Practice bulletin no. 123: thromboembolism in pregnancy

Pregnant women have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women (1, 2). Approximately 80% of thromboembolic events in pregnancy are venous (3), with a prevalence of 0.5–2.0 per 1,000 pregnant women (4–9). Venous thromboembolism, including pulmonary embolism, accounts for 1.1 deaths per 100,000 deliveries (3), or 9 % of all maternal deaths in the United States (10). In the developing world, the leading cause of maternal death is hemorrhage (11); however, in developed nations, where hemorrhage is more often successfully treated and prevented, thromboembolic disease is one of the leading causes of death (12). The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. The purpose of this document is to provide information regarding the risk factors, diagnosis, management, and prevention of thromboembolism, particularly venous thromboembolism in pregnancy.     

Thromboembolism in pregnancy: recurrence and its prevention

Fifteen to 25% of thromboembolic events in pregnancy are recurrent events. Women with a history of thrombosis have a three- to fourfold increased risk of recurrence when they are pregnant compared with when they are not. The risks are even higher postpartum. The rate of recurrent venous thromboembolic events without anticoagulation is 2.4% to 12.2%, whereas the rate with anticoagulation is 0% to 2.4%. Because the rates of recurrent thromboembolism can be reduced with anticoagulation, women with a history of thrombosis who are not on lifelong anticoagulation will likely require anticoagulation during pregnancy, or at least during the postpartum period. Women who are already on lifelong warfarin for the prevention of recurrent venous thromboembolism should be counseled about the teratogenic effects of warfarin and offered the opportunity to be converted to heparin before conception. During pregnancy, low-molecular-weight heparin, with fewer side effects and a longer half-life, is generally preferred over unfractionated heparin. Unfractionated heparin with its shorter half-life is generally preferred around the time of delivery. Women on antiplatelet medication for prevention of arterial thromboembolism may be converted to low-dose aspirin after conception and supplemented with low-dose heparin or low-molecular-weight heparin during pregnancy. Because current recommendations rely on case series and expert opinion, additional studies including randomized trials might enhance our ability to prevent recurrent thromboembolism in pregnancy.     

Risk factor scoring for predicting venous thromboembolism in obstetric patients

OBJECTIVE: The aim of this study was to develop a risk factor scoring system for the prediction of venous thromboembolism in obstetric patients. STUDY DESIGN: We conducted a retrospective case-control study of all pregnant or postpartum women admitted to the Jack D. Weiler Hospital from 1987 through 1998 with a discharge diagnosis indicating thromboembolism. For each study subject the three women who were delivered immediately before that index patient were selected for the control group. Data collected included the following: history of thrombosis, age, body mass index, previous abdominal surgical procedures, presence of systemic diseases, and blood type. Each patient was assigned a score that was based on the risk factors identified. RESULTS: We identified 21 patients who had sustained thromboembolic events during pregnancy or 6 weeks post partum. Nineteen of the thromboembolic events (90%) were diagnosed during pregnancy, and these cases were distributed throughout gestation-8 (42%) in the first trimester, 2 (10%) in the second trimester, and 9 (48%) in the third trimester. Six (28%) of these patients had pulmonary embolisms. Two cases of postpartum thromboembolic events were documented. Both were cases of pulmonary embolism. There was 1 maternal death. Patients with a score >2 were at significantly increased risk for having a thromboembolism, with an odds ratio of 4.8 (P <.05). The sensitivity, specificity, positive predictive value, and negative predictive value of this cutoff point were 21%, 95%, 57%, and 78%, respectively. CONCLUSION: Obstetric patients with high risk factor scores were at increased risk for thromboembolism.     

Anticoagulant prophylaxis in women affected by thrombophilia and previous obstetric complications

Pregnancy is a condition of excessive clotting due to a decrease of some coagulation factors and a reduction of anticoagulant proteins, such as protein S. It is known that the causes of congenital or acquired thrombophilia may be associated with an increased risk of venous thromboembolism during pregnancy and/or obstetric complications, such early or late fetal loss, intrauterine fetal deaths, pre-eclampsia, fetal growth restriction. During pregnancy the use of a prophylaxis with antithrombotic drugs is considered at present a promising opportunity to significantly reduce the prevalence of thromboembolic complications, improving maternal and fetal outcomes. This article is a review to most recent evidence of pregnant anticoagulant prophylaxis in women with previous thromboembolic events.     

Factor V Leiden and prothrombin 20210 G-A mutations in controls and in patients with thromboembolic events during pregnancy or the puerperium

Factor V Leiden and prothrombin 20210 G-A mutations are independent risk factors for venous thrombosis. We studied the frequency of these mutations in 35 patients who had thromboembolic events during pregnancy and puerperium, and in 32 women who had a history of uncomplicated pregnancy, delivered either vaginally or by cesarean section, and did not have a past history of thromboembolism. Factor V Leiden mutation was present in 7 patients (20%) in the study group. Of these 7 patients, 1 was homozygote, whereas the remaining 6 were heterozygote for the mutation. Prothrombin 20210 G-A mutation was present in 2 patients (5.7%) in the study group. In the control group none of the 32 patients was positive for the factor V Leiden and prothrombin 20210 G-A mutations. Our findings indicate that the factor V Leiden mutation is an important risk factor for thromboembolic disease during pregnancy or puerperium.     

Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes

Venous thromboembolism and adverse pregnancy outcomes are potential complications of pregnancy. Numerous studies have evaluated both the risk factors for and the prevention and management of these outcomes in pregnant patients. This consensus group was convened to provide concise recommendations, based on the currently available literature, regarding the use of antithrombotic therapy in pregnant patients at risk for venous thromboembolic events and adverse pregnancy outcomes.     

Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series

Objectives To assess the use of low molecular weight heparin for the treatment of venous thromboembolism in pregnancy.
Design A prospective observational study.
Setting The maternity units in two university teaching hospitals and one district general teaching hospital.
Population Thirty-six consecutive women presenting with objectively diagnosed venous thromboembolism during pregnancy and the immediate puerperium.
Methods Treatment with the low molecular weight heparin enoxaparin, approximately 1 mg/kg sc, twice daily, based on early pregnancy weight.
Main outcome measures Peak anti-Xa activity (three hours post-injection), alterations in treatment, side effects and the use of regional anaesthesia.
Results In 33 women, the initial dose of enoxaparin provided satisfactory peak anti-Xa activity (median 0.8 u/mL, range 0.44–1.0 u/mL) and was continued. Three women required dose reduction since peak anti-Xa activities were above the therapeutic range (1.2, 1.2 and 1.1 u/mL). No woman developed thrombocytopaenia, haemorrhagic complication or further thromboembolic episode. Two women developed allergic skin reactions on enoxaparin and were changed to tinzaparin. Fifteen women had regional anaesthesia for delivery, with a reduced dose of enoxaparin (40 mg once daily), all without complication.
Conclusions Enoxaparin is a safe and effective treatment for venous thromboembolism during pregnancy and confers a major advantage over unfractionated heparin through its simplified regimen of administration.     

Prophylactic and therapeutic enoxaparin during pregnancy: indications, outcomes and monitoring

OBJECTIVES: To evaluate the efficacy and safety of prophylactic and therapeutic enoxaparin in pregnancy. STUDY DESIGN: Three-year prospective audit. SETTING: Tertiary level obstetric hospital. POPULATION: Fifty-two women who received subcutaneous enoxaparin, either a prophylactic dose (40 mg daily) in 26 pregnancies or therapeutic dose (1 mg/kg twice daily) in 32 pregnancies. MATERIALS AND METHODS: Pregnant women treated with enoxaparin were prospectively entered into a register. Data were retrieved by case note review. MAIN OUTCOME MEASURES: Pregnancy outcomes, treatment complications and anti-Xa levels. RESULTS: In the prophylactic group there were no fetal losses, thromboembolic events or complications related to enoxaparin. In the therapeutic group there were four first trimester miscarriages, a termination and 27 live births. Therapeutic enoxaparin prevented further thromboembolism without complications. One woman was treated with intermediate dose enoxaparin when she presented at 5 weeks' gestation on warfarin and 7 weeks after a venous thromboembolism. She developed a recurrent pulmonary embolus 3 weeks later and was subsequently treated with therapeutic enoxaparin. In the therapeutic group the enoxaparin dose/kg correlated poorly with anti-Xa levels, and dose adjustments were made. Therapeutic mean (SD) trough and peak anti-Xa levels were 0.33 U/mL (0.14) and 0.86 U/mL (0.24) in the first trimester and 0.48 U/mL (0.19) and 0.84 U/mL (0.23) in the third trimester. CONCLUSIONS: In the present series, prophylactic and therapeutic enoxaparin treatment during pregnancy was effective and safe. Studies are required to determine the optimal duration of treatment with therapeutic enoxaparin following venous thromboembolism in pregnancy and the clinical relevance of anti-Xa monitoring.     

The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus

OBJECTIVE: We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes. METHODS: Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality. RESULTS: One hundred thirty-four FVL mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0-2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.08%, 95% confidence interval 0.02-0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were observed between FVL mutation carriers, carriers of other coagulation disorders, and controls. Maternal FVL mutation carriage was not associated with increased pregnancy loss, preeclampsia, placental abruption, or small for gestational age births. However, fetal FVL mutation carriage was associated with more frequent preeclampsia among African-American (15.0%) and Hispanic (12.5%) women than white women (2.6%, P = .04), adjusted odds ratio 2.4 (95% confidence interval 1.0-5.2, P = .05). CONCLUSION: Among women with no history of thromboembolism, maternal heterozygous carriage of the FVL mutation is associated with a low risk of venous thromboembolism in pregnancy. Neither universal screening for the FVL mutation, nor treatment of low-risk carriers during pregnancy is indicated. LEVEL OF EVIDENCE: II-2.     

Thromboembolic disease in pregnancy

Venous thromboembolic disease is a major cause of maternal morbidity and mortality. Virchow's triad of hypercoagulability, venous stasis, and vascular damage all occur during pregnancy. The risk of venous thromboembolism is five to six times higher during pregnancy and the puerperium. Risk factors include age greater than 35, antiphospholipid antibodies, inherited thrombophilias, operative delivery, increased parity, obesity, mechanical heart valves,and family history. Prophylactic and therapeutic anticoagulation is recommended for women at risk. Low molecular weight heparins are safe and effective in most cases.     

Thromboembolism in pregnancy

PURPOSE OF REVIEW: Venous thromboembolism is the leading cause of maternal death in the UK. Thrombophilia underlies many thrombotic disorders in pregnancy. The high prevalence of thrombophilic defects in the population, the association of defects with venous thromboembolism and the special considerations for management make it a widely debated subject. RECENT FINDINGS: A limited number of studies measuring the risk of venous thromboembolism in pregnancy with thrombophilia have been conducted within the last year. Studies confirm that heritable thrombophilias are associated with increased risk of venous thromboembolism in pregnancy. However, estimated risks vary between individual studies. The risk of venous thromboembolism with acquired thrombophilia remains unclear. Guidelines have been published to guide clinicians in preventing and treating venous thromboembolism in pregnancy; however, large-scale, randomized controlled trials need to be conducted to establish the effectiveness of administering antithrombotic agents in pregnancy. Although selective thrombophilia screening based on prior history of venous thromboembolism has been proposed, the overall clinical and economic benefit of universal and selective screening is unsupported. SUMMARY: Due to the lack of studies, gaps still exist in our knowledge of the risk of pregnancy-related venous thromboembolism associated with thrombophilia. In particular, accurate estimates are required for the risks of acquired thrombophilias. Furthermore, the true effectiveness of anticolagulants in pregnancy needs to be established through well-conducted studies and randomized controlled trials. These studies will inform clinicians and help to determine the optimum management and prevention strategies for thrombophilia and venous thromboembolism in pregnancy.     

Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy

Objective To assess the safety and efficacy of enoxaparin use for thromboprophylaxis or treatment of venous thromboembolism during pregnancy.
Design Retrospective review of casenotes of women who received enoxaparin during pregnancy.
Setting Obstetric Medicine Unit at Glasgow Royal Maternity Hospital.
Sample Data were obtained on 57 pregnancies in 50 women over six years.
Methods Information was obtained from case records in relation to outcome measures, the presence of underlying thrombophilia and indication for anticoagulation.
Main outcome measures Incidences of venous thromboembolism, haemorrhage, thrombocytopenia, peak plasma anti-factor Xa levels and symptomatic osteoporosis.
Results There were no thromboembolic events in the thromboprophylaxis group. There were no incidences of heparin-induced thrombocytopenia. Twenty-two women had spinal or epidural anaesthesia and no complications were encountered. There was one instance of antepartum haemorrhage following attempted amniotomy in a woman with previously unknown vasa praevia. Two women sustained postpartum haemorrhage, both secondary to vaginal lacerations, resulting in blood loss > 1000 mL. Blood loss following caesarean section was not excessive. No instances of vertebral or hip fracture were encountered. The median peak plasma anti-factor Xa level on a dose of 40 mg once daily was 0.235 U/mL; peak plasma anti-factor Xa levels were not affected by gestational age.
Conclusions The use of enoxaparin in pregnancy is associated with a low incidence of complications and a dose of 40 mg once daily throughout pregnancy provides satisfactory anti-factor Xa levels and appears effective in preventing venous thromboembolism.     

Bilateral internal jugular venous thrombosis following successful assisted conception in the absence of ovarian hyperstimulation syndrome

The majority of the venous thromboembolic events seen in patient following gonadotropin administration were associated with the development of ovarian hyperstimulation syndrome (OHSS). However, in this case report, a 29-year-old woman that conceived by controlled ovarian hyperstimulation, intracytoplasmic sperm injection and subsequent embryo transfer without conjunction of OHSS was described. Bilateral jugular venous thrombi were detected by duplex Doppler in the 8th week of pregnancy when she was admitted to the emergency room for difficulty in swallowing and bilateral neck pain. She had unremarkable history and negative results for thrombophilia screening. Full anticoagulation with intravenous heparin was initiated and continued subcutaneously throughout pregnancy. She delivered two healthy babies at 36 weeks of pregnancy. Venous thromboembolism should be taken in account in patients undergoing gonadotropin administration for assisted conception with the complaint of extremity pain regardless of having risk factors for thromboembolism.     

Incidence of thromboembolic complications in cesarean sections and heparin prophylaxis]

BACKGROUND AND AIM: Venous thromboembolism is a rare but severe complication of pregnancy and puerperium: it is the most frequent cause of death and maternal morbidity. Pregnancy leads to hemodynamic, hormonal and hematological changes which make hypercoagulability a secondary condition. In particular, surgical birth via an abdominal route is burdened with a higher risk of thromboembolic disease compared to spontaneous birth. The aim of this study was to highlight the increased incidence of deep venous thrombosis and pulmonary embolism after caesarean section. METHODS: All the pregnant women (no = 879) admitted to the institute from January 1997 to May 1998 were monitored: their clinical conditions were followed both during the last period of pregnancy and after birth in order to identify the onset of pre- and post-partum thromboembolic episodes. RESULTS: Among the women examined, 9 cases (1.02%) of lung embolism were observed, one of which was fatal. All 9 women had undergone caesarean section and in all cases the thromboembolic episode occurred between the second and fourth day after birth. Prophylactic therapy was not administered in any of the above cases. CONCLUSIONS: It is important that anti-thrombotic prophylaxis with heparin should be administered. Although this presents a number of collateral effects (hemorrhage, platelet deficiency, osteoporosis), it protects the woman from the risk of thromboembolic episodes, above all if a caesarean section is performed or if the personal and/or family medical history is positive for this pathology.     

Management of thromboembolism in pregnancy

The incidence of venous thromboembolism is increased during pregnancy and the postpartum period. This risk is high for women with documented hereditary or acquired risk factors who have experienced a prior thrombotic event. These individuals require a minimum of prophylactic dose anticoagulation with unfractionated or low molecular weight heparin during pregnancy, with anticoagulation continuing for 4 to 6 weeks postpartum. Women receiving therapeutic dose anticoagulation with warfarin before pregnancy for a hereditary or acquired condition should be transitioned to therapeutic doses of unfractionated heparin or low molecular weight heparin before or within 6 weeks of becoming pregnant, and can then resume warfarin postpartum. Women experiencing a thromboembolic event during pregnancy should receive therapeutic treatment with unfractionated heparin or low molecular weight heparin during pregnancy, with anticoagulation continuing for 4 to 6 weeks postpartum, and for a total of at least 6 months.     

Venous thromboembolism during pregnancy. Clinical suspicion warrants evaluation

OBJECTIVE: To determine the incidence, signs, symptoms and clinical outcomes of venous thromboembolism (VTE) during pregnancy. STUDY DESIGN: A retrospective review was conducted from 1997 to 2001 including women with a diagnosis or suspicion of VTE during pregnancy. Demographics and clinical characteristics of patients with a suspicion for VTE were reviewed. RESULTS: Of 70 patients assessed for evidence of a VTE, 25.7% (n = 18) had confirmatory diagnostic testing. There was no difference in the clinical signs or symptoms between groups with a pulmonary embolism (PE) compared to those without a PE. For those patients with negative diagnostic testing (n = 52), an alternative diagnosis was confirmed in 55.8%. Of the patients with positive diagnostic testing, 30% had a concurrent condition contributing to their pulmonary symptoms. CONCLUSION: Lack of definitive signs and symptoms of thromboembolic disease during pregnancy warrants complete evaluation of patients clinically suspected of having VTE.     

Thromboembolic risk in pregnant women with SARS-CoV-2 infection – A systematic review

The infection by SARS-CoV-2 is associated with a thromboembolic complications risk theoretically increased. Pregnancy, isolated, is considered a pro-thrombotic state.This systematic review has the main goal to evaluate the thromboembolic risk in pregnant women with COVID-19 disease, namely for pulmonary embolism (PE) and deep vein thrombosis (DVT). The secondary goal is the evaluation of the need for thromboprophylaxis in these cases.Three databases - PubMed, Scopus and Web of Science – were searched on October 2021, using the following Mesh terms and keywords: “(covid-19 OR SARS-CoV-2 OR Covid) AND (pregnancy) AND (coagulopathy OR blood coagulation disorders OR thrombotic complications OR thromboembolic risk OR venous thromboembolism OR venous thrombosis)”. Information about thrombotic complications in pregnancy and thromboprophylaxis was collected, by two independent reviewers.In total, 12 articles were analyzed, corresponding to 18205 pregnant women with SARS- CoV-2 infection. A total of 85 cases of thromboembolic events were diagnosed (0.46%, 95% CI 0.37–0.58%), of which only 17 reported the use of thromboprophylaxis (20.00%, 95% CI 12.10–30.08%). There were 3 deaths due to thromboembolic complications (3.53%, 95% CI 0.73–9.97%).In conclusion, in pregnant women, the SARS-CoV-2 infection increases the risk of thromboembolic complications. However, the risk is not greater than in the general population. It is recommended thromboprophylaxis with low molecular weight heparin for hospitalized pregnant women, and in groups with moderate to high thromboembolic risk at home self-isolation.     

Thrombophilia and adverse pregnancy outcome

PURPOSE OF REVIEW: Recent case-control studies and metaanalyses have attempted to quantify the risks associated with individual thrombophilic defects and adverse clinical events in pregnancy, including fetal loss, preeclampsia, placental abruption and intrauterine growth restriction. This review has examined the evidence. RECENT FINDINGS: The literature is in general agreement that thrombophilia increases the risk of venous thromboembolism and adverse pregnancy outcomes, including pregnancy loss, preeclampsia, placental abruption and intrauterine growth restriction in pregnancy. However, the size of the estimated risks varies between individual studies due to heterogeneity in study design. Low-molecular-weight heparin has been shown to be the superior choice, on the grounds of safety and effectiveness, in preventing venous thromboembolism and improving pregnancy loss. Large-scale, randomized controlled studies are required, however, to confirm these findings. Although selective thrombophilia screening based on prior venous thromboembolism history has been shown to be marginally more cost-effective than universal screening in pregnancy, the overall clinical and economic benefit of universal and selective screening is unsupported. SUMMARY: Despite the growing evidence in the literature, there are still gaps in our knowledge of thrombophilia and pregnancy. In particular, accurate estimates are required of the risks of venous thromboembolism and adverse pregnancy outcomes associated with some thrombophilias and the relative clinical and cost-effectiveness of different anticoagulation therapies in the prevention of venous thromboembolism and pregnancy loss. More large-scale studies are required to better inform clinicians and help determine optimum management and prevention strategies of thrombophilia and associated adverse clinical events in pregnancy.     

妊娠期及产褥期静脉血栓12例临床分析

目的 探讨妊娠期和产褥期静脉血栓的发生率,病因诊断,预防和治疗。方法 回顾性分析１９８４年１月至１９９７年１２月间,我院住院诊治的１２例妊娠期及产褥期深静脉血栓栓塞患者的临床资料,并对４例患者进行蛋白Ｃ、蛋白Ｓ、抗凝血酶Ⅲ活性和活化蛋白Ｃ抵抗（ＡＰＣ－Ｒ）的测定,同时进行凝血因子Ｖ（ＦＶ）１６９１位核苷酸基因变异（ＦＶ Ｌｅｉｄｅｎ变异）筛选。结果 ４例血栓发生在妊娠期,８例发生在产褥期;２例合并     

Factor V Leiden mutation: the most commonly inherited risk factor for venous thromboembolism

Factor V Leiden mutation is a common genetic risk factor for venous thrombosis. It has been documented in up to 65% of patients with unexplained venous thromboembolism. This genetic mutation is now known to be the most common inherited cause of activated protein C (APC) resistance. Recently, FV Leiden mutation has been associated with adverse pregnancy outcomes (including recurrent fetal loss, severe preeclampsia, placental abruption, intrauterine growth restriction and stillbirth), in addition to venous thromboembolic disorders. In this article, we discuss the genetic basis, diagnosis and clinical significance of FV Leiden mutation. Awareness of the clinical manifestations associated with FV Leiden mutation should ensure screening of appropriate populations and prophylaxis against thromboembolic disease when indicated.