Clinical Pearls: Venous Thromboembolism in Pregnancy 

January 16, 2023
By Duaa Osman

This article is part of a series appearing in Interactions, our biweekly newsletter, written and researched by CSHP's students. We've created this series as a valuable learning activity for pharmacy students undertaking rotations at CSHP. Crafting these pieces not only helps students gain in-depth knowledge of specific conditions, treatments, and resources, it also helps them hone their skills in research, critical appraisal, evaluation, synthesis, and writing – all of which will serve them well in clinical practice. The Professional Practice Team works with the students to select hot topics that are of interest and utility to both the students and to you, the reader. We hope you enjoy this piece by one of our future colleagues! Let us know what you think: If you would like to provide any comments or constructive feedback for our students, please email us at practice@cshp.ca.

Background

In Canada, venous thromboembolism (VTE) is the second most common cardiovascular disorder and is estimated to cause the healthcare system $600 million per year.1 Pregnancy is a well-established risk factor for VTE, with all stages of pregnancy resulting in increased risk, especially the post-partum period. When compared to non-pregnant women of similar age, pregnant women experience a 5 to 10-fold increase in risk of VTE during pregnancy and a 15 to 35-fold increase during the post-partum period.2

VTE is comprised of two main conditions, deep vein thrombosis (DVT) and pulmonary embolism (PE) – both of which are well established complications of pregnancy. Thrombosis typically occurs due to over-activation of hemostasis at the site of an injured or uninjured blood vessel. In general, factors that increase the risk of VTE are those that increase hypercoagulability, stasis of the blood, or vessel wall injury – also known as Virchow’s triad.3 Increases in clotting factors during pregnancy results in a hypercoagulable state. During the second and third trimesters, an increased resistance to activated protein C is observed, resulting in poor anticoagulant response. Stasis of the blood increases due to decreased venous capacitance and compression of the large veins caused by the enlargement of the uterus. Finally, an increase in vessel wall injury can occur due to labour and delivery, increasing the risk of VTE during the post-partum period.4 

VTE can manifest during pregnancy as an isolated DVT in the lower extremities, or a portion of the embolus may travel from the lower extremity to the lungs resulting in a PE. Early detection and treatment of DVT and PE during pregnancy is crucial as PE represents the 7th leading cause of maternal mortality, accounting for 9% of maternal deaths.4

Diagnosing VTE in pregnancy

Distinguishing symptoms of DVT from symptoms of pregnancy can be difficult as there are many hemodynamic changes that occur during pregnancy. With respect to clinical presentation, pregnant women have a higher likelihood to experience left-sided DVT than non-pregnant women, with greater than 80% of DVT cases in pregnancy occurring in the left leg.2 DVT in pregnant women is also more likely to be isolated to the iliac and/or femoral veins than in non-pregnant patients.2 This is thought to be due to the right common iliac artery compressing the left common iliac vein as a result of the enlargement of the uterus.5 Signs and symptoms of DVT include erythema, leg swelling, and warmth of the lower extremity.2

The Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends investigating suspected DVT using compression ultrasound of the proximal venous system from the iliac to the popliteal vein. Doppler studies should also be performed on the external iliac vein to ensure presence of blood flow. If the initial examination is negative, the test should be repeated within 7 days. If an isolated DVT is suspected to be in the iliac vein, an MRI can be considered following the initial examination.6 Suspected cases of PE can be investigated using D-dimer test combined with compression ultrasonography.6 Once an acute case of VTE is confirmed, anticoagulation therapy should be promptly initiated. The SOGC guidelines recommend that pregnant women should be hospitalized or closely monitored as outpatients for the first two weeks of VTE treatment following diagnosis.6

Therapeutic options: Anticoagulants 

The cornerstone of VTE therapy is anticoagulation therapy; however, during pregnancy certain safety considerations must be kept in mind to uphold maternal and fetal safety.  

Table 1: Anticoagualnt options available for the treatment of VTE 7,8

*Except in patients with a history of heparin-induced thrombocytopenia

In most cases, subcutaneous LMWH is the drug of choice for the treatment of DVT in pregnancy due to its safety and efficacy profile. UFH is preferred for patients with severe renal failure, or those at increased risk of bleeding or persistent hypotension resulting from PE.6

Warfarin is contraindicated during the first trimester of pregnancy since it can cause warfarin embryopathy resulting in stippled bones, midfacial and limb malformations. Warfarin use during pregnancy can also result in fetal hemorrhage or death. Therefore, the use of warfarin should only be considered in exceptional circumstances, for example, in women with mechanical heart valves.9

Anticoagulants should be administered for a minimum of 3 months when treating acute VTE. Following this initial treatment period, anticoagulant use can be decreased to intermediate or prophylactic use for the remainder of the pregnancy. Treatment can be discontinued at 6 weeks post-partum.6

Thromboprophylaxis in pregnancy  

The need for thromboprophylaxis in pregnancy should be assessed during pregnancy, the post-partum period, and at any transitions of care. Pharmacologic and non-pharmacologic options are available for thromboprophylaxis. Non-pharmacologic options include graduated compression stockings or use of intermittent pneumatic compression devices.  
 
Pharmacologic prophylaxis can be considered for pregnant women with a history of multiple VTEs or estrogen associated VTE. The preferred agent for pharmacologic prophylactic treatment is LMWH. In patients with severe renal insufficiency, UFH is preferred. It is recommended that prophylactic therapy be continued through the pregnancy. During the final weeks of pregnancy, prophylactic treatment should be reassessed to determine if any changes or discontinuation is needed.10 

Determining the optimal dosing for LMWH during pregnancy and the post-partum period remains to be a challenge due to existing knowledge gaps.5 A recent multicentre open-label, randomised controlled trial, the Highlow study, sought to determine optimal dosing of LMWH in pregnant and post-partum women with a history of VTE.11 The primary efficacy outcome of the study was incidence of confirmed VTE, and the primary safety outcome was assessing for risk of bleeding. The study randomised 1110 pregnant women to receive either a weight-adjusted intermediate dose of LMWH or a fixed low dose of LMWH. The study found that fixed low dose of LMWH is an appropriate thromboprophylaxis dosing strategy during pregnancy in patients with a history of VTE. With respect to the post-partum period, a post-hoc analysis of the study suggested that an intermediate dose of LMWH may be more effective than a low dosing strategy, however this needs to be confirmed through future studies.11

Pharmacist's role

 As part of a multidisciplinary team, pharmacists can play a vital role in the care of patients with VTE. Anticoagulation therapy requires frequent assessment and monitoring to ensure safety and efficacy. Several studies have found that effective patient education and regular long-term follow-up help improve medication adherence.12 In an assessment of the impacts of a pharmacist-led DOAC monitoring clinic, Haché et al. found an increase in patient adherence to guideline-directed care along with a decrease in observed adverse events. In this clinic, pharmacists were the first point of contact for patients during follow-up appointments where patients were assessed for adverse events and adherence. During these visits pharmacists were also able to make changes to medication regimens based on patient assessment, ensuring medication management was in accordance with guideline recommendations.12 In addition, a study by Ogilvie et al. assessing a pharmacist-lead prescribing model in an Australian emergency department found a significant improvement in accuracy and safety of the medications prescribed to patients for VTE.13   With respect to oral contraceptive medication use during the post-partum period, it is recommended that women at risk of VTE avoid combined oral contraceptives during the first 6 weeks of the post-partum period.7 This presents an opportunity for pharmacist intervention for patients at high risk of VTE. Pharmacists are well positioned to make tailored recommendations regarding oral contraceptives based on a patient’s risk of VTE. They can also play a significant role in patient education, effectively enhancing patient safety. 

 

References

  1. Canadian Venous Thromboembolism Clinical Trials and Outcomes Research Network. Venous thromboembolism. Accessed December 14, 2022. https://www.canvector.ca/venous-thromboembolism  
  2. Thrombosis Canada. Pregnancy: Diagnosis of DVT and PE. Updated September 14, 2021. Accessed December 14, 2022. https://thrombosiscanada.ca/clinicalguides/?search=pregnancy#  
  3. Nicholson M, Chan N, Bhagirath V, Ginsberg J. Prevention of Venous Thromboembolism in 2020 and Beyond. J Clin Med. 2020;9(8):2467. Published 2020 Aug 1. doi:10.3390/jcm9082467 
  4. Malhotra A, Weinberger SE. Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis. In: Post T, ed. UpToDate. UpToDate; 2022. Accessed December 9, 2022. www.uptodate.com  
  5. Devis P, Knuttinen MG. Deep venous thrombosis in pregnancy: incidence, pathogenesis and endovascular management. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S309-S319. doi:10.21037/cdt.2017.10.08 
  6. Chan WS, Rey E, Kent NE, et al. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can. 2014;36(6):527-553. doi:10.1016/s1701-2163(15)30569-7 
  7. Kosar L, LeBras M. Peri-Pregnancy: Drug treatment considerations for women. May 2022. Available from www.rxfiles.ca 
  8. Thrombosis Canada. Pregnancy: Venous thromboembolism treatment. Updated 2, 2022. Accessed December 14, 2022. https://thrombosiscanada.ca/clinicalguides/?search=pregnancy#  
  9. Malhotra A, Weinberger SE. Deep vein thrombosis and pulmonay embolism in pregnancy: treatment. In: Post T, ed. UpToDate. UpToDate; 2022. Accessed December 9, 2022. www.uptodate.com  
  10. Malhotra A, Weinberger SE. Deep vein thrombosis and pulmonay embolism in pregnancy: Prevention. In: Post T, ed. UpToDate. UpToDate; 2022. Accessed December 9, 2022. www.uptodate.com  
  11. Bistervels IM, Buchmüller A, Wiegers HMG, et al. Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial. Lancet. 2022;400(10365):1777-1787. doi:10.1016/S0140-6736(22)02128-6 
  12. Haché J, Bonsu KO, Chitsike R, Nguyen H, Young S. Assessment of a Pharmacist-Led Direct Oral Anticoagulant Monitoring Clinic. Canadian journal of hospital pharmacy. 2021;74(1):7-14. doi:10.4212/CJHP.V74I1.3035 
  13. Ogilvie M, Nissen L, Kyle G, Hale A. An evaluation of a collaborative pharmacist prescribing model compared to the usual medical prescribing model in the emergency department. Research in social and administrative pharmacy. 2022;18(10):3744-3750. doi:10.1016/j.sapharm.2022.05.005 
     
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