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Pregnancy-related venous thromboembolism: Progress but questions remain

  • Author Footnotes
    # Professor, Eli Lilly Canada/May Cohen Chair in Women's Health
    Shannon M. Bates
    Correspondence
    Corresponding author at:3V50, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4K1, Canada.
    Footnotes
    # Professor, Eli Lilly Canada/May Cohen Chair in Women's Health
    Affiliations
    Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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  • Author Footnotes
    # Professor, Eli Lilly Canada/May Cohen Chair in Women's Health
Published:February 01, 2022DOI:https://doi.org/10.1016/j.ejim.2022.01.034

      Keywords

      The care of pregnant persons at risk for or with known or suspected venous thromboembolism (VTE) has many challenges; including specialized content knowledge, a limited high-quality evidence base upon which to make decisions, conflicting guideline recommendations, the need to consider the wellbeing of both the mother and the fetus, and an informed and engaged patient population that appropriately embraces shared decision making. For some, these challenges are what makes this area of thrombosis medicine rewarding, while for others they provoke anxiety.
      In this issue of the Journal, Bukhari and colleagues help to address the first of these challenges with their helpful, well written review on the epidemiology, pathogenesis, diagnostic approaches and therapeutic options for pregnancy-associated VTE [
      • Bukhari S.
      • Fatima S.
      • Barakat A.F.
      • Fogerty A.E.
      • Weinberg I.
      • Elgency I.Y.
      Venous thromboembolism during pregnancy and postpartum period.
      ]. Limitations of this review include the absence of any discussion of the impact of coronavirus disease 2019 (COVID-19), reliance on odds ratios and relative risks when discussing risk factors, and generalization of some of the data on diagnosis of pregnancy-associated pulmonary embolism and deep vein thrombosis.
      There is an increased risk of venous and arterial thrombosis in pregnant patients with COVID-19 infection, compared to those without COVID-19 [
      • Servante J.
      • Swallow G.
      • Thornton J.G.
      • et al.
      Haemostatic and thrombo-embolic complications in pregnant women with COVID-19: a systematic review and critical analysis.
      ,
      • Jering K.S.
      • Claggett B.L.
      • Cunningham J.W.
      • et al.
      Clinical characteristics and outcomes of hospitalized women giving birth with and without COVID-19.
      ]. Although the risk of a thrombotic event in pregnant persons with COVID-19 appears low (less than 1%) [
      • Servante J.
      • Swallow G.
      • Thornton J.G.
      • et al.
      Haemostatic and thrombo-embolic complications in pregnant women with COVID-19: a systematic review and critical analysis.
      ,
      • Jering K.S.
      • Claggett B.L.
      • Cunningham J.W.
      • et al.
      Clinical characteristics and outcomes of hospitalized women giving birth with and without COVID-19.
      ,
      • Kazi S.
      • Othman M.
      • Khoury R.
      • et al.
      ISTH Registry on Pregnancy and COVID-19 Associated Coagulopathy (COV-PREG-COAG) – First Report.
      ,
      • Gabrieli D.
      • Cahen-Peretz A.
      • Shimonovitz T.
      • et al.
      Thromboembolic events in pregnant and puerperal women after COVID-19 lockdowns: a retrospective cohort study.
      ], information is still accruing. Additional factors, including severity of COVID-19 illness and other traditional risk factors for pregnancy-associated VTE, may further increase this risk. There is less information known about the risk of thrombosis in the postpartum period for pregnant patients with COVID-19 [
      • Gabrieli D.
      • Cahen-Peretz A.
      • Shimonovitz T.
      • et al.
      Thromboembolic events in pregnant and puerperal women after COVID-19 lockdowns: a retrospective cohort study.
      ]. Pregnant patients were systematically excluded from large randomized controlled trials that studied the role of prophylactic, intermediate or therapeutic-dose of low-molecular-weight heparin (LMWH) for the prevention of VTE and other outcomes in the setting of COVID-19 infection [
      • D'Souza R.
      • Malhamé I.
      • Teshler L.
      • Acharya G.
      • Hunt B.J.
      • McLintock C
      A critical review of the pathophysiology of thrombotic complications and clinical practice recommendations for thromboprophylaxis in pregnant patients with COVID-19.
      ] and so there are no high-quality pregnancy-specific data to guide prescription of thromboprophylaxis when these patients have COVID-19.
      Although most of the available data regarding the impact of clinical factors on the risk of pregnancy-associated VTE are in the form of relative risks, consideration of absolute risks is vital when making treatment decisions and counselling patients, particularly given the low absolute baseline risks of VTE with pregnancy cited in this review. For example, although a fourfold greater risk of VTE might seem worthy of prophylaxis, the associated absolute VTE risk of less than 5/1000 is likely to be perceived differently. Studies in other settings have shown patient perception of a given risk differs when it is presented as a relative risk or absolute risk [
      • Machado R.B.
      • Morimoto M.
      • Santana N.
      • Arruda L.F.
      • Bernardes C.R.
      • de Souza I.M.
      Effect of information on the perception of users and prospective users of combined oral contraceptives regarding the risk of venous thromboembolism.
      ]. The latter enables greater understanding, likely for healthcare providers, as well.
      The authors advocate for normal (negative) d-dimer levels to rule out VTE in pregnant patients with a low or intermediate clinical pretest probability. A meta-analysis that investigated the safety of using d-dimer to exclude pregnancy-associated VTE reported a high sensitivity and negative predictive value for the test and these authors also suggested based on these findings that d-dimer can safely rule out VTE in pregnancy when the disease prevalence is consistent with a low/intermediate or unlikely pretest probability [
      • Bellesini M.
      • Robert-Ebadi H.
      • Combescure C.
      • Dedionigi C.
      • Le Gal G.
      • Righini M
      d-dimer to rule out venous thromboembolism during pregnancy: a systematic review and meta-analysis.
      ]. However, the number of studies (three prospective, one retrospective) and subjects with VTE (n = 69) were small and only two of the included studies were prospective management studies and both of those involved patients with suspected pulmonary embolism. There are no published prospective management studies using d-dimer (with or without pre-test probability assessment) to exclude deep vein thrombosis in pregnancy, suggesting this recommendation might be premature. There is an ongoing study (LEaD: clinicaltrials.gov ID NCT02507180) to prospectively validate the use of the LEFt rule (Left leg, Edema of calf circumference of 2 cm or over, and a First Trimester presentation) [
      • Chan W.-.S.
      • Lee A.
      • Spencer F.A.
      • et al.
      Predicting Deep Vein Thrombosis in Pregnancy: out in “LEFt” Field?.
      ] in combination with d-dimer in pregnant persons with suspected deep vein thrombosis.
      In their section on prophylaxis, Bukhari and colleagues highlight the inconsistency between recommendations from different guidelines. These differences are usually found in recommendations for those at low or moderate risk and result from the low quality of available evidence, limited data on benefits and risks of prophylaxis, the role of expert opinion, the scoring system (if any) to be used, the risk threshold for recommending prophylaxis, differences in strategies for handling multiple combined risks, statistical methods for combining data, and date of guideline publication [
      • Sibai B.M.
      • Rouse D.J.
      Pharmacologic thromboprophylaxis in obstetrics: broader use demands better data.
      ,
      • Bates S.M.
      • Middeldorp S.
      • Rodger M.
      • James A.H.
      • Greer I.
      Guidance for the treatment and prevention of obstetric-associated venous thromboembolism.
      ]. There is a need for guideline bodies to be more transparent about these details. I would also propose that guidelines that have not been updated within an acceptable period should no longer be considered relevant. We certainly wouldn't look to a cardiology reference published ten years ago for helpful guidance!
      The review appropriately ends with a plea for further research - into risk scores and predictive models specifically for suspected pregnancy-related VTE, clinical VTE risk factors, diagnostic algorithms, and advanced therapeutic options for high-risk VTE patients. These are certainly high priority items. My list is much longer and I would include further study of the safety of fondaparinux and the direct oral anticoagulants during pregnancy and, for the latter, while breastfeeding; optimal therapeutic and prophylactic anticoagulant management during pregnancy and the postpartum periods, as well as around the time of delivery; prevention and management of pregnancy-related superficial vein thrombosis; absolute risks of VTE with combinations of clinical risk factors; the impact of COVID-19 during pregnancy on VTE risk; pregnancy-specific risk stratification for complications associated with treatment of VTE and to identify pregnant patients who require hospital admission for initial management; and patient values and preferences for treatment and prophylaxis options and how best to incorporate these into effective shared decision making. Research involving pregnant patients is difficult for many reasons. However, a quick scan of clinical trial registry sites, like ClinicalTrials.gov, shows many active studies. This is very encouraging; for although the prevention, diagnosis, and management of pregnancy-related VTE has become much more evidence based, there is still a way to go.

      Conflict of Interest Statement

      Dr. Bates receives unencumbered salary support as McMaster University's Eli Lilly Canada / May Cohen Chair in Women's Health. She has received honoraria from the Foundation for Women and Girls with Blood Disorders, Leo Pharma Canada, Inc., and ROVI; as well as consulting fees from Leo Pharma Canada, Inc.

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      Linked Article

      • Venous thromboembolism during pregnancy and postpartum period
        European Journal of Internal MedicineVol. 97
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          The maternal mortality rates in the United States (US) remain the highest among developed countries, and continue to rise (1). Cardiovascular diseases are the leading etiology of maternal deaths in developed countries (2), and account for more than a third of pregnancy-related deaths. Most importantly many are preventable (3). Venous thromboembolism (VTE), (i.e., deep venous thrombosis [DVT] and/or pulmonary embolism [PE]), is one of the leading cardiovascular etiologies of maternal morbidity and mortality (3), accounting for ∼9% of pregnancy-related deaths (4).
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