Thromboembolism in Pregnancy

Author: Edward Henry Springel, MD, FACOG; Chief Editor: Thomas Chih Cheng Peng, MD more...

Updated: Apr 30, 2014

Practice Essentials
Pregnancy increases the risk of venous thromboembolism (VTE) 4- to 5-fold over
that in the nonpregnant state.[1, 2] The 2 manifestations of VTE are deep venous
thrombosis (DVT) and pulmonary embolus (PE). Although most reports suggest
that VTE can occur at any trimester in pregnancy, some studies suggest that VTE
is more common during the first half of pregnancy (see the image below).
Sequelae of DVT and PE include complications such as pulmonary hypertension,
post-thrombotic syndrome, and venous insufficiency.

Estimated gestational age at time of diagnosis of antepartum deep venous thrombosis (n=94).

Signs and symptoms

The signs and symptoms of VTE are nonspecific and common in pregnancy.
Diagnosis of VTE by physical examination is frequently inaccurate, even though
one study found that 80% of pregnant women with DVT experience pain and
swelling of the lower extremity.

Clinical signs and symptoms of PE are rarely encountered together; the classic
symptoms are as follows[3] :

Dyspnea - 82%
Abrupt onset of chest pain - 49%
Cough - 20%

The most common presenting signs of PE are as follows:

Tachypnea
Crackles
Tachycardia

Patients with massive PE may present with the following:

Syncope
Hypotension
Pulseless cardiac electrical activity
Death

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

D-dimer testing is often used in the diagnosis of DVT in nonpregnant patients due
to its high negative predictive value. Pregnancy decreases the specificity of d-
dimer testing, but the study still retains good negative predictive value. D-dimer is
also used for its negative predictive value in the diagnosis of PE.

Imaging studies

Imaging for DVT and/or PE is the best means of screening and evaluation for
these conditions. The current initial test of choice in the evaluation of VTE is
compression ultrasonography (CUS) of the lower extremity veins.

CUS has been shown to be more than 95% sensitive and specific for proximal
lower extremity DVT.[4] CUS is less accurate for the diagnosis of pelvic DVT.[5] In
pregnancy, CUS should be performed with the patient in the left lateral decubitus
position and with Doppler analysis of flow variation during respiration to maximize
the study’s ability to diagnose pelvic DVT.[6]

However, if the CUS study is equivocal, if Doppler testing is abnormal, or if

suspicion of pelvic DVT is high, further evaluation with magnetic resonance
imaging (MRI) is recommended.[7, 8, 9] MRI has been shown to have 97%
sensitivity and 95% specificity for pelvic DVT in nonpregnant patients.[10]

Imaging studies used in the diagnosis of PE include the following:

Chest radiography: Recommended prior to the evaluation for PE to

determine whether other etiologies may explain the patient’s symptoms (eg,
pneumonia, atelectasis) and to identify the next appropriate imaging test
Ventilation/perfusion (V/Q) scanning: In a pregnant patient with no known
pulmonary disease and a normal chest radiograph, V/Q scanning is the
recommended study to evaluate for PE
Spiral computed tomography pulmonary angiography (CT-PA): If the patient
has an abnormal chest radiograph or known pulmonary disease, spiral CT-
PA is recommended [11]

See Workup for more detail.

Management
Once the diagnosis of VTE is made, therapeutic anticoagulation should be initiated
in the absence of contraindications. The common classes of anticoagulation drugs
are as follows:

Indirect thrombin inhibitors: Include unfractionated heparin and low ̶ -

molecular-weight heparin (LMWH), as well as synthetic heparin
pentasaccharides and orally administered Factor Xa inhibitors
Direct thrombin inhibitors: Include argatroban, lepirudin, and bivalirudin
Vitamin K antagonist: Warfarin is included in this class

Heparin (unfractionated and low molecular weight) is the preferred drug for
managing VTE in pregnancy.

See Treatment and Medication for more detail.

Background
Venous thromboembolism (VTE) may occur at any time during gestation. Studies
report conflicting data as to the timing in pregnancy. Although most reports suggest
that VTE can occur at any trimester in pregnancy, some studies suggest that VTE
is more common during the first half of pregnancy. One study of 165 episodes of
VTE in pregnancy documented a higher incidence in the first trimester (see the
image below).[12] Other studies have not confirmed an association between
gestational age and frequency of VTE.[13, 14]

Estimated gestational age at time of diagnosis of antepartum deep venous thrombosis (n=94).

Note that most evidence suggests that VTE is more common in the postpartum
period.[1, 15, 16] In a 30-year population-based study, Heit et al documented that the
risk of VTE and pulmonary embolism (PE) was 5-fold and 15-fold, respectively, in
the postpartum period compared to during pregnancy.[2]
Special considerations in pregnancy - Location of DVT

In pregnancy, deep venous thrombosis (DVT) is much more likely to occur in the
left leg compared with the right leg. One study examined 60 cases of DVT in
pregnancy: 58 occurred in the left leg, 2 were bilateral, and none occurred in the
right leg.[17] The predilection for left lower extremity DVT is postulated to be the
consequence of May-Thurner syndrome, in which the left iliac vein is compressed
by the right iliac artery (see the image below).

May-Thurner syndrome

Another special consideration relevant to accurate diagnosis in pregnancy is that

12% of DVTs in pregnancy are in pelvic veins, whereas only 1% of DVTs in the
general population are in pelvic veins.[5] This predilection for pelvic site DVTs in
pregnancy warrants special consideration when Doppler ultrasound studies of the
lower extremities do not demonstrate noncompressible regions of lower extremity
veins, yet suspicion for VTE is high or Doppler flow analysis of venous flow is
abnormal.

Pathophysiology
Pregnancy is a state characterized by Virchow’s triad (1: hypercoagulability, 2:
venous stasis and turbulence, 3: endothelial injury and dysfunction). Pregnancy is
a state of hypercoagulability due to alterations of coagulation proteins. Factors I, II,
VII, VIII, IX, and X increase in pregnancy. Pregnancy increases resistance to the
anti-thrombotic factors such as protein C and protein S.[18] Thrombophilias can
exacerbate these changes in coagulation proteins, further increasing the patient’s
risk for VTE (see the image below).

Factors affecting thrombosis in Pregnancy

Venous stasis also increases as dilation of lower extremity veins occurs followed
by venous compression by the gravid uterus and enlarging iliac arteries. Situations
of decreased mobility (eg, surgery, cesarean delivery, bed rest, prolonged travel or
air travel) may exacerbate these factors. Endothelial injury may transpire at time of
delivery.[19] These factors work together to increase risk of VTE in the pregnant
and postpartum patient.

Sequelae of VTE

Sequelae of DVT and PE include complications such as pulmonary hypertension,

post-thrombotic syndrome, and venous insufficiency. Post-thrombotic syndrome is
not well defined; however, most definitions consist of a constellation of symptoms
(pain, cramps, heaviness, pruritus, and paresthesia) and signs (edema, skin
induration, hyperpigmentation, venous ectasia, redness, pain during calf
compression, and in more severe forms, venous stasis ulcer) in the extremity
affected by DVT. Mild post-thrombotic syndrome occurs in 20-40% of patients after
VTE, and severe post-thrombotic syndrome occurs in 5% of patients after VTE.[20]

Epidemiology
According to the Center for Disease Control’s National Pregnancy Registry
Surveillance System, between 1991 and 1999, pulmonary embolism (PE) was the
leading cause of maternal mortality. Of the 4,200 pregnancy related deaths
reported in the United States during those years, 20% of maternal death was
attributed to PE, surpassing pregnancy-related hypertensive disorders, postpartum
hemorrhage, and infection.[21] In a retrospective study of 1,461,270 deliveries, PE
accounted for 9% (9 of 95) of pregnancy-related deaths.[22]

Pregnancy increases the risk of VTE 4-fold to 5-fold over the nonpregnant state.[2,
1]
Overall, the prevalence of VTE in pregnancy is 0.5-2.0 per 1,000 pregnancies
and accounts for 1.1 deaths per 100,000 pregnancies.[23, 12, 24, 25, 15, 26, 27]
Approximately 75-80% of embolic events in pregnancy are venous.[27]

The 2 manifestations of VTE are deep venous thrombosis (DVT) and pulmonary
embolus (PE). DVT is approximately 3 times more common that PE in pregnancy.
[2]

Clinical Presentation

Contributor Information and Disclosures

Author
Edward Henry Springel, MD, FACOG Attending Physician in Obstetrics/Gynecology, Lourdes Medical
Associates

Edward Henry Springel, MD, FACOG is a member of the following medical societies: American Medical
Association

Disclosure: Nothing to disclose.

Coauthor(s)
Thomas Chih Cheng Peng, MD Professor (Collateral), Department Obstetrics and Gynecology, Virginia
Commonwealth University School of Medicine, VCU Health System

Thomas Chih Cheng Peng, MD is a member of the following medical societies: American College of
Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Society for Maternal-Fetal
Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center
College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor
Thomas Chih Cheng Peng, MD Professor (Collateral), Department Obstetrics and Gynecology, Virginia
Commonwealth University School of Medicine, VCU Health System

Thomas Chih Cheng Peng, MD is a member of the following medical societies: American College of
Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Society for Maternal-Fetal
Medicine

Disclosure: Nothing to disclose.

References

1. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and
prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008 Apr.
6(4):632-7. [Medline].

2. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ 3rd. Trends in the incidence of
venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern
Med. 2005 Nov 15. 143(10):697-706. [Medline].

3. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International
Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999 Apr 24. 353(9162):1386-9. [Medline].

4. Polak JF, Wilkinson DL. Ultrasonographic diagnosis of symptomatic deep venous thrombosis in
pregnancy. Am J Obstet Gynecol. 1991 Sep. 165(3):625-9. [Medline].

5. Pabinger I, Grafenhofer H, Kyrle PA, et al. Temporary increase in the risk for recurrence during pregnancy
in women with a history of venous thromboembolism. Blood. 2002 Aug 1. 100(3):1060-2. [Medline].
 6. Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep
venous system of the leg in pregnancy. Br J Obstet Gynaecol. 1997 Feb. 104(2):191-7. [Medline].

7. American College of Obstetricians and Gynecologists Practice Bulletin No 123: Thromboembolism in

pregnancy. Sep 2011.

8. Nijkeuter M, Ginsberg JS, Huisman MV. Diagnosis of deep vein thrombosis and pulmonary embolism in
pregnancy: a systematic review. J Thromb Haemost. 2006 Mar. 4(3):496-500. [Medline].

9. Spritzer CE, Norconk JJ Jr, Sostman HD, Coleman RE. Detection of deep venous thrombosis by magnetic
resonance imaging. Chest. 1993 Jul. 104(1):54-60. [Medline].

10. Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL. Multidetector-row computed tomography
in suspected pulmonary embolism. N Engl J Med. 2005 Apr 28. 352(17):1760-8. [Medline].

11. Leung, et al. American Thoracic Society: PE in Pregnancy.

12. Gherman RB, Goodwin TM, Leung B, Byrne JD, Hethumumi R, Montoro M. Incidence, clinical
characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet
Gynecol. 1999 Nov. 94(5 Pt 1):730-4. [Medline].

13. O'Connor DJ, Scher LA, Gargiulo NJ 3rd, Jang J, Suggs WD, Lipsitz EC. Incidence and characteristics of
venous thromboembolic disease during pregnancy and the postnatal period: a contemporary series. Ann
Vasc Surg. 2011 Jan. 25(1):9-14. [Medline].

14. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the
period of risk and the leg of presentation. Obstet Gynecol Surv. 1999 Apr. 54(4):265-71. [Medline].

15. Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in
pregnancy and puerperium--a register-based case-control study. Am J Obstet Gynecol. 2008 Feb.
198(2):233.e1-7. [Medline].

16. Treffers PE, Huidekoper BL, Weenink GH, Kloosterman GJ. Epidemiological observations of thrombo-
embolic disease during pregnancy and in the puerperium, in 56,022 women. Int J Gynaecol Obstet. 1983
Aug. 21(4):327-31. [Medline].

17. Ginsberg JS, Brill-Edwards P, Burrows RF, et al. Venous thrombosis during pregnancy: leg and trimester
of presentation. Thromb Haemost. 1992 May 4. 67(5):519-20. [Medline].

18. Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol. 2003 Jun. 16(2):153-68.
[Medline].

19. Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med. 2008 Nov 6.
359(19):2025-33. [Medline].

20. Kahn SR, Kearon C, Julian JA, Mackinnon B, Kovacs MJ, Wells P. Predictors of the post-thrombotic
syndrome during long-term treatment of proximal deep vein thrombosis. J Thromb Haemost. 2005 Apr.
3(4):718-23. [Medline].

21. Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance--United States, 1991-
-1999. MMWR Surveill Summ. 2003 Feb 21. 52(2):1-8. [Medline].

22. Clark SL. Am J Obstet Gynecol. 2008. 52:No SS-2.

23. Andersen BS, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. The cumulative incidence of venous
thromboembolism during pregnancy and puerperium--an 11 year Danish population-based study of
63,300 pregnancies. Acta Obstet Gynecol Scand. 1998 Feb. 77(2):170-3. [Medline].

24. Lindqvist P, Dahlbäck B, Marsál K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol.
1999 Oct. 94(4):595-9. [Medline].

25. Simpson EL, Lawrenson RA, Nightingale AL, Farmer RD. Venous thromboembolism in pregnancy and the
puerperium: incidence and additional risk factors from a London perinatal database. BJOG. 2001 Jan.
108(1):56-60. [Medline].

26. Liu S, Rouleau J, Joseph KS, et al. Epidemiology of pregnancy-associated venous thromboembolism: a
population-based study in Canada. J Obstet Gynaecol Can. 2009 Jul. 31(7):611-20. [Medline].

27. James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the
postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006 May. 194(5):1311-5.
[Medline].

28. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J
Obstet Gynecol. 2005 Jul. 193(1):216-9. [Medline].

29. Weinberger SE, Weiss ST, Cohen WR, Weiss JW, Johnson TS. Pregnancy and the lung. Am Rev Respir
Dis. 1980 Mar. 121(3):559-81. [Medline].

30. Chan WS, Lee A, Spencer FA, Crowther M, Rodger M, Ramsay T. Predicting deep venous thrombosis in
pregnancy: out in "LEFt" field?. Ann Intern Med. 2009 Jul 21. 151(2):85-92. [Medline].

31. James AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol. 2009 Mar. 29(3):326-
31. [Medline].

32. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous thromboembolism, thrombophilia,
antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th Edition). Chest. 2008 Jun. 133(6 Suppl):844S-886S. [Medline].
33. Clark SL, Belfort MA, Dildy GA, Herbst MA, Meyers JA, Hankins GD. Maternal death in the 21st century:
causes, prevention, and relationship to cesarean delivery. Am J Obstet Gynecol. 2008. 342:

34. Danilenko-Dixon DR, Heit JA, Silverstein MD, Yawn BP, Petterson TM, Lohse CM. Risk factors for deep
vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based, case-
control study. Am J Obstet Gynecol. 2001 Jan. 184(2):104-10. [Medline].

35. Larsen TB, Sorensen HT, Gislum M, Johnsen SP. Maternal smoking, obesity, and risk of venous
thromboembolism during pregnancy and the puerperium: a population-based nested case-control study.
Thromb Res. 2007. 120(4):505-9. [Medline].

36. Knight M,. Antenatal pulmonary embolism: risk factors, management and outcomes. BJOG. 2008 Mar.
115(4):453-61. [Medline].

37. Chan WS, Chunilal S, Lee A, Crowther M, Rodger M, Ginsberg JS. A red blood cell agglutination D-dimer
test to exclude deep venous thrombosis in pregnancy. Ann Intern Med. 2007 Aug 7. 147(3):165-70.
[Medline].

38. Wells PS, Anderson DR, Rogers M, et al. Evaluation of d-dimer in the diagnosis of suspected deep
venous thromboembolism. N Engl J Med. 2003. 349:1227-1235.

39. Powrie RO, Larson L, Rosene-Montella K, Abarca M, Barbour L, Trujillo N. Alveolar-arterial oxygen
gradient in acute pulmonary embolism in pregnancy. Am J Obstet Gynecol. 1998 Feb. 178(2):394-6.
[Medline].

40. Ridge CA, McDermott S, Freyne BJ, Brennan DJ, Collins CD, Skehan SJ. Pulmonary embolism in
pregnancy: comparison of pulmonary CT angiography and lung scintigraphy. AJR Am J Roentgenol. 2009
Nov. 193(5):1223-7. [Medline].

41. Cahill AG, Stout MJ, Macones GA, Bhalla S. Diagnosing pulmonary embolism in pregnancy using
computed-tomographic angiography or ventilation-perfusion. Obstet Gynecol. 2009. 193:114-124.

42. Gomes MP, Deitcher SR. Risk of venous thromboembolic disease associated with hormonal
contraceptives and hormone replacement therapy: a clinical review. Arch Intern Med. 2004 Oct 11.
164(18):1965-76. [Medline].

43. American College of Obstetricians and Gynecologists Practice Bulletin No 73: Use of hormonal
contraception in women with coexisting medical conditions. Obstet Gynecol. 2006. 107:1453-72.

44. American College of Obstetricians and Gynecologists Practice Bulletin No 124: Inherited thrombophilias in
pregnancy. Obstet Gynecol. 2011.

45. van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular weight
heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database
Syst Rev. 2004. (4):CD001100. [Medline].

46. Guidelines on diagnosis and management of acute pulmonary embolism. Task Force on Pulmonary
Embolism, European Society of Cardiology. Eur Heart J. 2000 Aug. 21(16):1301-36. [Medline].

47. Casele HL, Laifer SA, Woelkers DA, Venkataramanan R. Changes in the pharmacokinetics of the low-
molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol. 1999 Nov. 181(5
Pt 1):1113-7. [Medline].

48. Ginsberg JS, Hirsh J. Anticoagulants during pregnancy. Annu Rev Med. 1989. 40:79-86. [Medline].

49. Paralkar VR, Rubin RN. Anticoagulation: An Update for Primary Care. Consultant. 2011. 51(10):

50. Schaefer C, Hannemann D, Meister R, Eléfant E, Paulus W, Vial T. Vitamin K antagonists and pregnancy
outcome. A multi-centre prospective study. Thromb Haemost. 2006 Jun. 95(6):949-57. [Medline].

51. Schulman S, Beyth RJ, et al. Hemorrhagic complications and thrombolytic treatment: American College of
Chest Physicians Evidence Based Clinical Practice Guidelines. Chest. 8th Ed. 2008. 133: 257S-298S.

52. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin induced
thrombocytopenia: American College of Chest Physicians Evidence Based Clinical Practice Guidelines
(8th Ed). Chest. 2008. 133:340S-80S.

53. Dulitzki M, Pauzner R, Langevitz P, et al. Low molecular weight heparin during pregnancy and delivery: a
preliminary experience with 41 pregnancies. Obstet Gynecol. 1996. 87:830.

54. Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK,. Executive summary: regional anesthesia in the
patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and
Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010 Jan-Feb.
35(1):102-5. [Medline].

55. Chan WS, Spencer FA, Lee AY, Chunilal S, Douketis JD, Rodger M, et al. Safety of withholding
anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial
compression ultrasound and iliac vein imaging. CMAJ. 2013 Mar 5. 185(4):E194-200. [Medline].

56. Henderson D. DVT in Pregnancy Ruled Out by Serial Doppler Ultrasound. Medscape Medical News.
Available at http://www.medscape.com/viewarticle/777659. Accessed: Mar 5 2013.
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