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Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the Highlow study, a randomised trial of two doses
Abstract
Background:
Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study.
Methods:
The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events.
Conclusion:
The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VTE.
... Women with a personal VTE history have a higher recurrent VTE risk during pregnancy [53,54], with highest risks reported for women with an unprovoked or a hormone-provoked VTE [54][55][56][57][58]. It appears that this risk is reduced with LMWH [59]. ...
... Women with a personal VTE history have a higher recurrent VTE risk during pregnancy [53,54], with highest risks reported for women with an unprovoked or a hormone-provoked VTE [54][55][56][57][58]. It appears that this risk is reduced with LMWH [59]. ...
... Previous guidelines have suggested various approaches to VTE prevention in these women, with strategies including a low prophylactic or an intermediate (half-therapeutic) dose [60,61]. The optimal LMWH dose for women with prior VTE in the context of no or a non-major transient risk factor (including hormones) is currently being investigated in the ongoing Highlow RCT (NCT 01828697), a multicentre, multinational RCT evaluating efficacy and safety of a fixed low dose of LMWH compared with an intermediate weight-adjusted dose in the prevention of VTE recurrence during pregnancy [54]. ...
... For women with a low risk of recurrence of venous thromboembolism, it has been recommended to start only thromboprophylaxis with LMWH during puerperium. 44 The optimal dose of LMWH in pregnant women with moderate to high risk of recurrence of venous thromboembolism is the subject of debate as there are no randomized controlled trials or clear evidence-based guidelines available. The current practice is based on consensus guidelines and the results of a few retrospective studies. ...
... Therapeutic doses of LMWH are not widely accepted because of the possible bleeding risk during delivery. 44 Until the results of the Highlow study -an international open-label randomized trial that will explore the optimal dose of LMWH thromboprophylaxis -are published, prophylactic or intermediate doses of LMWH remain the two options as thromboprophylaxis for women with moderate to high risk for recurrence of venous thromboembolism. 44 The question remains whether women with thrombophilia benefit from intermediate or even therapeutic doses of thromboprophylaxis with LMWH in order to reduce the obstetric complications. ...
... 44 Until the results of the Highlow study -an international open-label randomized trial that will explore the optimal dose of LMWH thromboprophylaxis -are published, prophylactic or intermediate doses of LMWH remain the two options as thromboprophylaxis for women with moderate to high risk for recurrence of venous thromboembolism. 44 The question remains whether women with thrombophilia benefit from intermediate or even therapeutic doses of thromboprophylaxis with LMWH in order to reduce the obstetric complications. ...
Sex-specific risk factors for cerebral venous thrombosis (CVT) in women include oral contraceptives, pregnancy, puerperium, and hormone replacement therapy. The acute treatment of CVT is anticoagulation using therapeutic doses of low molecular weight heparin, which is also the preferred treatment in the post-acute phase in pregnancy and during breastfeeding. In patients with imminent brain herniation decompressive surgery is probably life-saving. A medical history of CVT alone is not a contraindication for future pregnancies. The optimal dosage of low molecular weight heparin as thrombosis prophylaxis during future pregnancies after a history of venous thrombosis including CVT is the topic of an ongoing trial.
... Women with a personal VTE history have a higher risk of recurrent VTE during pregnancy. 18,29 The absolute reported recurrence risk varies widely 30-33 but appears highest for women with an unprovoked or a hormone-provoked VTE, in which the reported absolute risk in the absence of thromboprophylaxis exceeded ~2% to 6% in some studies. [29][30][31][32]34 Two retrospective studies reported a higher VTE recurrence rate (although not reaching statistical significance) during pregnancy in women with a history of a VTE event provoked by oral hormonal contraceptive use or pregnancy than in women with an unprovoked or nonhormonal transient risk factor-provoked event. ...
... 18,29 The absolute reported recurrence risk varies widely 30-33 but appears highest for women with an unprovoked or a hormone-provoked VTE, in which the reported absolute risk in the absence of thromboprophylaxis exceeded ~2% to 6% in some studies. [29][30][31][32]34 Two retrospective studies reported a higher VTE recurrence rate (although not reaching statistical significance) during pregnancy in women with a history of a VTE event provoked by oral hormonal contraceptive use or pregnancy than in women with an unprovoked or nonhormonal transient risk factor-provoked event. 31,32 Moreover, a large retrospective cohort study reported a higher risk of recurrence during pregnancy in women with pregnancy-associated VTE than women with unprovoked VTE (4.5% vs. ...
... Women with a personal VTE history have a higher risk of recurrent VTE during pregnancy. 18,29 The absolute reported recurrence risk varies widely 30-33 but appears highest for women with an unprovoked or a hormone-provoked VTE, in which the reported absolute risk in the absence of thromboprophylaxis has exceeded ~2% to 6% in some studies. [29][30][31][32]34 It appears that this risk may be reduced with LMWH: Pooled proportions of recurrent major VTE reported in studies evaluating LMWH during the antepartum and postpartum periods in women with prior VTE (including provoked [nonestrogen], unprovoked, or estrogen-associated VTE as a single group) reported antepartum recurrence risks of 0.9% (95% CI, 0.5%-1.8%) ...
A State of the Art lecture, “VTE Risk Assessment in Pregnancy,” was presented at the ISTH congress in Melbourne, Australia, in 2019. Venous thromboembolism (VTE) remains a leading cause of death in pregnancy and in the postpartum period. Moreover, VTE can result in lifelong disability. The elevated baseline pregnancy‐associated VTE risk is further increased by additional maternal, pregnancy, and delivery characteristics, highlighting the importance of VTE risk assessment in early pregnancy, at delivery, and if risk factors change. This review will provide an overview of the impact and epidemiology of VTE in pregnancy (including reported risk factors for pregnancy‐associated VTE), will address VTE risk‐reduction strategies (including ongoing studies), and will provide a summary of critical knowledge gaps. Finally, throughout this review, relevant new data presented during the 2019 ISTH annual congress in Melbourne will be summarized.
... gov 01828697). 3 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. ...
... 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 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. ...
... Prophylaxis has been successfully used to treat patients with hemophilia, 2 and although it is logical to assume that this success could translate to severe VWD, there is limited documented experience on the long-term benefit of prophylaxis in these patients. 3 Data from the prophylaxis network showed that patients with type 1 and type 2 VWD were rarely treated prophylactically, and although patients with type 3 VWD were more likely to be treated prophylactically, it was only used in 28.7% and 12.2% of patients in Europe and the United States, respectively. 4 We are in a new era of treatment for VWD and there is a need to understand how rVWF should be used in the perioperative period. ...
... VTE is substantially more likely to occur in pregnant people who have a personal history of VTE [18,26] than in those who do not have a personal history of VTE. In the absence of thromboprophylaxis, the reported absolute risk is estimated to be 2-6% in the antepartum period [27][28][29] and 6-8% in the postpartum weeks [26,28,29] with the risk appearing to be higher in those with an unprovoked or hormone-related VTE in these circumstances. ...
... VTE is substantially more likely to occur in pregnant people who have a personal history of VTE [18,26] than in those who do not have a personal history of VTE. In the absence of thromboprophylaxis, the reported absolute risk is estimated to be 2-6% in the antepartum period [27][28][29] and 6-8% in the postpartum weeks [26,28,29] with the risk appearing to be higher in those with an unprovoked or hormone-related VTE in these circumstances. People who had an unprovoked or non-hormonal transient risk factor-provoked VTE event in the presence of oral hormonal contraceptive use or pregnancy had a higher VTE recurrence rate during pregnancy [28,29]. ...
... Anticoagulation therapy is not devoid of adverse effects, and according to reports, heparin and low molecular weight heparin (LMWH) carry a 2% risk of maternal bleeding problems. 8 Thromboprophylaxis to prevent VTE during pregnancy is challenging ,because it requires long-term parenteral administration of LMWH or unfractionated heparin(UFH). 9 Both medications have risks of bleeding, osteoporosis, and heparin-induced thrombocytopenia (HIT); however, these side effects, particularly HIT, are extremely rare with LMWH. ...
... Given that the risk of DVT is distributed rather evenly across all trimesters, it is recommended that antenatal prophylaxis be started as soon as possible in the first trimester in women with high risk. 8,11,12 According to the currently available information, recurrent DVT is reported in 2-10% of pregnant women with a history of VTE. However, the efficacy of thromboprophylaxis in expecting mothers with past DVT has not been studied in significant clinical trials. ...
In pregnancy, venous thromboembolism (VTE) remains a leading cause of direct maternal mortality. It is approximatelyfive times more common in pregnant women, with an incidence of 0.5-2 in 1000. The highest risk of deep venous thrombosis(DVT) leading to pulmonary embolism (PE) is during the postnatal period, especially after a cesarean section. A clinician who doesnot treat pregnant women regularly may not routinely identify pregnancy-specific risk factors for VTE. In patients with DVT,treatment with anticoagulation is associated with a high risk of bleeding during the immediate postpartum state, and patients dowell with monitored anticoagulation and proper supportive treatment, as described in this case report. We are reporting a caseof a 20-year-old primigravida who presented with labor pains at 39 (+6) weeks of gestation at Sree Balaji Medical College andHospital, Chrompet, Chennai. The patient had no comorbidities and did not report any past or family history of VTE. An emergencycesarean section was performed due to fetal distress, and on the first postoperative day, she developed swelling pain andtenderness in the left lower limb. Color Doppler ultrasound showed left anterior tibial vein thrombosis, following whichanticoagulant therapy was started with low molecular weight heparin. The patient was closely monitored for signs of bleeding orPE and was eventually discharged on oral anticoagulation. In conclusion, all women should be assessed for the risk factors of DVTduring the antenatal period, and early ambulation in the postoperative period is crucial to prevent such deadly complications.
... Fetal loss is a major health problem that has unfavorable pregnancy consequences. Treatment during subsequent pregnancies with unfractionated heparin improves pregnancy outcomes [17]. The aim of the current study was to estimate the effect of enoxaparin on fetal-loss women with BV and CMV infection who had a normal or high fibrinogen level and to confirm that enoxaparin was an effective anticoagulant and improved pregnancy outcome. ...
Fetal loss is one of the most important problems of the woman’s health, which significantly affects her psychological status. It has different causes, so there is no unique method for its diagnosis and treatment.The objective: to evaluate the enoxaparin effect in pregnancy with recurrent fetal loss related to genital infections.Materials and methods: a cross-sectional study 205 included pregnant women with fetal loss in the history who were managed at Hospital from January 1st, 2022, to October31st, 2023. Serodiagnosis of IgG and IgM against cytomegalovirus (CMV) was performed by using ELISA. Bacterial vaginosis (BV) was diagnosed by microscopic examination of vaginal discharges. Also, fibrinogen level was determined. Enoxaparin (low molecular weight heparin) was prescribed to all infected patients.Results. It was found that the largest proportion of the study population was women aged 21–25 years, 70.65% of patients lived in rural areas. Among 205 women with a history of fetal loss, 81% were diagnosed with BV and CMV infection, and 19% had no infectious diseases. 95.8% of patients with CMV infection and BV responded positively to enoxaparin therapy, which was manifested by normalization of fibrinogen level and a favorable course of pregnancy. At the same time, 4.19% of women did not have an adequate response to treatment, which was associated with lower fibrinogen level.Conclusions. The presence of an infectious process leads to an increased level of inflammatory cytokines in the placenta, which can lead to the formation of blood clots, atherosclerotic changes with or without increased blood clotting factors, in particular fibrinogen, which reduce blood transport to the fetus. This, in turn, can lead to miscarriage, preeclampsia and premature birth. Enoxaparin is a safe and effective medication for preventing fetal loss in pregnant women with genital infectious diseases. Furthermore, it helps to reduce the frequency of fetal loss. However, studies on the effectiveness and safety of enoxaparin for the prevention of thromboembolic complications and thrombosis are currently insufficient, which requires further scientific observations.
... It looks at the true risk of recurrence of VTE, the optimal dose, and the safety of LMWH for prophylaxis. The Netherlands, Ireland, Belgium, France, and Norway are participating, with an expected sample size approaching 1,000 women [25,26] . Many studies tried to look into the relationship between congenital thrombophilias and VTE. ...
... This compromises external validity and broader applicability. In addition, considering the low incidence of VTE, a larger sample size is essential to establish statistically significant differences in roles of enoxaparin to prevent VTE after childbirth [2]. ...
... За последние 4 года, которые прошли с момента публикации вышеуказанных документов, появилась необходимость в обновлении клинических данных, объединяющих ранее накопленный опыт и последние рекомендации по отдельным нозологиям за этот период. Важным моментом явилась ожидаемая публикация результатов международного многоцентрового клинического исследования Highlow в журнале The Lancet [3,4], в котором сравнивались эффективность и безопасность использования двух режимов дозирования низкомолекулярных гепаринов (НМГ) для профилактики венозных тромбоэмболических осложнений (ВТЭО) у беременных с высоким риском их развития. В исследовании принимали участие 70 центров из 9 стран мира, включая Российскую Федерацию. ...
On December 18, 2022, an interdisciplinary Expert Council was held in St. Petersburg, dedicated to the debatable issues of anticoagulation in the prevention of venous thromboembolism in pregnant women with cardiovascular and systemic diseases, at which a number of proposals and guidelines were adopted, and the results of the Highlow study were considered. Leading experts from the Russian Society of Cardiology, the Russian Society of Obstetricians and Gynecologists, the National Association of Specialists in Thrombosis, Clinical Hemostaseology and Hemorheology took part in the Expert Council.
... Taking into consideration the family history of VTE and patient's obstetric history, her calculated VTE recurrence is well above 1% and potentially exceeding 3%, 26 which is an acceptable cut-off for employing antenatal thromboprophylaxis. [27][28][29][30][31] According to the RAM suggested by Sarig et al., 11 patient' risk group may be categorized as intermediate and therefore, post-partum LMWH prophylaxis for 6 weeks is recommended, while antenatal LMWH is suggested. 12 Given the low levels of Protein S outside pregnancy, which are expected to further reduce during pregnancy, as well as the family history of VTE and personal history of recurrent miscarriages strengthen the decision to give thromboprophylaxis in this case. ...
The management of pregnant women with thrombophilia and a history of gestational vascular complications remains debatable. Treatment of the latter is often based on clinical outcome rather than disease mechanism. While the use of venous thromboembolism prophylaxis in pregnancy is recommended for those at increased risk, the ability of anticoagulant and/or antiplatelet agents to lower the risk of placenta‐mediated complications in this clinical setting remains controversial. The available guidelines are inconsistent in some situations, which reflects the limited evidence base. This review critically discusses risk assessment models (RAMs) and management strategies of women with thrombophilia and pregnancy complications, using clinical vignettes. RAMs, taking into account obstetric and thrombotic history as well as thrombophilia status, could drive a precision medicine approach, based on disease mechanism, and guide individual therapeutic interventions in high‐risk clinical settings.
... The trial rationale and design have been reported previously. 21 Pregnant women aged 18 years or older with a history of ...
Background
Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain.
Methods
In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete.
Findings
Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32–1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65–2·09]).
Interpretation
In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism.
Funding
French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer.
... An unresolved issue is the prophylactic dose of LMWH in pregnant women who have previously had a VTE. The trial HIGHLOW [21] is underway: the goal of the study is to provide data on the incidence of post-partum haemorrhage, risk of VTE, delivery outcomes and the degree of healthcare services utilisation among pregnant womencomparing the groups with LMWH prophylactic versus therapeutic dose. ...
This article aims to summarise the latest research presented at the virtual 2021 European Respiratory Society (ERS) International Congress in the field of pulmonary vascular disease. In light of the current guidelines and proceedings, knowledge gaps are addressed and the newest findings of the various forms of pulmonary hypertension as well as key points on pulmonary embolism are discussed.
Despite the comprehensive coverage of the guidelines for pulmonary embolism at previous conferences, discussions about controversies in the diagnosis and treatment of this condition in specific cases were debated and are addressed in the first section of this article.
We then report on an interesting pro–con debate about the current classification of pulmonary hypertension.
We further report on presentations on Group 3 pulmonary hypertension, with research exploring pathogenesis, phenotyping, diagnosis and treatment; important contributions on the diagnosis of post-capillary pulmonary hypertension are also included.
Finally, we summarise the latest evidence presented on pulmonary vascular disease and COVID-19 and a statement on the new imaging guidelines for pulmonary vascular disease from the Fleischner Society.
... Median age at subsequent pregnancy was 30 (27-34); 35 women (18.5%) were 35 years old or more at delivery. Median prepregnancy BMI was 24 (21)(22)(23)(24)(25)(26)(27)(28)(29); 41 women (21.7%) were obese at pregnancy start. One hundred and eleven women (58.7%) were nulliparous. ...
Background
Women with a previous venous thromboembolism (VTE) are at risk of recurrence during pregnancy.
Objectives
We aimed to assess the incidence rate of recurrent VTE during pregnancy, according to the period of pregnancy, and the clinical parameters associated with recurrence, in a prospective cohort of women of childbearing age after a first VTE.
Patients/Methods
189 women aged 15-49 years with a first documented VTE were followed up until a subsequent pregnancy of at least 20 weeks of gestation between 2000 and 2020. VTE recurrences during pregnancy were recorded, as well as potential clinical risk factors for recurrence.
Results
Recurrent VTE occurred in six women during antepartum: five during first trimester (incidence rate 106.4 per 1000 women-years (95% confidence interval (CI) 46.3-226.0); none during second trimester; and one during third trimester (incidence rate 27.0 per 1000 women-years (95%CI 4.8-138.2)). During postpartum, recurrences occurred in 11 women (incidence rate 212.8 per 1000 women-years (95%CI 119.9-349.1). These 17 recurrent VTE presented as PE +/- DVT in five patients and isolated DVT in 12. Failure of thromboprophylaxis occurred in two cases (33.3%) during antepartum and in 10 cases (90.9%) during postpartum. In multivariable analysis, only obesity (defined on pre-pregnancy body mass index) was associated with recurrent VTE (OR 3.34 (95%CI 1.11-10.05, p=0.03).
Conclusions
This study confirms a high risk of recurrent VTE in postpartum, despite thromboprophylaxis, in women with a previous VTE. Only obesity was associated with VTE recurrence during pregnancy, suggesting that low-dose anticoagulation might not be appropriate in obese pregnant women.
... Diversity of practice is also apparent regarding use of prophylactic versus intermediate LMWH dosing. The results of an ongoing randomized controlled trial (High-Low study NCT01828697) 26 of prophylactic or intermediate dose LMWH should help answer this question. To establish optimal care for women with thrombophilia during pregnancy, we encourage registries of current practices and patient outcomes as well as prospective clinical trials of monitoring of anticoagulation, and the role of mechanical prophylaxis. ...
Background:
During pregnancy and in the postpartum period women are at increased risk of venous thromboembolism (VTE) owing to hypercoagulability and mechanical issues, as well as nonpregnancy conditions including inherited and acquired thrombophilia. Although guidelines exist for the use of thromboprophylaxis in this setting, there are differences in the specifics of the recommendations among expert societies. We assessed the current practice patterns of North American providers in the prevention of pregnancy-associated VTE in women with thrombophilia.
Methods:
A survey was created and distributed with case studies and questions addressing VTE prevention during the antepartum and postpartum periods.
Results:
Surveys were completed by 28% of adult providers queried, with broad geographic representation. There was consistent use of a prophylactic dose of low-molecular weight heparin (LMWH) ante- and postpartum for individuals with low-risk thrombophilia and past estrogen-provoked VTE but a lack of a consensus of anticoagulant (AC) use and dose in individuals with higher risk thrombophilia. There was variability in the dose selection and monitoring of AC when using induction versus spontaneous labor, with 47% of providers switching from LMWH to unfractionated heparin for those not having a scheduled delivery, and there were differences in the duration of postpartum prophylaxis based upon delivery mode.
Conclusion:
In this survey of North American experienced specialists' responses to a variety of commonly encountered scenarios of thrombophilia and pregnancy and the management of AC were not always consistent with published guidelines.
... As of today only two very small randomized controlled trials (n = 16 and n = 40), with limitations in their methodological quality, were published. 72 74 As of today, more than 965 patients have been enrolled and results are expected in 2022. ...
Approximately 1–2 per 1000 pregnancies are complicated by venous thromboembolism (VTE). VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE) and the diagnostic management of pregnancy-related VTE is challenging. Current guidelines vary greatly in their approach to diagnosing PE in pregnancy as they base their recommendations on scarce and weak evidence. The pregnancy-adapted YEARS diagnostic algorithm is well tolerated and is the most efficient diagnostic algorithm for pregnant women with suspected PE, with 39% of women not requiring computed tomographic pulmonary angiography. Low-molecular-weight heparin is the first-choice anticoagulant treatment in pregnancy and should be continued until 6 weeks postpartum and for a minimum of 3 months. Direct oral anticoagulants should be avoided in women who want to breastfeed. Management of delivery needs a multidisciplinary approach in order to decide on an optimal delivery plan. Neuraxial analgesia can be given in most patients, provided time windows since last low-molecular-weight heparin dose are respected. Women with a history of VTE are at risk of recurrence during pregnancy and in the postpartum period. Therefore, in most women with a history of VTE, thromboprophylaxis in subsequent pregnancies is indicated.
The reviews of this paper are available via the supplemental material section.
... The ideal dosage of LMWHs for thromboprophylaxis during pregnancy is unknown and will possibly be clarified after the publication of the results of the Highlow Trial (NCT 01828697; www.highlowstudy.org), a randomized and multicenter study being done that intends to comparatively assess the safety and effectiveness of prophylactic versus intermediate dosages of LMWHs. 33 It should be observed that robust data is not available to support the use of a specific regimen by pregnant or puerperal obese women, therefore, in practice, the recommendations of the RCOG 13 are followed. A single randomized clinical trial was published with data on thromboprophylaxis in the population of obese pregnant women undergoing cesarean delivery, showing that when compared to the fixed daily dose (40mg/day), the weight-based enoxaparin dose administered twice daily (0.5mg/ kg 12/12h) more effectively achieved prophylactic levels of anti-Xa activity without reaching therapeutic levels. ...
Objective To identify current strategies and recommendations for venous thromboembolism prophylaxis associated with the pregnancy-puerperal cycle, a condition of high morbidity and mortality among women.
Methods The literature search was performed between May and October 2019, using the PubMed database, including papers published in Portuguese, English and Spanish. The terms thromboembolism (Mesh) AND pregnancy (Mesh) OR postpartum (Mesh) were used as descriptors, including randomized controlled trials, meta-analyses, systematic reviews and guidelines published from 2009 to 2019, presenting strategies for prevention of thromboembolism during pregnancy and the postpartum.
Results Eight articles met the inclusion criteria. Many studies evaluated were excluded because they did not address prevention strategies. We compiled the recommendations from the American Society of Hematologists, the American College of Obstetricians and Gynecologists, the Royal College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynaecologists of Canada, the American College of Chest Physicians and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists.
Conclusion: There are some gaps in the research, and clinical studies with appropriate methodology are needed to support decisions made regarding the risk of thromboembolism in the perigestational period. Thus, the attention of the professionals involved in the care of pregnant and postpartum women is crucial, as it is a condition associated with high morbidity and mortality.
... Physiological changes (increased volume of distribution and renal clearance) during pregnancy alter the pharmacokinetics of drugs, [16] but until the study [17] evaluating required dosages for VTE prophylaxis in pregnancy is completed, the 2018 ASH guidelines suggest against the use of intermediate dosages in antepartum prophylaxis compared with standard dosages, and for the use of standard-or intermediatedose low-molecular-weight heparin (LMWH) for postpartum VTE prophylaxis. [13] The SASTH guideline [12] also suggests standard prophylactic dosages, but in view of the physiological changes in pregnancy, recommends that regular anti-factor X activity (FXa) measurement be done, especially in women at extremes of weight, with renal disease and severe pre-eclampsia. ...
Pregnancy-related venous thromboembolic events are important preventable causes of morbidity and mortality in South Africa. All pregnant patients should be evaluated for thrombotic risk at different stages of their pregnancy and appropriate preventive steps taken. Maternal and fetal wellbeing must be kept in mind, as well as physiological changes leading to altered drug pharmacokinetics. Managing the patient with thrombotic risk in pregnancy, diagnosing venous thromboembolism (VTE) during pregnancy and treatment of venous thromboembolic events should be managed by a team. Excellent recent reviews on this subject are available, including risk factor stratification in anticoagulant therapy; managing the patient at time of labour; diagnosing VTE; and managing neuraxial anaesthesia in the pregnant patient on anticoagulant therapy.
... Some of the experts have questioned the ideal dose of LMWH for thromboprophylaxis and treatment in pregnancy. The ongoing Highlow study, an RCT of intermediate-dose LMWH adjusted to actual body weight versus fixed low-dose nadroparin, may inform this clinical question for thromboprophylaxis [37]. ...
Background:
Venous thromboembolism (VTE) accounts for an estimated 900,000 cases per year in the US alone and constitutes a considerable burden on healthcare systems across the globe.
Objective:
To understand why the burden is so high, qualitative and quantitative research was carried out to gain insights from experts, guidelines and published studies on the unmet clinical needs and therapeutic strategies in VTE prevention and treatment in three populations identified as being at increased risk of VTE and in whom VTE prevention and treatment were regarded as suboptimal: pregnant women, the elderly and obese patients.
Methodology:
A gap analysis methodology was created to highlight unmet needs in VTE management and to discover the patient populations considered most at risk. A questionnaire was devised to guide qualitative interviews with 44 thrombosis and haemostasis experts, and a review of the literature on VTE in the specific patient groups from 2015 to 2017 was completed. This was followed by a Think Tank meeting where the results from the research were discussed.
Results:
This review highlights the insights gained and examines in detail the unmet needs with regard to VTE risk-assessment tools, biomarkers, patient stratification methods, and anticoagulant and dosing regimens in pregnant women, the elderly and obese patients.
Conclusions:
Specifically, in pregnant women at high risk of VTE, low-molecular-weight heparin (LMWH) is the therapy of choice, but it remains unclear how to use anticoagulants when VTE risk is intermediate. In elderly patients, evaluation of the benefit of VTE prophylaxis against the bleeding risk is particularly important, and a head-to-head comparison of efficacy and safety of LMWH versus direct oral anticoagulants is needed. Finally, in obese patients, lack of guidance on anticoagulant dose adjustment to body weight has emerged as a major obstacle in effective prophylaxis and treatment of VTE.
... compared with pregnant women without previous VTE. 76 The risk increase depends on the circumstances under which the first VTE occurred. These findings should be considered when decisions are made about VTE prophylaxis in women with a history of pregnancy-related VTE. ...
Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality during pregnancy and the postpartum period. Due to a lack of adequate study data, therapeutic strategies for pregnancy-related VTE are deduced from observational studies and extrapolated from recommendations for nonpregnant patients. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low-molecular-weight heparins (LMWHs) are the anticoagulant treatment of choice in cases of VTE during pregnancy. Once- and twice-daily dosing regimens are suitable. There is no evidence that measurement of factor Xa activities and consecutive LMWH dose adjustments improve clinical outcomes. There is no support for the routine use of vitamin K antagonists, direct oral thrombin or factor Xa inhibitors, fondaparinux, or danaparoid in uncomplicated pregnancy-related VTE. Management of delivery deserves special attention, and treatment strategies depend on the time interval between the diagnosis of acute VTE and the expected delivery date. In lactating women, an overlapping switch from LMWH to warfarin is possible. Anticoagulation should be continued for at least 6 weeks postpartum or for a minimum period of 3 months.
Georg Thieme Verlag KG Stuttgart · New York.
... 62 In a retrospective study of 25 pregnant women on intermediate-dose UFH, the mean UFH dose required to achieve a target anti-factor Xa level of 0.1 to 0.3 U/mL was 236.9 U/kg/day. 63 64 Delivery via cesarean section increases the risk for VTE by 3-fold compared with vaginal delivery. Given this risk and based on data from perioperative studies, women who deliver by cesarean section require mechanical prophylaxis with pneumatic compression devices. ...
Venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism, is one of the leading causes of non-obstetric maternal death in the United States. Physiologic and anatomic changes associated with pregnancy set the stage for a hypercoagulable state. In addition, other risk factors-including those associated with certain fetal characteristics such as low birth weight or stillbirth-have been correlated with an increased risk for VTE. Women with a personal or strong family history of VTE, as well as documented thrombophilia, represent a unique group in whom antepartum and/or postpartum prophylaxis can be considered. The choice of anticoagulant therapy for either treatment or prophylaxis in most cases is heparin, most commonly low-molecular-weight heparin. This is owing to the fact that vitamin K antagonists and the direct oral anticoagulants are contraindicated in pregnancy because of potential teratogenicity. With careful management and vigilant monitoring, appropriate anticoagulation can be used safely and effectively to improve patient outcomes.
... For women with an intermediate to high risk of recurrent VTE (i.e., multiple unprovoked VTEs, pregnancy-or estrogenrelated VTE), the guidelines recommend low-or intermediate-dose LMWH during the antepartum period and the standard 6 weeks of postpartum prophylaxis detailed above (Bates et al. 2012). The optimal dosing of LMWH for thromboprophylaxis in pregnant women with a moderate to high risk of recurrent VTE is unclear, but a randomized controlled trial is currently underway to answer this question (Bleker et al. 2016). ...
In developing countries, the leading cause of maternal death is postpartum hemorrhage, and in industrialized nations, the leading cause of maternal death is venous thromboembolism. Furthermore, there are several other hematologic maladies that may present additional challenges in maintaining the health and well-being of the mother and child during pregnancy, delivery, and the postpartum period. In this chapter, we discuss the hematologic disease states that most commonly complicate pregnancy and offer insight into the diagnosis and management of these conditions.
... We are very encouraged that our study has provoked such a thoughtful and considered response; its authors are to be congratulated that they are carrying out the first randomized clinical exploring optimal lowmolecular-weight heparin (LMWH) dosing for prevention of pregnancy-associated venous thromboembolism (VTE) in women considered to have a personal history of high-risk VTE. 1 As they state, women with personal history of VTE been excluded from studies of LMWH dosing, and we agree that there is a knowledge gap relating to the efficacy of different doses of LMWH in this clinical setting. However, arguably there is a more fundamental knowledge gap that should be addressed first. ...
... corded and validated. The methodology of only one study (Highlow, NCT01828697) has been reported in the literature, including the planned use of an independent adjudication committee to validate both thromboembolic and bleeding events.28 4 | D ISCUSS I ON AND PROP OSAL SFirst of all, it is important to remember that during pregnancy, hypervolemia and hemodilution induce physiological fluctuations in hemoglobin concentration and the subsequent resolution of hemodilution at delivery and postpartum induces a rise in hemoglobin. The most widely cited definition of anemia is that of the World Health Organization (WHO), which defines anemia as a hemoglobin level <110 g/L for pregnant women and severe anemia during pregnancy is defined as hemoglobin <70 g/L. ...
The evaluation of antithrombotic drugs relies on the assessment of their benefit/risk ratio in various distinct settings. In venous thromboembolism diseases (VTE), the endpoint for efficacy is usually the rate of objectively proven recurrent venous thromboembolism, while the endpoint for safety is usually the rate of bleeding, both including fatal events. The evaluation of bleeding severity is crucial. The ISTH has proposed international definitions for major bleeding, clinically relevant non‐major bleeding, and minor bleeding. These definitions are used in most of the modern trials evaluating antithrombotic drugs for the prevention and/or treatment of VTE, but may not be well suited to specific settings like pregnancy and post‐partum that carry particular bleeding risks. The World Health Organization (WHO) has proposed an international definition of post‐partum hemorrhage (PPH), but this definition may not be suitable for the evaluation of antithrombotic therapies. Based on our experience in adjudication committees of trials evaluating antithrombotic therapies during the pregnancy and postpartum, we provide a comprehensive and systematic review of available definitions of bleeding events, and propose a dedicated classification of bleeding events for future trials evaluating antithrombotic drugs during pregnancy and postpartum. This article is protected by copyright. All rights reserved.
... 8 This prompted the authors to develop a randomized clinical study (the Highlow study) comparing standard-dose with intermediate-dose LMWH for prevention of PA-VTE. 9 Our clinical experience in National Women's Hospital, Auckland, New Zealand, had not indicated a high failure rate using our approach of giving the majority of women standard thromboprophylactic doses of enoxaparin (40 mg once daily). Furthermore, we were concerned that routine implementation of higher doses of LMWH may increase the risk of bleeding complications, limit access to neuraxial analgesia/anesthesia, and increase pharmaceutical costs. ...
Background
Low‐molecular weight heparin (LMWH) is used to prevent pregnancy‐associated venous thromboembolism (PA‐VTE) but there are limited data to inform which women require thromboprophylaxis in pregnancy and debate about which LMWH dose is effective and safe.
Aims
To evaluate the efficacy and rate of complications using enoxaparin for thromboprophylaxis in a cohort of women at risk of PA‐VTE managed between 1999 and 2014 at National Women's Hospital, a tertiary obstetric referral centre in Auckland, New Zealand.
Methods
A retrospective, observational study of women who received thromboprophylaxis with enoxaparin for prevention of PA‐VTE while under the care of the obstetric or maternal fetal medicine team.
Results
172 pregnancies in 123 women were identified. A single daily dose of 40mg enoxaparin was used in 94.8% of pregnancies. Two breakthrough PA‐VTE occurred [1.2% (95% CI 0.32‐4.14)]. Postpartum haemorrhage (PPH) > 500ml was reported in 36.6% of births and PPH > 1000ml in 9.3% births. Only four women were transfused. Neuraxial analgesia/anaesthesia was used in 52.4% births including in 39.6% of vaginal births.
Conclusion
Use of standard doses enoxaparin thromboprophylaxis in our cohort was effective at preventing PA‐VTE. Neuraxial analgesia /anaesthesia was used frequently during labour and birth and using higher doses of enoxaparin may limit access to this. Postpartum hemorrhage was common and higher doses of thromboprophylaxis may increase obstetric bleeding complications. These data do not suggest an urgent need to consider higher doses of enoxaparin for thromboprophylaxis in this clinical setting.
This article is protected by copyright. All rights reserved.
... Это категория женщин наиболее подвержена риску развития тромбоэмболии легочной артерии (ТЭЛА), что чаще требует назначения более высоких доз НМГ. S. Bleker и соавт. [6] провели первое крупное рандомизированное контролируемое исследование у пациенток во время беременности, которое предоставило доказательства оптимальной дозы тромбопрофилактики НМГ при рецидивирующих ВТЭО у беременных с отягощенным тромботическим анамнезом. ...
Venous thromboembolism (VTE) remains the leading cause of maternal mortality in pregnancy and the postpartum period. In addition to the higher pregnancy-associated baseline VTE risk, there are several well-established risk factors that can further increase the risk of VTE. At present, a thorough interrogation of these risk factors remains our only tool for estimating which pregnant people may be at an increased risk of VTE, and thus potentially benefit from thromboprophylaxis. However, an important knowledge gap still exists surrounding the duration of increased risk and the interaction of risk factors with each other. Furthermore, up to now, once significant risk has been established, prevention strategies have been largely based on expert opinion rather than high-quality data. Recent trials have successfully bridged a proportion of this knowledge gap; however, the challenge of conducting high-quality clinical trials with pregnant people remains. In this article, we provide an update on the recent evidence surrounding VTE risk factors in pregnancy while concurrently outlining knowledge gaps and current approaches to VTE prevention.
An issue of venous thromboembolic events (VTEs) in pregnant women and puerperas in Russia as well as throughout the world remains relevant. Specialized events with expert’s participation could not be better to promote active discussion and constructive solution of complex problems, which refer to issues of VTEs prevention. Indeed, not disputable issues can be solved, but critical look and reasoned opinion leader presentations in the field undoubtedly improve our understanding and approaches to prevention of threatening complications in pregnant women and puerperas such as VTEs. In addition, actively discussed new data for dosing of low molecular weight heparins (LMWH) in pregnant women will allow to update current clinical guidelines, which would probably improve clinical outcomes of therapy.
Objective:
Cerebral venous thrombosis (CVT), thrombosis of the dural sinus, cerebral veins, or both, is a rare cerebrovascular disease. Although mortality rates after CVT have declined over time, this condition can result in devastating neurologic outcomes. This article reviews the latest literature regarding CVT epidemiology, details new factors associated with the development of CVT, and describes advances in CVT treatment. It also contains a discussion of future directions in the field, including novel diagnostic imaging modalities, and potential strategies to reduce the risks associated with CVT.
Latest developments:
The incidence of CVT may be as high as 2 per 100,000 adults per year. It remains a difficult condition to diagnose given its variable clinical manifestations and the necessity of neuroimaging for confirmation. The COVID-19 pandemic has revealed a novel CVT trigger, vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as an association between COVID-19 infection and CVT. Although VITT is a very rare event, timely diagnosis and treatment of CVT due to VITT likely improves patient outcomes. Direct oral anticoagulants are currently being used to treat CVT and emerging data suggest that these agents are as safe and effective as vitamin K antagonists. The role of endovascular therapy to treat CVT, despite a recent clinical trial, remains unproven.
Essential points:
The incidence of CVT has increased, outcomes have improved, and the use of direct oral anticoagulants to treat CVT represents an important advance in the clinical care of these patients. Rates of CVT as a complication of COVID-19 vaccines using adenoviral vectors are very low (<5 per million vaccine doses administered), with the benefits of COVID-19 vaccination far outweighing the risks.
Background:
Peripartum management of women using low-molecular-weight heparin (LMWH) varies widely. Minimum time intervals are required between LMWH injection and neuraxial procedure, and they differ by dose.
Objectives:
The objective of this study was to describe the onset of labor and use of analgesia in women using LMWH and to compare practices between intermediate-dose and low-dose LMWH.
Methods:
In the Highlow study (NCT01828697), 1110 women were randomized to intermediate-dose or low-dose LMWH and were instructed to discontinue LMWH when labor commenced unplanned or 24 hours prior to planned delivery. The required time interval since last injection to receive a neuraxial procedure was ≥24 hours for intermediate-dose LMWH or ≥12 hours for low-dose LMWH.
Results:
In total, 1018 women had an ongoing pregnancy for ≥24 weeks. Onset of labor was spontaneous in 198 of 509 (39%) women on intermediate-dose LMWH and in 246 of 509 (49%) on low-dose LMWH. With unplanned onset, a neuraxial procedure was performed in 37% on intermediate-dose and in 48% on low-dose LMWH (risk difference -11%, 95% CI -20% to -2%). Based on time interval, 61% on intermediate-dose and 82% on low-dose LMWH were eligible for a neuraxial procedure. With planned onset, 68% on intermediate-dose and 66% on low-dose LMWH received a neuraxial procedure, whereas 81% and 93%, respectively, were eligible for a neuraxial procedure (risk difference -13%, 95% CI -18% to -8%).
Conclusion:
With spontaneous onset of labor, neuraxial procedures were performed less often in women using intermediate-dose LMWH. Irrespective of onset, fewer women on intermediate-dose LMWH than those on low-dose LMWH were eligible for neuraxial procedures based on required time intervals since the last LMWH injection.
Pulmonary embolism can be acutely life-threatening and is associated with long-term consequences such as recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension. In 2020, the American Society of Hematology published updated guidelines on the management of patients with venous thromboembolism. Here, a hematologist and a cardiology and vascular medicine specialist discuss these guidelines in the context of the care of a patient with pulmonary embolism. They discuss advanced therapies such as catheter-directed thrombolysis in the short-term management of patients with intermediate-risk disease, recurrence risk stratification at presentation, and ideal antithrombotic regimens for patients whose pulmonary embolism was associated with a transient minor risk factor.
Compared with nonpregnant women, pregnancy carries a four- to fivefold higher risk of venous thromboembolism (VTE). Despite increasing use of heparin prophylaxis in identified high-risk patients, pulmonary embolism still is the leading cause of maternal mortality in the western world. However, evidence on optimal use of thromboprophylaxis is scarce. Thrombophilia, the hereditary or acquired tendency to develop VTE, is also thought to be associated with complications in pregnancy, such as recurrent miscarriage and preeclampsia. In this review, the current evidence on optimal thromboprophylaxis in pregnancy is discussed, focusing primarily on VTE prevention strategies but also discussing the potential to prevent recurrent pregnancy complications with heparin in pregnant women with thrombophilia.
1175275006940 ИНН/КПП 5258135227/525801001 А дрес в интернете: тчм.рМеЪоип'юп.ги, А дрес электронной почты: рМеЪоипюп(а)устс1ех.ги Телефон: + 7 (903) 836-24-17
Thrombosis in pregnancy is a major cause of maternal and fetal morbidity and mortality. Risk stratification of venous thromboembolism (VTE) during pregnancy is complex. The hypercoagulability observed in pregnant women can reduce bleeding during childbirth, but may cause thrombosis especially in the presence of additional prothrombotic risk factors such as antiphospholipid antibodies or genetic thrombophilic defects. The availability of large datasets allows for the identification of additional independent risk factors, including assisted reproductive technologies (ARTs), endometriosis, and recurrent pregnancy loss. Data on the risk of VTE linked to COVID-19 in pregnant women are very limited, but suggest that infected pregnant women have an increased risk of VTE. Current guidelines on the prevention and treatment of VTE in pregnancy are based on available, albeit limited, data and mainly present expert opinion. Low-molecular-weight heparins (LMWHs) are the mainstay of anticoagulation to be employed during pregnancy. Administration of LMWH for VTE treatment in pregnancy should be based on the personalized approach, taking into account a weight-based adjusted scheme. During gestation, due to physiological changes, in women at high risk of VTE, monitoring of anti-Xa activity is performed to ensure adequate LMWH dosing. As for the treatment duration for pregnant women with acute VTE, guidelines suggest that anticoagulation should be continued for at least 6 weeks postpartum for a minimum total duration of therapy of 3 months.
Background:
Venous thromboembolism (VTE), although rare, is a major cause of maternal mortality and morbidity. Some women are at increased risk of VTE during pregnancy and the early postnatal period (e.g. caesarean section, family history of VTE, or thrombophilia), and so prophylaxis may be considered. As some methods of prophylaxis carry risks of adverse effects, and risk of VTE is often low, benefits of thromboprophylaxis may be outweighed by harms.
Objectives:
To assess the effects of thromboprophylaxis during pregnancy and the early postnatal period on the risk of venous thromboembolic disease and adverse effects in women at increased risk of VTE.
Search methods:
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (18 October 2019). In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports (18 October 2019).
Selection criteria:
Randomised trials comparing one method of thromboprophylaxis with placebo or no treatment, or two (or more) methods of thromboprophylaxis.
Data collection and analysis:
At least two review authors assessed trial eligibility, extracted data, assessed risk of bias, and judged certainty of evidence for selected critical outcomes (using GRADE). We conducted fixed-effect meta-analysis and reported data (all dichotomous) as summary risk ratios (RRs) with 95% confidence intervals (CIs).
Main results:
Twenty-nine trials (involving 3839 women), overall at moderate to high risk of bias were included. Trials were conducted across the antenatal, peripartum and postnatal periods, with most in high-income countries. Interventions included types and regimens of heparin (low molecular weight heparin (LMWH) and unfractionated heparin (UFH)), hydroxyethyl starch (HES), and compression stockings or devices. Data were limited due to a small number of trials in comparisons and/or few or no events reported. All critical outcomes (assessed for comparisons of heparin versus no treatment/placebo, and LMWH versus UFH) were considered to have very low-certainty evidence, downgraded mainly for study limitations and imprecise effect estimates. Maternal death was not reported in most studies. Antenatal (± postnatal) prophylaxis For the primary outcomes symptomatic thromboembolic events pulmonary embolism (PE) and/or deep vein thrombosis (DVT), and the critical outcome of adverse effects sufficient to stop treatment, the evidence was very uncertain. Symptomatic thromboembolic events: - heparin versus no treatment/placebo (RR 0.39; 95% CI 0.08 to 1.98; 4 trials, 476 women; very low-certainty evidence); - LMWH versus UFH (RR 0.47; 95% CI 0.09 to 2.49; 4 trials, 404 women; very low-certainty evidence); Symptomatic PE: - heparin versus no treatment/placebo (RR 0.33; 95% CI 0.02 to 7.14; 3 trials, 187 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 287 women); Symptomatic DVT: - heparin versus no treatment/placebo (RR 0.33; 95% CI 0.04 to 3.10; 4 trials, 227 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 287 women); Adverse effects sufficient to stop treatment: - heparin versus no treatment/placebo (RR 0.49; 95% CI 0.05 to 5.31; 1 trial, 139 women; very low-certainty evidence); - LMWH versus UFH (RR 0.07; 95% CI 0.01 to 0.54; 2 trials, 226 women; very low-certainty evidence). Peripartum/postnatal prophylaxis Vaginal or caesarean birth When UFH and no treatment were compared, the effects on symptomatic thromboembolic events (RR 0.16; 95% CI 0.02 to 1.36; 1 trial, 210 women; very low-certainty evidence), symptomatic PE (RR 0.16; 95% CI 0.01 to 3.34; 1 trial, 210 women; very low-certainty evidence), and symptomatic DVT (RR 0.27; 95% CI 0.03 to 2.55; 1 trial, 210 women; very low-certainty evidence) were very uncertain. Maternal death and adverse effects sufficient to stop treatment were not reported. Caesarean birth Symptomatic thromboembolic events: - heparin versus no treatment/placebo (RR 1.30; 95% CI 0.39 to 4.27; 4 trials, 840 women; very low-certainty evidence); - LMWH versus UFH (RR 0.33; 95% CI 0.01 to 7.99; 3 trials, 217 women; very low-certainty evidence); Symptomatic PE: - heparin versus no treatment/placebo (RR 1.10; 95% CI 0.25 to 4.87; 4 trials, 840 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 217 women); Symptomatic DVT: - heparin versus no treatment/placebo (RR 1.30; 95% CI 0.24 to 6.94; 5 trials, 1140 women; very low-certainty evidence); LMWH versus UFH (RR 0.33; 95% CI 0.01 to 7.99; 3 trials, 217 women; very low-certainty evidence); Maternal death: - heparin versus placebo (no events, 1 trial, 300 women); Adverse effects sufficient to stop treatment: - heparin versus placebo (no events; 1 trial, 140 women). Postnatal prophylaxis No events were reported for LMWH versus no treatment/placebo for: symptomatic thromboembolic events, symptomatic PE and symptomatic DVT (all 2 trials, 58 women), or maternal death (1 trial, 24 women). Adverse effects sufficient to stop treatment were not reported. We were unable to conduct subgroup analyses due to lack of data. Sensitivity analysis including the nine studies at low risk of bias did not impact overall findings.
Authors' conclusions:
The evidence is very uncertain about benefits and harms of VTE thromboprophylaxis in women during pregnancy and the early postnatal period at increased risk of VTE. Further high-quality very large-scale randomised trials are needed to determine effects of currently used treatments in women with different VTE risk factors. As sufficiently large definitive trials are unlikely to be funded, secondary data analyses based on high-quality registry data are important.
Pregnant women with obesity are at increased risk of a multitude of complications of pregnancy and adverse perinatal outcomes. The risk of some of these complications, such as neural tube defects or preeclampsia, may be mitigated by some medications. Other complications, such as diabetes, venous thromboembolism, and infections, require treatment with medications. Given the changes in pharmacokinetics and pharmacodynamics during pregnancy, which is further enhanced by obesity, the optimal medication and its dose is often researched. This chapter further explores the different complications and common medications that women with obesity are likely to require.
Of 1,000 pregnant women, one to two will experience venous thromboembolism (VTE) during pregnancy or the postpartum period. Pulmonary embolism (PE) is a leading cause of maternal mortality and deep vein thrombosis (DVT) leads to maternal morbidity and may diminish quality of life due to post-thrombotic syndrome during the rest of a woman's life. Despite this important burden, the evidence base for the management of pregnancy-related VTE is weak. Recommendations from evidence-based guidelines are often extrapolated from the non-pregnant population and thus weak or conditional. As a consequence, there is wide variation of practice. In women with a suspicion of PE, the pregnancy-adapted YEARS algorithm is safe and efficient, with 39% of women not needing computed tomographic pulmonary angiography (CTPA) to rule out PE. Low-molecular-weight heparin (LMWH) in therapeutic doses is the treatment of choice during pregnancy, and anticoagulation (LMWH or vitamin K antagonists [VKA] postpartum) should be continued until 6 weeks after delivery with a minimum total duration of 3 months. Use of LMWH or vitamin K antagonists does not preclude breastfeeding. Postpartum, direct oral anticoagulants (DOACs) are an option if women do not breastfeed and long-term use is intended. Management of delivery, including the type of analgesia, requires a multidisciplinary approach and depends on local preferences and patient-specific conditions. Several options are possible and include waiting for spontaneous delivery with temporary interruption of LMWH. Prophylaxis for the prevention of recurrent VTE in subsequent pregnancies is indicated in most women with a history of VTE.
Introduction: The risk of developing venous thromboembolism (VTE) in women is 5 to 6 times higher during pregnancy. In addition, this risk can be significantly higher if the patient has a history or family history of hypercoagulate states. VTE is a leading cause of morbidity and mortality in this population, so in order to assess if it is appropriate to use thromboprophylaxis during pregnancy, whether pharmacological or non-pharmacological, it is necessary to timely recognize the clinical risk factors associated with this condition.
Objective: To describe the use, on the one hand, of screening tests for hypercoagulate states and, on the other, of pharmacological and non-pharmacological thromboprophylaxis to prevent the development of VTE during pregnancy, labor and the puerperium Materials and methods: A literature review was conducted in the Embase, ClinicalKey, ScienceDirect, Acces Medicine, Scopus, ProQuest, PubMed and LILACS databases. The search included studies on thrombophilia and thrombophylaxis during pregnancy published in English or Spanish between January 2004 and March 2018.
Results: After completing the initial search, 128 studies were identified, of which 54 met the inclusion criteria. Most studies were narrative reviews (n=16), clinical practice guidelines (n=13) and systematic reviews (n=8). Conclusion: The use of screening tests for hypercoagulate states during pregnancy, labor and the puerperium is recommended, since the timely identification of VTE will allow the reduction of morbidity and mortality rates in this population through the implementation of thromboprophylactic measures, whether they are pharmacological or non-pharmacological.
Sex matters when it comes to venous thromboembolism (VTE). We defined 5P's – period, pill, prognosis, pregnancy, and post‐thrombotic syndrome – that should be discussed with young women with VTE. Menstrual blood loss (Period) can be aggravated by anticoagulant therapy. This seems particularly true for direct oral anticoagulants. Abnormal uterine bleeding can be managed by hormonal therapy, tranexamic acid or modification of treatment. The use of combined oral contraceptives (Pill) is a risk factor for VTE. The magnitude of the risk depends on progestagen types and estrogen doses used. In women using therapeutic anticoagulation, concomitant hormonal therapy does not increase the risk of recurrent VTE. Levonorgestrel‐releasing intrauterine devices and low‐dose progestin‐only pills do not increase the risk of VTE. VTE in young women is often provoked by transient hormonal risk factors which affects Prognosis. Sex is incorporated as predictor in recurrent VTE risk assessment models. However, current guidelines do not propose using these to guide treatment duration. Pregnancy increases the risk of VTE by 4 to 5‐fold. Thrombophilia and obstetric risk factors further increase the risk of pregnancy‐related VTE. In women with a history of VTE, the risk of recurrence during pregnancy or postpartum appears to be influenced by risk factors present during the first VTE. In most women with a history of VTE, antepartum and postpartum thromboprophylaxis with low‐molecular‐weight heparin is indicated. Women generally are affected by VTE at younger age then men, and they have to deal with long‐term complications (Post‐thrombotic syndrome) of deep vein thrombosis early in life. This article is protected by copyright. All rights reserved.
INTRODUCTION:
The antiphospholipid syndrome (APS) is defined by the occurrence of venous and/or arterial thrombosis and/or pregnancy-related morbidity, combined with the presence of antiphospholipid antibodies (aPL) and/or a lupus anticoagulant (LAC). Large, controlled, intervention trials in APS are limited. This paper aims to provide clinicians with an expert consensus on the management of APS.
METHODS:
Relevant papers were identified by literature search. Statements on diagnostics and treatment were extracted. During two consensus meetings, statements were discussed, followed by a Delphi procedure. Subsequently, a final paper was written.
RESULTS:
Diagnosis of APS includes the combination of thrombotic events and presence of aPL. Risk stratification on an individual base remains challenging. 'Triple positive' patients have highest risk of recurrent thrombosis. aPL titres > 99th percentile should be considered positive. No gold standard exists for aPL testing; guidance on assay characteristics as formulated by the International Society on Thrombosis and Haemostasis should be followed. Treatment with vitamin K-antagonists (VKA) with INR 2.0-3.0 is first-line treatment for a first or recurrent APS-related venous thrombotic event. Patients with first arterial thrombosis should be treated with clopidogrel or VKA with target INR 2.0-3.0. Treatment with direct oral anticoagulants is not recommended. Patients with catastrophic APS, recurrent thrombotic events or recurrent pregnancy morbidity should be referred to an expert centre.
CONCLUSION:
This consensus paper fills the gap between evidence-based medicine and daily clinical practice for the care of APS patients.
Inherited and acquired thrombophilias and hypercoagulable states, such as active cancer, estrogen-induced, autoimmune disorders, major surgery, hospitalization, and trauma, are well-known risk factors for venous thromboembolism (VTE). The effect of these on recurrent VTE is different for each specific risk factor. The major risk factors affecting VTE recurrence include the presence of active cancer and an unprovoked first VTE. In addition, the use of combined female hormones in a woman with a previous history of estrogen-related VTE is a major risk factor for VTE recurrence. The extent of influence of inherited thrombophilia on the risk of recurrence is controversial. Conversely, the presence of antiphospholipid antibodies, specifically triple positive carriers, appears to increase the risk of VTE recurrence. Understanding the rates of recurrent VTE in a patient and the individual risk of bleeding is important in determining the duration of anticoagulation therapy.
Background:
Optimal prophylactic strategies in pregnant women with a history of venous thromboembolism (VTE) are unknown.
Patients and methods:
We conducted a retrospective cohort study of consecutive pregnant patients with a previous VTE history. Patients were followed until 6 weeks postpartum. Patients with a previous unprovoked event (including antepartum VTE) received antenatal prophylaxis, mostly with low dose low molecular weight heparin (LMWH). All patients received prophylaxis for six weeks after delivery.
Results:
We included a total of 199 pregnancies in 142 women. Of these, 147 pregnancies occurred in women with unprovoked or estrogen-related VTE history and 52 pregnancies in women with provoked VTE. There were 8 recurrences in 199 pregnancies (4%; 95%CI: 2.05-7.73), of which 5 were antepartum recurrences (2.5%; 95%CI 1.08-5.75) and 3 were postpartum (1.5%; 95% CI 0.51-4.34). In the unprovoked VTE group there were 7 recurrences (4.7%; 95%CI: 2.32-9.50), whereas in the provoked VTE group there was 1 (1.9%; 95%CI: 0.34-10.12). There was one major bleeding event in a patient not receiving LMWH secondary to placental abruption.
Conclusion:
This study suggests that the use of prophylactic doses of LMWH during pregnancy and puerperium, as described in this study, results in low occurrence of ante- and postpartum VTE recurrences in patients with previous VTE. Further studies are required to confirm this observation.
Importance:
In industrialized countries, venous thromboembolism remains a leading cause of mortality in pregnant women. Low-molecular-weight heparin (LMWH) is the most commonly recommended anticoagulant in pregnancy, having been proven effective and safe in multiple prospective clinical trials.
Objective:
The aim of this article is to outline existing recommendations for proper use of LMWH in pregnancy and data on risks of LMWH.
Evidence acquisition:
Wereviewed guidelines froma number of professional societies.We also examined the current literature behind the various risks associated with LMWH use.
Results:
Our review outlines the current data that guide the use of LMWH in pregnancy. With prophylactic dosing, LMWH comes with a 0.5% risk of antepartum bleeding and a 1% risk of postpartum hemorrhage that is not different from clinical trial controls. With treatment dosing, there is a 1.5% risk of antepartum bleeding and a 2% risk of postpartum hemorrhage. Overall, current evidence behind these risks is limited, and this review suggests areas of further study moving forward.
A variety of definitions of major bleeding have been used in published clinical studies, and this diversity adds to the difficulty in comparing data between trials and in performing meta-analyses. In the first step towards unified definitions of bleeding complications, the definition of major bleeding in non-surgical patients was discussed at the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis. Arising from that discussion, a definition was developed that should be applicable to studies with all agents that interfere with hemostasis, including anticoagulants, platelet function inhibitors and fibrinolytic drugs. The definition and the text that follows have been reviewed and approved by the cochairs of the subcommittee and the revised version is published here. The intention is to also seek approval of this definition from the regulatory authorities.
The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy.
The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.
We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin (Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfill the laboratory criteria for antiphospholipid antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B).
Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies in this population.
Background
Low-molecular-weight heparin (LMWH) is the drug of choice to prevent venous thrombosis in pregnancy, but the optimal dose for prevention while avoiding bleeding is unclear. This study investigated whether therapeutic doses of LMWH increase the incidence of postpartum haemorrhage (PPH) in a retrospective controlled cohort.
Methods
All pregnant women who received therapeutic doses of LMWH between 1995 and 2008 were identified in the Academic Medical Center, Amsterdam, The Netherlands. The controls were women registered for antenatal care in the same hospital who did not use LMWH during pregnancy, matched by random electronic selection for age, parity and delivery date to LMWH users. The incidence of PPH (blood loss >500 ml), severe PPH (blood loss >1000 ml) and median blood loss were compared in two cohorts of LMWH users and non-users.
Results
The incidence of PPH was 18% in LMWH users (N=95) and 22% in non-users (N=524) (RR 0.8; 95% CI 0.5 to 1.4). The incidence of severe PPH was 6% in both groups (RR 1.2; 0.5 to 2.9). The median amount of blood loss differed only in normal vaginal deliveries. It was 200 ml in LMWH users and 300 ml in non-users (difference −100 ml; 95% CI −156 to −44).
Conclusion
Therapeutic doses of LMWH in pregnancy were observed not to be associated with a clinically meaningful increase in the incidence of PPH or severe PPH in women delivered in this hospital, although this observation may be confounded by the differential use of strategies to prevent bleeding. A randomised controlled trial is necessary to provide a definite answer about the optimal dose of LMWH in pregnancy.
To determine the incidence of venous thromboembolism in pregnancy and the puerperium and to identify risk factors for pregnancy-related venous thromboembolism.
Cohort study and case-control study.
London, UK.
395,335 women with live births or pregnancies of 24 or more weeks of gestation between 1988 and 1997.
Data extraction from the St Mary's Maternity Information System database. Random sample of 5% for case-control study.
Incidence of venous thromboembolism; odds ratios for variables associated with venous thromboembolism.
The incidence of venous thromboembolism was 85/100,000 maternities. There were approximately twice as many postpartum as antepartum events. Blood group A, multiple pregnancy, caesarean section, cardiac disease, delivery at gestational age of < 36 weeks, a body mass index of > or = 25, or more and maternal age of 35 or over were all found to increase incidence of venous thromboembolism.
Although venous thromboembolism is the leading cause of maternal deaths in the UK, it is still a rare event. Most of these events are deep vein thromboses occurring in the postpartum period. Antenatally multiple birth is an important risk factor. Postnatally women who have had a caesarean section, premature delivery or history of cardiac disease should be assessed carefully for venous thromboembolism.
Evidence-based medicine guidelines based on venographic end points recommend in-hospital prophylaxis with low-molecular-weight heparin (LMWH) in patients having elective hip surgery. Emerging data suggest that out-of-hospital use may offer additional protection; however, uncertainty remains about the risk-benefit ratio. To provide clinicians with a practical pathway for translating clinical research into practice, we systematically reviewed trials comparing extended out-of-hospital LMWH prophylaxis versus placebo.
Studies were identified by 1) searching PubMed, MEDLINE, and the Cochrane Library Database for reports published from January 1976 to May 2001; 2) reviewing references from retrieved articles; 3) scanning abstracts from conference proceedings; and 4) contacting pharmaceutical companies and investigators of the original reports.
Randomized, controlled trials comparing extended out-of-hospital prophylaxis with LMWH versus placebo in patients having elective hip arthroplasty.
Two reviewers extracted data independently. Reviewers evaluated study quality by using a validated four-item instrument.
Six of seven original articles met the defined inclusion criteria. The included studies were double-blind trials that used proper randomization procedures. Compared with placebo, extended out-of-hospital prophylaxis decreased the frequency of all episodes of deep venous thrombosis (placebo rate, 150 of 666 patients [22.5%]; relative risk, 0.41 [95% CI, 0.32 to 0.54; P < 0.001]), proximal venous thrombosis (placebo rate, 76 of 678 patients [11.2%]; relative risk, 0.31 [CI, 0.20 to 0.47; P < 0.001]), and symptomatic venous thromboembolism (placebo rate, 36 of 862 patients [4.2%]; relative risk, 0.36 [CI, 0.20 to 0.67; P = 0.001]). Major bleeding was rare, occurring in only one patient in the placebo group.
Extended LMWH prophylaxis showed consistent effectiveness and safety in the trials (regardless of study variations in clinical practice and length of hospital stay) for venographic deep venous thrombosis and symptomatic venous thromboembolism. The aggregate findings support the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty surgery.
To assess the safety and efficacy of low-molecular-weight heparins (LMWHs) for thromboprophylaxis and treatment of venous thromboembolism (VTE) in pregnancy, a systematic review of studies to the end of 2003 was undertaken. Data on VTE recurrence and side effects were extracted and cumulative incidences of VTE and adverse effects calculated. Of 81 reports identified, 64 reporting 2777 pregnancies were included. In 15 studies (174 patients) the indication for LMWH was treatment of acute VTE, and in 61 studies (2603 pregnancies) it was thromboprophylaxis or adverse pregnancy outcome. There were no maternal deaths. VTE and arterial thrombosis (associated with anti-phospholipid syndrome) were reported in 0.86% (95% confidence interval [CI], 0.55%-1.28%) and 0.50% (95% CI, 0.28%-0.84%) of pregnancies, respectively. Significant bleeding, generally associated with primary obstetric causes, occurred in 1.98% (95% CI, 1.50%-2.57%), allergic skin reactions in 1.80% (95% CI, 1.34%-2.37%), heparin-induced thrombocytopenia in 0%, thrombocytopenia (unrelated to LMWH) in 0.11% (95% CI, 0.02%-0.32%), and osteoporotic fracture in 0.04% (95% CI, < 0.01%-0.20%) of pregnancies. Overall, live births were reported in 94.7% of pregnancies, including 85.4% in those receiving LMWH for recurrent pregnancy loss. LMWH is both safe and effective to prevent or treat VTE in pregnancy.
This study was undertaken to estimate the incidence of venous thromboembolism in pregnancy and puerperium and to identify risk factors for pregnancy-related venous thromboembolism.
A register-based case-control study with 613,232 pregnancies from 1990-2003 in 11 Norwegian counties. Medical records for eligible cases were revisited and relevant medical data were transferred to a specific case-report form. The diagnosis of venous thromboembolism was based on strict criteria. Data were analyzed by chi2 test and forward stepwise logistic regression.
In total, 615 cases were detected. The incidence of venous thromboembolism was 1 per 1000 pregnancies. The ante- and postnatal incidences were quite similar. Antenatal risk factors were assisted reproduction, gestational diabetes, age older than 35 years, multiple pregnancies, and primi-parity. Postnatal risk factors were cesarean section, preeclampsia, assisted reproduction, abruptio placenta, and placenta previa.
We found different ante- and postnatal risk patterns. Assisted reproduction and gestational diabetes were significant antenatal risk factors; whereas cesarean section and preeclampsia were strong postnatal risk factors.
3132
Poster Board III-69
Women with a past history of venous thrombosis are at higher risk for venous thromboembolism (VTE) during and after pregnancy. The highest risk period is the first four weeks post partum. For a woman whose previous event was secondary to a major transient risk factor the antepartum risk of recurrent VTE is low whereas for women whose previous event was idiopathic the antepartum risk is higher. In our institution, for women whose previous event was secondary to a major transient risk factor, standard treatment is to follow closely with no thromboprophylaxis antepartum and then receive either prophylactic low molecular weight heparin (LMWH) or warfarin for six weeks postpartum. For women whose previous event was idiopathic or who were on warfarin at the time of becoming pregnant they receive prophylactic LMWH antepartum with a scheduled delivery and are put back on warfarin if they have long term anticoagulation needs or LMWH for six weeks if they don't have longterm anticoagulation needs. We report the outcome for our patients from 1997 to 2008. All patients were followed for the duration of pregnancy and for 6 weeks postpartum for pregnancy outcome, recurrent VTE, and major bleeding in the thrombosis clinic of London Health Sciences Centre. There were a total of 90 women; 30 women (mean age 30.6 years) with a history of previous secondary thrombosis with 37 pregnancies and 60 women (mean age 29.5 years) with past idiopathic thrombosis with 99 pregnancies. For the secondary group there was 1 episode (2.70%; 95% CI 0.48-13.82) of antepartum recurrent VTE whereas for the idiopathic group there were 3 episodes (3.03%; 95% CI 1.04-8.53). There was no statistical difference between groups (p=1.0). There were no episodes of postpartum VTE recurrence or major hemorrhage for either group. For the secondary group there was 1 fetal loss at 23 weeks (2.7%; 95% CI 0.48-13.82) whereas for the idiopathic group there were 6 fetal losses at 8, 10, 10, 11, 22, 37 weeks gestation (6.06%; 95% CI 2.81-12.60). There was no statistically significant difference between groups (p=0.77). This retrospective review suggests that for pregnant women with a past history of VTE, a strategy of no antepartum prophylaxis for previous secondary thrombosis and antepartum prophylactic LMWH for previous idiopathic thrombosis as well as prophylactic LMWH or warfarin postpartum is efficacious and safe.
Disclosures
Off Label Use: low molecular weight heparin for prevention of VTE in pregnancy.
Background: The risk for venous thromboembolism during pregnancy or postpartum is uncertain. Objectives: To estimate the relative and absolute risk for deep venous thrombosis and pulmonary embolism during pregnancy and postpartum and to describe trends in incidence. Design: Population-based inception cohort study using the resources of the Rochester Epidemiology Project. Setting: Olmsted County, Minnesota. Patients: Women with deep venous thrombosis or pulmonary embolism first diagnosed between 1966 and 1995, including women with venous thromboembolism during pregnancy or the postpartum period (defined as delivery of a newborn no more than 3 months before the deep venous thrombosis or pulmonary embolism event date, including delivery of a stillborn infant after the first trimester). Measurements: The authors obtained yearly counts of live births in Olmsted County between 1966 and 1995 from the Minnesota Department of Health. Results: The relative risk (standardized incidence ratio) for venous thromboembolism among pregnant or postpartum women was 4.29 (95% Cl, 3.49 to 5.22; P< 0.001), and the overall incidence of venous thromboembolism (absolute risk) was 199.7 per 100 000 woman-years. The annual incidence was 5 times higher among postpartum women than pregnant women (511.2 vs. 95.8 per 100 000), and the incidence of deep venous thrombosis was 3 times higher than that of pulmonary embolism (151.8 vs. 47.9 per 100 000). Pulmonary embolism was relatively uncommon during pregnancy versus the postpartum period (10.6 vs. 159.7 per 100 000). Over the 30-year study period, the incidence of venous thromboembolism during pregnancy remained relatively constant whereas the postpartum incidence of pulmonary embolism decreased more than 2-fold. Limitations: Because the Olmsted County population was 98% white and of non-Hispanic ethnicity, the results may not be generalizable to other ethnicities. Conclusions: Among pregnant women, the highest risk period for venous thromboembolism and pulmonary embolism in particular is during the postpartum period. Any prophylaxis against these events should be particularly targeted to postpartum women. Although the incidence of pulmonary embolism has decreased over time, the incidence of deep venous thrombosis remains unchanged, indicating the need to better identify pregnant women at increased risk.
Purpose: Evidence-based medicine guidelines based on venographic end points recommend in-hospital prophylaxis with low-molecular-weight heparin (LMWH) in patients having elective hip surgery. Emerging data suggest that out-of-hospital use may offer additional protection; however, uncertainty remains about the risk-benefit ratio. To provide clinicians with a practical pathway for translating clinical research into practice, we systematically reviewed trials comparing extended out-of-hospital LMWH prophylaxis versus placebo. Data Sources: Studies were identified by 1) searching PubMed, MEDLINE, and the Cochrane Library Database for reports published from January 1976 to May 2001; 2) reviewing references from retrieved articles; 3) scanning abstracts from conference proceedings; and 4) contacting pharmaceutical companies and investigators of the original reports. Study Selection: Randomized, controlled trials comparing extended out-of-hospital prophylaxis with LMWH versus placebo in patients having elective hip arthroplasty. Data Extraction: Two reviewers extracted data independently. Reviewers evaluated study quality by using a validated four-item instrument. Data Synthesis: Six of seven original articles met the defined inclusion criteria. The included studies were double-blind trials that used proper randomization procedures. Compared with placebo, extended out-of-hospital prophylaxis decreased the frequency of all episodes of deep venous thrombosis (placebo rate, 150 of 666 patients [22.5%]; relative risk, 0.41 [95% Cl, 0.32 to 0.54; P < 0.001]), proximal venous thrombosis (placebo rate, 76 of 678 patients [11.2%]; relative risk, 0.31 [Cl, 0.20 to 0.47; P < 0.001]), and symptomatic venous thromboembolism (placebo rate, 36 of 862 patients [4.2%]; relative risk, 0.36 [Cl, 0.20 to 0.67; P = 0.001]). Major bleeding was rare, occurring in only one patient in the placebo group. Conclusions: Extended LMWH prophylaxis showed consistent effectiveness and safety in the trials (regardless of study variations in clinical practice and length of hospital stay) for venographic deep venous thrombosis and symptomatic venous thromboembolism. The aggregate findings support the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty surgery.
Background:
The postpartum state is associated with a substantially increased risk of thrombosis. It is uncertain to what extent this heightened risk persists beyond the conventionally defined 6-week postpartum period.
Methods:
Using claims data on all discharges from nonfederal emergency departments and acute care hospitals in California, we identified women who were hospitalized for labor and delivery between January 1, 2005, and June 30, 2010. We used validated diagnosis codes to identify a composite primary outcome of ischemic stroke, acute myocardial infarction, or venous thromboembolism. We then used conditional logistic regression to assess each patient's likelihood of a first thrombotic event during sequential 6-week periods after delivery, as compared with the corresponding 6-week period 1 year later.
Results:
Among the 1,687,930 women with a first recorded delivery, 1015 had a thrombotic event (248 cases of stroke, 47 cases of myocardial infarction, and 720 cases of venous thromboembolism) in the period of 1 year plus up to 24 weeks after delivery. The risk of primary thrombotic events was markedly higher within 6 weeks after delivery than in the same period 1 year later, with 411 events versus 38 events, for an absolute risk difference of 22.1 events (95% confidence interval [CI], 19.6 to 24.6) per 100,000 deliveries and an odds ratio of 10.8 (95% CI, 7.8 to 15.1). There was also a modest but significant increase in risk during the period of 7 to 12 weeks after delivery as compared with the same period 1 year later, with 95 versus 44 events, for an absolute risk difference of 3.0 events (95% CI, 1.6 to 4.5) per 100,000 deliveries and an odds ratio of 2.2 (95% CI, 1.5 to 3.1). Risks of thrombotic events were not significantly increased beyond the first 12 weeks after delivery.
Conclusions:
Among patients in our study, an elevated risk of thrombosis persisted until at least 12 weeks after delivery. However, the absolute increase in risk beyond 6 weeks after delivery was low. (Funded by the National Institute of Neurological Disorders and Stroke.).
Background:
Low-molecular-weight heparins (LMWH) are the most commonly used anticoagulants for the treatment and prophylaxis of venous thromboembolism in pregnancy. Hypersensitivity skin reactions associated with the use of LMWH are frequently seen, but are probably underreported.
Objective:
To evaluate the incidence of hypersensitivity skin reactions due to the use of LMWH in pregnancy, and the subsequent management of anticoagulation.
Patients/methods:
From 1999 to 2009, we followed consecutive women who used therapeutic anticoagulation for venous indications. Women visited a combined obstetric/coagulation clinic and were seen by a thrombosis specialist every two months until six weeks postpartum. All women were started on nadroparin.
Results:
We included 135 pregnancies in 88 women. Overall, in 52 of 135 pregnancies (39%), women switched at least once to another anticoagulant because of the development of hypersensitivity skin reactions. Switching to another preparation of LMWH was effective in 77% of the cases. In 23% of the cases skin reactions recurred and another switch had to be made.
Conclusion:
In almost half of the pregnancies, women had to switch at least once to another anticoagulant preparation due to the development of hypersensitivity skin reactions on LMWH. In most cases, skin reactions did not recur on the second preparation of LMWH used.
This article addresses the treatment of VTE disease.
We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence.
For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C).
Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences.
Knowledge of the absolute and relative risk of venous thromboembolism (VTE) in and around pregnancy would be crucial in identifying when to commence and cease thromboprophylaxis in women who would benefit from such intervention. We addressed this hypothesis using a large prospective primary care database from the United Kingdom, containing details on 972683 women aged 15-44years between 1987 and 2004. Risks of a first VTE during antepartum, postpartum and outside of pregnancy were compared using Poisson regression. The rate of VTE during the third trimester antepartum was six times higher than time outside pregnancy [Incidence Rate Ratio (IRR)=6·1; 95% confidence interval, 4·7-7·9]. In contrast, both the first (IRR=1·6) and second (IRR=2·1) trimesters conferred little increase in risk. The first 6weeks postpartum was associated with a 22-fold increase in risk, with the peak occurring in the first 3weeks. Increased age was found to be associated with VTE during postpartum and outside of pregnancy, but not during antepartum. Our findings of a notably raised risk of VTE persisting for 3 weeks postpartum and of a raised antepartum risk constrained to the third trimester have implications for modifying the current recommendations for VTE prophylaxis in pregnancy and the puerperium.
Background:
Early-onset hypertensive disorders (HD) of pregnancy and small-for-gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk.
Objectives:
Adding low-molecular-weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early-onset HD (pre-eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies.
Patients/methods:
In a multicenter randomized control trial (RCT), 139 women included were< 12 weeks gestation.
Inclusion criteria:
previous delivery< 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected.
Intervention:
either daily LMWH (dalteparin, 5000 IU weight-adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone.
Main outcome measures:
Primary outcomes:
recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age.
Secondary outcomes:
recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention-to-treat.
Results:
Low-molecular-weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects.
Trial registration:
http://www.isrctn.org) (isrctn87325378).
Conclusions:
Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.
In the triennium 2006-2008, 261 women in the UK died directly or indirectly related to pregnancy. The overall maternal mortality rate was 11.39 per 100,000 maternities. Direct deaths decreased from 6.24 per 100,000 maternities in 2003-2005 to 4.67 per 100,000 maternities in 2006–2008 (p = 0.02). This decline is predominantly due to the reduction in deaths from thromboembolism and, to a lesser extent, haemorrhage. For the first time there has been a reduction in the inequalities gap, with a significant decrease in maternal mortality rates among those living in the most deprived areas and those in the lowest socio-economic group. Despite a decline in the overall UK maternal mortality rate, there has been an increase in deaths related to genital tract sepsis, particularly from community acquired Group A streptococcal disease. The mortality rate related to sepsis increased from 0.85 deaths per 100,000 maternities in 2003-2005 to 1.13 deaths in 2006-2008, and sepsis is now the most common cause of Direct maternal death. Cardiac disease is the most common cause of Indirect death; the Indirect maternal mortality rate has not changed significantly since 2003-2005. This Confidential Enquiry identified substandard care in 70% of Direct deaths and 55% of Indirect deaths. Many of the identified avoidable factors remain the same as those identified in previous Enquiries. Recommendations for improving care have been developed and are highlighted in this report. Implementing the Top ten recommendations should be prioritised in order to ensure the overall UK maternal mortality rate continues to decline.
To study the efficacy of thromboprophylaxis with low molecular weight heparin (LMWH) in pregnant women with one previous venous thromboembolic event (VTE). Secondary aims were to study the long-term risk of secondary recurrence, bleeding and obstetric complications.
A prospective national study of long-term LMWH thromboprophylaxis in Sweden.
All hospitals in Sweden during January 1998-December 2002,
Pregnant women with one previous VTE and controls drawn from the Swedish Medical Birth Registry. The women were cross-matched with the Swedish Hospital Discharge Register to identify all recurrences and to ascertain the annual risk of recurrence.
Recurrence of VTE, bleeding complications at delivery and obstetric complications.
326 of 393 registered women could be evaluated. The relative risk reduction in VTE was 88%. There was an absolute increased risk of VTE during the thromboprophylaxis period: 1.2% compared to 0.2% among controls (p<0.001). The risk during the immediate post-treatment period (43-100 days post-partum) was increased 28-fold. The annual incidence of VTE after delivery was 1%. The risk of hematoma and major blood loss at delivery was increased during thromboprophylaxis (p<0.001). There were no differences in the incidences of preeclampsia, intrauterine growth restriction or placental abruption.
The relative risk reduction in VTE during thromboprophylaxis was 88%. After pregnancy, the annual long-term risk of recurrence was 1%. The risk was most pronounced in the post-treatment period. There was an increased risk of bleeding complications among women given LMWH, but there was no effect on obstetric complications.
The optimal approach for venous thrombosis (VTE) prophylaxis during pregnancy and postpartum in women with an increased risk of VTE is not established.
To evaluate the effectiveness, represented as the incidence of pregnancy-related VTE, and safety, represented as incidence of postpartum hemorrhage (PPH), of a protocol recommending prophylaxis with low-dose low-molecular-weight heparin (LMWH) in women at intermediate to high risk of VTE.
In this retrospective cohort study, we analyzed 34 women (44 pregnancies) with intermediate risk of VTE who received low-dose LMWH for 6 weeks postpartum and 57 women (82 pregnancies) with high risk of VTE who received low-dose LMWH during pregnancy and for 6 weeks postpartum. Pregnancy-related VTE was defined as VTE during pregnancy or ≤ 3 months postpartum. PPH was defined as blood loss >500 mL and severe PPH as blood loss > 1000 mL.
The incidence of pregnancy-related VTE was 5.5% (95% CI, 2.4-12.3) despite prophylaxis with low-dose LMWH. All events occurred in women at high risk, with a postpartum incidence of 7.0% (95% CI, 2.9-16.7) and antepartum incidence of 1.8% (95% CI, 0.4-9.2). The risk of PPH was 21.6% (95% CI, 14.3-31.3) and severe PPH 9.1% (95% CI, 4.7-16.9), which was not different in women who started LMWH postpartum and those who used LMWH during pregnancy.
Although prophylaxis with low-dose LMWH during pregnancy and postpartum proved to be safe, the risk of pregnancy-related VTE is considerable in women with a high risk of VTE. VTE prophylaxis with low-dose LMWH may not be sufficiently effective in these women.
Recently, there has been an increasing number of reports regarding adverse skin reactions to subcutaneous heparin administration. Case series have implied that heparin-induced skin lesions are predominantly associated with life-threatening heparin-induced thrombocytopenia (HIT) in at least 22% of patients. Skin lesions, therefore, have been included in clinical scores for HIT.
To determine the association of heparin-induced skin lesions with HIT. This would have a pivotal impact on further anticoagulatory management in patients with heparin-induced skin lesions.
In our observational cohort study, 87 consecutive patients with heparin-induced skin lesions (85 occurring during low-molecular-weight heparin administration) were evaluated using a standardized internal protocol, including HIT diagnostics (heparin-platelet factor 4-ELISA, heparin-induced platelet activation assay), platelet count monitoring, clinical/sonographical screening for thrombosis, skin allergy testing and, if necessary, histology. Results: None of the observed heparin-induced skin lesions was due to HIT; all lesions were caused by delayed-type IV-hypersensitivity reactions (DTH) instead. Even the cutaneous reaction in one patient with concomitant HIT could be classified histologically as DTH reaction, amounting to an association of heparin-induced skin lesions and HIT in 1.2% (1/87; 95% confidence interval, 0.00-0.06).
Heparin-induced skin lesions associated with use of low-molecular-weight heparins do not seem to be strongly associated with a systemic immunologic reaction in terms of HIT and might rather be due to DTH reactions than due to microvascular thrombosis. Hence, we propose refining existing pretest probability scores for HIT, unless underlying causes have been clarified.
It is not known whether women who develop venous thromboembolism (VTE) during pregnancy have a higher or lower incidence of recurrent VTE than women with unprovoked VTE. The aim of the study was to compare the risk of recurrent VTE among women with pregnancy-associated VTE to women with unprovoked VTE. Hospital discharge data identified women age 18-46 years old with pregnancy-associated or unprovoked index VTE between 1994 and 2005. Risk of recurrent VTE was compared between six and 60 months after the index event using both age-matched comparison of disease-free survival and proportional hazard modelling, adjusting for age and other risk factors. The Kaplan-Meier incidence of recurrent VTE in 1085 women with pregnancy-associated VTE was 5.8% versus 10.4% in 7625 women with unprovoked VTE (p = 0.02). Twelve of 34 (35%) recurrent events in the pregnancy-associated group occurred during a subsequent pregnancy compared with 29 of 331 (8.7%) events in the unprovoked group (p < 0.001). In the risk-adjusted multivariate model, women with pregnancy-associated VTE had a significantly lower risk of recurrent VTE (HR = 0.6, 95%CI = 0.4-0.9). Overall, the incidence of recurrent VTE during subsequent pregnancies was higher in the pregnancy group, 21 of 465 (4.5%), than in the unprovoked group, 37 of 1353 (2.7%, RR = 1.7, CI: 1.0-2.8). Compared to women with unprovoked VTE, women with pregnancy-associated VTE had a significantly lower long-term risk of recurrent VTE but a higher risk of recurrent VTE during a subsequent pregnancy. These findings should be considered when decisions are made about VTE prophylaxis in women with a history of pregnancy-associated VTE.
By sending a questionnaire (response rate 93%) to 321 women with a history of venous thromboembolism and previous coagulation tests, 72 patients were identified who had a total of 87 pregnancies after the thromboembolic episode. The main aim of the study was to analyze the influence of prophylaxis during pregnancy and delivery on the development of further thromboembolic complications. During pregnancy there was no difference in frequency of thromboses between the group given prophylaxis (n = 20) and the group not receiving it (n = 67). At delivery the frequency of thrombosis was 5.3% among the 57 women given prophylaxis and 11.1% among the 30 without prophylaxis, a difference that is not significant. The implication of these findings is discussed both concerning the indications for giving prophylaxis and concerning the problem of designing relevant prophylactic trials.
The risks of long-term antenatal subcutaneous heparin therapy were assessed in a small controlled trial of prophylaxis of thromboembolism. Forty patients with a documented history of previous thromboembolism were randomly allocated either to receive heparin (10000 i.u. subcutaneously twice daily) throughout pregnancy and labour or to receive no treatment (control group). All patients were treated with heparin (8000 i.u. twice daily) for 6 weeks after delivery from the first postnatal day. There appeared to be no increased risk of antenatal or postnatal bleeding associated with subcutaneous heparin, but one patient in the control group developed a deep vein thrombosis and one in the treatment group developed severe debilitating osteopenia. The withholding of epidural analgesia may have contributed to both maternal and fetal morbidity in the treatment group. There was one abortion in each group but no other fetal or neonatal losses although more babies from the treated group entered the special care baby unit. Although the numbers are too small for statistical analysis, the findings indicate that the use of long-term low-dose subcutaneous heparin is not without complications and there is need for a larger, multicentre trial to allow precise quantification of fetal and maternal risks against the risk of recurrent thromboembolism.
Venous thromboembolic disease remains the commonest cause of maternal death. The management of thromboprophylaxis in high risk women during pregnancy is contentious. Low molecular weight heparins (LMW) have theoretical advantages compared with unfractionated heparin and warfarin but have been poorly studied in pregnancy. We report on the use of LMW heparin (Fragmin) as thromboprophylaxis in thirty four high risk pregnancies.
All the women had a previous thrombosis or a thrombosis in their current pregnancy +/- a recognised thrombophilic state (eleven had the antiphospholipid syndrome).
Fragmin was given subcutaneously to maintain trough anti-Xa activity of 0.15-0.2 U/ml and 2 h post injection levels of 0.4-0.6 U/ml. The levels were checked monthly during pregnancy. Most women required 5,000U Fragmin once daily during the first trimester unless they were greater than 100 kg at the start of pregnancy. The mean time for dosage increase was 20.5 week (S.D. 8.2). 26/34 pregnancies (76%) required twice daily at the end of pregnancy. Epidural anaesthesia was managed by omitting Fragmin dose or inserting the needle 6 hours after the previous Fragmin injection. There were no thromboembolic events, thrombocytopenias or excessive haemorrhage. One woman had osteoporotic vertebral collapse post partum, she had no other risk factors for osteoporosis.
LWM heparin (Fragmin) appears to be efficacious in preventing recurrent thromboembolic disease in pregnant women at high risk, but it is notable that osteoporotic fractures occurred post partum in one woman. Further trials are required to determine optimal dosage and safety.
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We performed a meta-analysis of all published studies of deep vein thrombosis during pregnancy and the puerperium using MEDLINE between 1966 and May 1998. Data were pooled using a random effects model. Fourteen studies included relevant information on deep vein thrombosis in pregnancy or the puerperium, and used objective testing to diagnose deep vein thrombosis. The pooled event rate for left sided or bilateral deep vein thrombosis was 82.2 percent (95 percent CI 75.1 to 87.5). There was no statistical evidence of heterogeneity for this figure (P = .08). Twelve studies reported on the trimester in which deep vein thrombosis was diagnosed. The deep vein thrombosis event rate during the first trimester was 21.9 percent (95 percent CI 17.4 to 27.3), 33.7 percent (95 percent CI 28.1 to 39.8) during the second trimester, and 47.6 percent (95 percent CI 39.2 to 56.2) for the third trimester. Heterogeneity testing was not significant. Nine studies compared deep vein thrombosis events between the antepartum and puerperium periods, with 65.5 percent (95 percent CI 58.1 to 72.1) arising during pregnancy, and 34.5 percent (95 percent CI 27.9 to 41.9) postpartum (P = .08, not heterogeneous). Using these figures, the estimated relative distribution of 100 deep vein thrombosis events during pregnancy and the puerperium would be 0.23 per day during pregnancy, and 0.82 per day in the postpartum period. During pregnancy and the puerperium, deep vein thrombosis is more likely to arise in the left leg. More than half of all deep vein thromboses during pregnancy occur during the first and second trimesters. Furthermore, during the puerperium, the risk of developing deep vein thrombosis is significantly higher than antepartum.
Target audience:
Obstetricians & Gynecologists, Family Physicians.
Learning objectives:
After completion of this article, the reader will be able to understand the incidence and distribution of DVTs during pregnancy and to be able to appreciate the differing risk of DVT during the various time periods in a pregnancy.
To estimate the incidence, timing, and associated clinical characteristics of objectively diagnosed pregnancy-associated venous thromboembolism.
We retrospectively reviewed venous thromboembolism cases (deep venous thrombosis and pulmonary embolism) that occurred between 1978 and 1996. Study inclusion criteria required the objective diagnosis with either Doppler ultrasound, venography, impedance plethysmography, pulmonary angiography, ventilation-perfusion scanning, or computed tomography or magnetic resonance imaging.
Among 268,525 deliveries there were 165 (0.06%) episodes of venous thromboembolism (one per 1627 births). There were 127 cases of deep venous thrombosis and 38 cases of pulmonary embolism. Only 14% (23 of 165 patients) had a history of venous thromboembolism. Most cases of deep venous thrombosis were in the left leg (104 of 127, 81.9%), with nearly three quarters of them (94 of 127, 74.8%) occurring during the antepartum period. Among cases of antepartum deep venous thrombosis, half were detected before 15 weeks' gestation (47 of 95, 49.5%), and only 28 cases occurred after 20 weeks (P < .001). Most of the pulmonary embolisms occurred in the postpartum period (23 of 38, 60.5%) and were strongly associated with cesarean delivery (19 of 36,470 compared with four of 232,032, P < .001).
The incidence of venous thromboembolism during pregnancy is lower than has been previously described. Most cases occurred in the antepartum period, with the risk of deep venous thrombosis appearing to begin even before the second trimester.
Women with a history of venous thromboembolism may be at increased risk for venous thromboembolic events during pregnancy. In these women, the decision to give or withhold heparin in the antepartum period is controversial, because accurate estimates of the frequency of recurrent thromboembolic events if antepartum heparin is withheld are not available.
We prospectively studied 125 pregnant women with a single previous episode of venous thromboembolism. Antepartum heparin was withheld, but anticoagulant therapy was given for four to six weeks post partum. Our primary objective was to determine the rate of antepartum recurrence of venous thromboembolism. Laboratory studies were performed to identify thrombophilia in 95 women.
Three of the 125 women (2.4 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 0.2 to 6.9 percent). There were no recurrences in the 44 women who had no evidence of thrombophilia and who also had a previous episode of thrombosis that was associated with a temporary risk factor. Among the 51 women with abnormal laboratory results or a previous episode of idiopathic thrombosis, or both, 3 (5.9 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 1.2 to 16.2 percent).
The risk of recurrent antepartum venous thromboembolism in women with a history of venous thromboembolism is low, and therefore routine antepartum prophylaxis with heparin is not warranted.
The purpose of this study was to conduct pilot studies for large randomized controlled trials to compare low-molecular-weight heparin with placebo for antenatal thromboprophylaxis (trial 1), and for thromboprophylaxis after cesarean delivery (trial 2).
Multicenter randomized controlled trials (trial 1, 23 units; trial 2, 8 units) were conducted. Pregnant women at increased risk for thromboembolic disease were eligible for trial 1; women who underwent cesarean delivery were eligible for trial 2. The interventions were once daily injections of low-molecular-weight heparin or placebo. Primary outcomes were as follows: trial 1, confirmed symptomatic thromboembolic events and symptomatic osteoporotic fractures; trial 2, confirmed symptomatic thromboembolic events and wound complications.
Sixteen women were recruited for trial 1; 1 woman in the placebo group had a symptomatic thromboembolic event. One hundred forty-one women were recruited for trial 2; 1 woman in the low molecular weight heparin group had a symptomatic thromboembolic event.
Poor recruitment indicates that large-scale trials using these designs would be difficult. Collection of data on the number of women that are eligible and the reasons for nonrecruitment in future trials of these interventions would allow a better understanding of the reasons for poor recruitment.
Limited data exist on the risk of pregnancy-associated venous thromboembolism (VTE) in women with a history of VTE. Objective: To evaluate the risk of recurrent pregnancy-associated thrombosis in women with previous VTE in a large retrospective cohort study.
One hundred and fifty-nine women with at least one pregnancy (293 pregnancies in total) after a VTE were included into the study. The patients underwent a standardized interview on their history of thrombosis and pregnancy-associated complications.
Eight recurrent events occurred during 197 pregnancies without thrombosis prophylaxis. The probability of VTE during pregnancy without thrombosis prophylaxis was 6.2% (95% confidence interval 1.6-10.9%). The risk was constant over the whole period of pregnancy. Of the eight women with VTE during pregnancy four had heterozygous FV:R506Q, two in combination with hyperhomocysteinemia. No VTE occurred during 87 pregnancies with thrombosis prophylaxis. In the postpartum period 15 VTEs occurred, two of 83 (2.4%) after pregnancy termination, one of 53 (1.9%) after miscarriage, three of 10 (30%) after stillbirth and nine of 138 (6.5%) after live birth.
Without thrombosis prophylaxis the risk for recurrent symptomatic VTE is substantial during the whole period of pregnancy in women with previous VTE. The majority of events occurred after delivery, reflecting the very high risk during the postpartum period. Prospective and comparative trials to ascertain efficacy and safety of prophylactic heparin are urgently needed.
The risk for venous thromboembolism during pregnancy or postpartum is uncertain.
To estimate the relative and absolute risk for deep venous thrombosis and pulmonary embolism during pregnancy and postpartum and to describe trends in incidence.
Population-based inception cohort study using the resources of the Rochester Epidemiology Project.
Olmsted County, Minnesota.
Women with deep venous thrombosis or pulmonary embolism first diagnosed between 1966 and 1995, including women with venous thromboembolism during pregnancy or the postpartum period (defined as delivery of a newborn no more than 3 months before the deep venous thrombosis or pulmonary embolism event date, including delivery of a stillborn infant after the first trimester).
The authors obtained yearly counts of live births in Olmsted County between 1966 and 1995 from the Minnesota Department of Health.
The relative risk (standardized incidence ratio) for venous thromboembolism among pregnant or postpartum women was 4.29 (95% CI, 3.49 to 5.22;P < 0.001), and the overall incidence of venous thromboembolism (absolute risk) was 199.7 per 100,000 woman-years. The annual incidence was 5 times higher among postpartum women than pregnant women (511.2 vs. 95.8 per 100,000), and the incidence of deep venous thrombosis was 3 times higher than that of pulmonary embolism (151.8 vs. 47.9 per 100,000). Pulmonary embolism was relatively uncommon during pregnancy versus the postpartum period (10.6 vs. 159.7 per 100,000). Over the 30-year study period, the incidence of venous thromboembolism during pregnancy remained relatively constant whereas the postpartum incidence of pulmonary embolism decreased more than 2-fold.
Because the Olmsted County population was 98% white and of non-Hispanic ethnicity, the results may not be generalizable to other ethnicities.
Among pregnant women, the highest risk period for venous thromboembolism and pulmonary embolism in particular is during the postpartum period. Any prophylaxis against these events should be particularly targeted to postpartum women. Although the incidence of pulmonary embolism has decreased over time, the incidence of deep venous thrombosis remains unchanged, indicating the need to better identify pregnant women at increased risk.
The purpose of this study was to estimate the incidence, risk factors, and mortality from pregnancy-related venous thromboembolism.
The Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality for the years 2000 to 2001 was queried for all pregnancy-related discharges with a diagnosis of venous thromboembolism.
The rate of venous thromboembolism was 1.72 per 1000 deliveries with 1.1 deaths per 100,000. The risk of venous thromboembolism was 38% higher for women ages 35 and older and 64% higher for black women. Other significant risk factors included thrombophilia, lupus, heart disease, sickle cell disease, obesity, fluid and electrolyte imbalance, postpartum infection, and transfusion. The risk factor with the highest odds ratio, 51.8 (38.7-69.2) was thrombophilia.
The incidence of pregnancy-related venous thromboembolism was higher than generally quoted. Women ages 35 and older, black women, and women with certain medical conditions and obstetric complications appear to be at increased risk.
Whether or not pregnant women with a previous episode of venous thromboembolism (VTE) should receive antithrombotic prophylaxis is a matter of debate. In order to estimate the rate of recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE) during pregnancy and puerperium we retrospectively investigated a cohort of 1104 women with previous VTE; after a single DVT or isolated PE, 88 of them became pregnant at least once without receiving antithrombotic prophylaxis. Overall, 155 pregnancies and 120 puerperium periods without prophylaxis were recorded. There were nine recurrences during pregnancy and 10 during puerperium, with a rate of 5.8% [95% confidence interval (CI) 3.0-10.6] and 8.3% (95%CI 4.5-14.6) respectively. In pregnancy, the rate of recurrence was 7.5% (95%CI 4.0-13.7) if the first VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the first VTE was related to other transient risk factors. In puerperium, the rate of recurrence was 15.5% (95%CI 7.7-28.7) in women with a pregnancy-related first VTE, with a risk 3.9-times higher than in the remaining women. Inherited thrombophilia was not associated with a statistically significant increase in risk of recurrence in pregnancy or in puerperium, yet the rate of recurrence in puerperium was 14.2% (95%CI 5.7-31.4) in overall carriers of factor V Leiden and 30% (95%CI 10.7-60.3) in carriers with a pregnancy-related first VTE, with a risk 6.8 times higher than in women without thrombophilia and with a non pregnancy-related first VTE.
Venous thrombosis is one of the leading causes of maternal morbidity and mortality. Objective: In the MEGA study, we evaluated pregnancy and the postpartum period as risk factors for venous thrombosis in 285 patients and 857 control subjects.
Between March 1999 and September 2004, consecutive patients with a first episode of venous thrombosis were included from six anticoagulation clinics. Partners of patients and a random digit dialing group were included as control subjects. Participants completed a questionnaire and DNA was collected.
The risk of venous thrombosis was 5-fold (OR, 4.6; 95% CI, 2.7-7.8) increased during pregnancy and 60-fold (OR, 60.1; 95% CI, 26.5-135.9) increased during the first 3 months after delivery compared with non-pregnant women. A 14-fold increased risk of deep venous thrombosis of the leg was found compared with a 6-fold increased risk of pulmonary embolism. The risk was highest in the third trimester of pregnancy (OR, 8.8; 95% CI, 4.5-17.3) and during the first 6 weeks after delivery (OR, 84.0; 95% CI, 31.7-222.6). The risk of pregnancy-associated venous thrombosis was 52-fold increased in factor V Leiden carriers (OR, 52.2; 95% CI, 12.4-219.5) and 31-fold increased in carriers of the prothrombin 20210A mutation (OR, 30.7; 95% CI, 4.6-203.6) compared with non-pregnant women without the mutation.
We found an increased risk of venous thrombosis during pregnancy and the postpartum period, with an especially high risk during the first 6 weeks postpartum. The risk of pregnancy-associated venous thrombosis was highly increased in carriers of factor V Leiden or the prothrombin 20210A mutation.
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