, Jackson RE, Kline JA. Utility of lower extremity venous ultrasound scanning in the diagnosis and exclusion of pulmonary embolism in outpatients. Ann Emerg Med 2000; 35:547–54.

q  Mac Gillavry MR, Sanson BJ, Buller HR, Brandjes DP;ANTELOPE- Study Group. Compression ultrasonography of the leg veins in patients with clinically suspected pulmonary embolism: is a more extensive assessment of compressibility useful? Thromb Haemost 2000;84:973–6.

q  Wells PS, Ginsberg JS,Anderson DR, Kearon C, Gent M,Weitz J, et al. Utility of ultrasound imaging of the lower extremities in the diagnostic approach in patients with suspected pulmonary embolism. J Intern Med 2001;250:262–4.

q  Ryu JH, Swensen SJ, Olson EJ, Pellikka PA. Diagnosis of pulmonary embolism with use of computed tomographic angiography. Mayo Clin Proc 2001;76:59–65.

q  Cook JV, Kyriou J. Radiation from CT and perfusion scanning in pregnancy. BMJ 2005;331:350.

q  Morse J Thromb Haemost 2004; 2: 1202–04

 Thank You for Your Attention!

Planning Committee  

 Mike Foley, Director Shad Deering, co-Director Helen Feltovich, co-Director Bill Goodnight, co-Director Loralei Thornburg, Content co-Chair Deirdre Lyell, Content co-Chair Suneet Chauhan, Testing Chair Mary d’Alton Daniel O’Keeffe Andrew Satin