Thromboprophylaxis in pregnant women: For whom and which LMWH dosage?

Abstract

Venous thromboembolism (VTE) is a leading cause of death and morbidity in pregnant women. Despite these high stakes, decision making in VTE prevention is frequently very challenging because of a dearth of high‐quality data. Therefore, we sincerely congratulate Cox et al. on their recent publication of a 15‐year retrospective cohort of 172 pregnancies (123 women) managed with a fixed regimen dose of enoxaparin during the antenatal and/or postpartum period.1.Cox S. Eslick R. McLintock C. Effectiveness and safety of thromboprophylaxis with enoxaparin for prevention of pregnancy‐associated venous thromboembolism.J Thromb Haemost. 2019; 17: 1160-1170https://doi.org/10.1111/jth.14452Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar In this manuscript, Cox et al. have provided valuable insights into rates of recurrent VTE and bleeding in women who received extended enoxaparin as outpatients for prevention of venous thromboembolism during pregnancy and/or post partum. Importantly, the authors recruited women qualifying for antenatal thromboprophylaxis in a variety of settings and therefore addressed an important knowledge gap surrounding outcomes in the setting of many common VTE risk factors. These risk factors included a family history of VTE and thrombophilia, personal thrombophilia or antiphospholipid antibodies, proteinuria, elevated body mass index, lower limb swelling, and a personal history of VTE that was either provoked or unprovoked (66.1%). In the entire cohort, the authors reported a low rate of pregnancy‐associated VTE (1.2%; 95% confidence interval 0.32‐4.14) and postpartum hemorrhage rates of 36.6% (500 mL) and 9.3% (1000 mL). These data were compared with the results of a previously reported Dutch cohort (126 pregnancies, 91 women) in which the VTE rate was 5.5% (95% confidence interval, 2.4‐12.3).2.Roeters van Lennep J.E. Meijer E. Klumper F.J. Middeldorp J.M. Bloemenkamp K.W. Middeldorp S. Prophylaxis with low‐dose low‐molecular‐weight heparin during pregnancy and postpartum: is it effective?.J Thromb Haemost. 2011; 9: 473-80Crossref PubMed Scopus (73) Google Scholar On the basis of the data of their cohort, the authors expressed a concern regarding the rationale to explore the efficacy and safety of higher doses of low‐molecular‐weight heparin (LMWH), as currently being evaluated in the first ever randomized controlled trial (RCT) exploring optimal LMWH dosing for prevention of VTE in women with a personal high‐risk VTE history: The HighLow study (Clinicaltrials.gov 01828697).3.Bleker S.M. Buchmüller A. Chauleur C. Ní Áinle F. Donnelly J. Verhamme P. et al.Low‐molecular‐weight heparin to prevent recurrent venous thromboembolism in pregnancy: rationale and design of the Highlow study, a randomised trial of two doses.Thromb Res. 2016; 144: 62-8Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar We share a common belief with the authors that personalized VTE risk assessment should aim to avoid unnecessary LMWH, particularly in the setting of lower‐risk conditions. However, women with prior VTE, particularly unprovoked and hormonally provoked VTE, have among the highest risk for VTE recurrence and until now have been excluded from randomized trials evaluating LMWH dosing. We share the authors’ desire to produce high‐quality data aimed at safe and effective VTE prevention, and this motivation has driven the design and conduct of this RCT, a trial that has successfully recruited >800 patients worldwide, overcoming the inherent challenges in performing RCTs in pregnant women. We wish to argue respectfully that the rationale for the HighLow study is valid and that this RCT addresses a crucial knowledge gap that is highlighted but not yet answered by current literature. First, among the 123 women reported by Cox et al., 41 patients (33.3%) did not have a personal history of VTE compared with 6 patients (7%) in the referenced Dutch cohort.2.Roeters van Lennep J.E. Meijer E. Klumper F.J. Middeldorp J.M. Bloemenkamp K.W. Middeldorp S. Prophylaxis with low‐dose low‐molecular‐weight heparin during pregnancy and postpartum: is it effective?.J Thromb Haemost. 2011; 9: 473-80Crossref PubMed Scopus (73) Google Scholar In addition, among women with a previous VTE, 12 had a previous provoked VTE not related to pregnancy or oral contraception. This is important, because, while the Auckland study provides crucial insights into the burden of enoxaparin prescribing, among these 123 women 53 (43%) presented with a very‐low risk of VTE (either no previous DVT or a non‐hormone‐related previous deep vein thrombosis) compared with 17 patients (18.7%) in the Dutch cohort. Hence, the low incidence of VTE observed in the Auckland cohort is not surprising and cannot be attributed to the prophylactic regimen per se. Second, concerning the increase of postpartum hemorrhage in the Auckland study, it is important to note that a cesarean section was performed in a particularly high proportion of women (44.5%) of pregnancies reported and is likely to have influenced reported postpartum hemorrhage rates. This is an important observation by the Auckland team in a setting characterized by high cesarean section rates, and experience in jurisdictions where cesarean section rates are lower may differ significantly. Of note, only three women of the Auckland cohort received at least two units of packed red cells, giving a total of 1.7% of bleeding leading to a major intervention. It is reassuring that the reported rate of major hemorrhage during antepartum and postpartum periods reported in a meta‐analysis was 1.4% (95% confidence interval: 0.62‐2.41) and 1.2% (95% confidence interval: 0.3‐2.50) respectively in pregnant women receiving LMWH or unfractionated heparin at therapeutic regimens for a venous thromboembolic event.4.Romualdi E. Dentali F. Rancan E. Squizzato A. Steidl L. Middeldorp S. et al.Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a metanalysis of the literature.J Thromb Haemost. 2013; 11: 270-81Crossref PubMed Scopus (85) Google Scholar We share a common strong concern with the Auckland group that evaluation of bleeding events in women receiving LMWH in the antenatal and postpartum periods is of critical importance and that this evaluation should include minor bleeding events. These events, although categorized as “minor,” are important to women under treatment with LMWH, and their rate is being prospectively evaluated in the HighLow study. Cox and al. express a concern regarding the HighLow study design in terms of LMWH dosing in the group of women assigned to a standard prophylactic dose and those allocated an intermediate dose. In women who are allocated to receive a standard‐dose regimen, the regimen is based on weight at randomization and is not changed throughout pregnancy and the postpartum period. In women who are allocated to receive the intermediate‐dose regimen, the women's weight is monitored at every follow‐up visit and, if necessary, the dose changed accordingly. The reasons underlying the permitting of four different LMWHs in the HighLow study reflect the inherent pragmatic design of this multicenter, multinational study: a design that has made recruitment realistic and achievable and that has been described previously.3.Bleker S.M. Buchmüller A. Chauleur C. Ní Áinle F. Donnelly J. Verhamme P. et al.Low‐molecular‐weight heparin to prevent recurrent venous thromboembolism in pregnancy: rationale and design of the Highlow study, a randomised trial of two doses.Thromb Res. 2016; 144: 62-8Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar One of the main barriers to imposing a single LMWH type across all countries would have been the associated costs if that particular LMWH were not available in participating hospitals (seven countries, 62 recruiting hospitals). The importance of this potential barrier cannot be overstated, given that HighLow is an academic trial. We agree that there is no absolute evidence to recommend weight adaptation of the LMWH dose during pregnancy. However, renal glomerular filtration rate and body weight increase throughout pregnancy, potentially affecting the pharmacokinetics of LMWH. In addition, from a clinical point of view, previous studies have shown that during pregnancy and the postpartum period, body mass index is a strong risk factor for VTE5.Larsen T.B. Sørensen H.T. Gislum M. Johnsen S.P. Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population‐based nested case‐control study.Thromb Res. 2007; 120: 505-9Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 6.Knight M. UKOSSAntenatal pulmonary embolism: risk factors, management and outcomes.BJOG. 2008; 115: 453-61Crossref PubMed Scopus (189) Google Scholar and the risk is amplified in those who have a high body mass index and were immobilized.7.Jacobsen A.F. Skjeldestad F.E. Sandset P.M. Ante‐ and postnatal risk factors of venous thrombosis: a hospital‐based case‐control study.J Thromb Haemost. 2008; 6: 905-12Crossref PubMed Scopus (285) Google Scholar In a systematic review of thromboprophylaxis after bariatric surgery, weight‐adjusted thromboprophylaxis showed a trend toward a lower rate of inpatient VTE complications without an increased rate of major bleeding.8.Ikesaka R. Delluc A. Le Gal G. Carrier M. Efficacy and safety of weight‐adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: a systematic review and meta‐analysis.Thromb Research. 2014; 133: 682-7Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar From a biological point of view, it has recently been shown that postcesarean obese patients have an increased procoagulant potential as determined by thrombin generation and anti‐Xa testing, which was diminished only in those receiving higher doses of LMWH.9.Rottenstreich A. Levin G. Elchalal U. Kleinstern G. Spectre G. Ziv E. et al.The effect on thrombin generation and anti‐Xa levels of thromboprophylaxis dose adjustment in post‐cesarean obese patients – a prospective cohort study.Thromb Res. 2018; 170: 69-74Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar In another study performed in 91 hospitalized obese patients (body mass index ≥ 30 kg/m2), thromboprophylaxis with enoxaparin 60 mg provides higher control of anti‐Xa activity, without more bleeding complications than the standard enoxaparin regimen. In particular, the proportions of anti‐Xa activity measurement below the normal range (target range: 0.2 and 0.5 U/mL) were 64% and 36% in the group of 40 mg/day of enoxaparin and in the group of 60 mg/day of enoxaparin (P < 10−3), respectively.10.Miranda S. Le Cam‐Duchez V. Benichou J. Donnadieu N. Barbay V. Le Besnerais M. et al.Adjusted value of thromboprophylaxis in hospitalized obese patients: a comparative study of two regimens of enoxaparin: the ITOHENOX study.Thromb Res. 2017; 155: 1-5Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Finally, in pregnant women, the American College of Chest Physicians guidelines stated that a modification of LMWH dose may be required at extremes of body weight11.Bates S.M. Greer I.A. Middeldorp S. Veenstra D.L. Prabulos A.M. Vandvik P.O. VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines.Chest. 2012; 141: S691-736Abstract Full Text Full Text PDF Scopus (1057) Google Scholar and this body weight adjustment of prophylactic doses of LMWH was also supported by the Royal College of Obstetricians and Gynaecologists.12.Royal College of Obstetricians and Gynaecologists. Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium. Green‐top Guideline No.37aGoogle Scholar The authors’ assertion that 16 different LMWH doses will be compared in the HighLow study is not accurate. The Highlow study simply compares two LMWH dose regimens: standard dose and intermediate dose, taking weight in early pregnancy into account in both study arms. Finally, while the authors should be congratulated for identifying women managed over the past 15 years, in order to provide as many data as was possible to address this very important issue for women's health, it is of course important to recognize that the long inclusion period carries the potential of bias due to incomplete follow‐up and data capturing. In conclusion, we believe that case series and cohort studies are a valuable source of data and further highlight the urgent need for experts in women's health throughout the world to work together to provide prospectively collected data. Prioritizing large multicenter collaborative trials such as HighLow and challenging the very real regulatory barriers that stand in the way of conducting such high‐quality research are among the most important ways in which we can advocate for women's health internationally. As was recently highlighted by the American Society of Hematology,13.Bates S.M. Rajasekhar A. Middeldorp S. McLintock C. Rodger M.A. James A.H. et al.American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.Blood Adv. 2018; 2: 3317-59Crossref PubMed Scopus (221) Google Scholar the data published by Cox et al. confirm that there is an urgent need to evaluate the efficacy and safety of standard dose versus intermediate dose of LMWH in pregnant women with a high risk of VTE recurrence. All authors are investigators in the HighLow study. All authors drafted and revised the manuscript and approved the final version.