Diagnosis and management of thrombosis in pregnancy

Pregnancy‐related thrombosis is a major cause of maternal mortality. Pregnancy and the puerperium are associated with a fourfold to fivefold increased risk of thrombosis when compared with the nonpregnant state. The greatest time of risk is in the postpartum period. Diagnosis of venous thromboembolism (VTE) during pregnancy can be challenging as many of the symptoms can be associated with normal pregnancy. Almost all deep venous thrombosis occurs in the left leg or iliac veins. Diagnostic procedures for pulmonary embolism carry some exposure to radiation, although risks are low when compared with risks associated with an undiagnosed maternal PE. The anticoagulant of choice during pregnancy is low‐molecular‐weight heparin. Certain medical conditions require alternative approaches as management around the time of delivery. In women with VTE during pregnancy, anticoagulation should continue for at least 3 months and until at least 6 weeks postpartum. Birth Defects Research (Part C) 105:185–189, 2015. © 2015 Wiley Periodicals, Inc.     

The Incidence of First Venous Thromboembolism in and around Pregnancy Using Linked Primary and Secondary Care Data: A Population Based Cohort Study from England and Comparative Meta-Analysis

Background

Recent linkage between primary and secondary care data has provided valuable information for studying heath outcomes that may initially present in different health care settings. The aim of this study was therefore, twofold: to use linked primary and secondary care data to determine an optimum definition for estimating the incidence of first VTE in and around pregnancy; and secondly to conduct a systematic literature review of studies on perinatal VTE incidence with the purpose of comparing our estimates.

Methods

We used primary care data from the Clinical Practice Research Datalink (CPRD), which incorporates linkages to secondary care contained within Hospital Episode Statistics (HES) between 1997 and 2010 to estimate the incidence rate of VTE in the antepartum and postpartum period. We systematically searched the literature on the incidence of VTE during antepartum and postpartum periods and performed a meta-analysis to provide comparison.

Findings

Using combined CPRD and HES data and a restrictive VTE definition, the absolute rate during the antepartum period and first six weeks postpartum (early postpartum) were 99 (95%CI 85–116) and 468 (95%CI 391–561) per 100,000 person-years respectively. These were comparable to the pooled estimates from our meta-analysis (using studies after 2005) during the antepartum period (118/100,000 person-years) and early postpartum (424/100,000 person-years). When we used only secondary care data to identify VTE events, incidence was lower during the early postpartum period (308/100,000 person-years), whereas relying only on primary care data lead to lower incidence during the time around delivery, but higher rates during the postpartum period (558/100,000 person-years).

Conclusion

Using combined CPRD and HES data gives estimates of the risk of VTE in and around pregnancy that are comparable to the existing literature. It also provides more accurate estimation of the date of VTE diagnosis which will allow risk stratification during specific pregnancy and postpartum periods.     

Pregnancy Incidence and Risk Factors among Women Participating in Vaginal Microbicide Trials for HIV Prevention: Systematic Review and Meta-Analysis

Introduction

Pregnancy is contraindicated in vaginal microbicide trials for the prevention of HIV infection in women due to the unknown maternal and fetal safety of the microbicides. Women who become pregnant are taken off the microbicide during pregnancy period but this result in reduction of the power of the trials. Strategies to reduce the pregnancy rates require an understanding of the incidence and associated risk factors of pregnancy in microbicide trials. This systematic review estimates the overall incidence rate of pregnancy in microbicide trials and describes the associated risk factors.

Methods

A comprehensive literature search was carried out to identify eligible studies from electronic databases and other sources. Two review authors independently selected studies and extracted relevant data from included studies. Meta-analysis of incidence rates of pregnancy was carried out and risk factors of pregnancy were reported narratively.

Results

Fifteen studies reporting data from 10 microbicide trials (N=27,384 participants) were included. A total of 4,107 participants (15.0%) fell pregnant and a meta-analysis of incidence rates of pregnancy from 8 microbicide trials (N=25,551) yielded an overall incidence rate of 23.37 (95%CI: 17.78 to 28.96) pregnancies per 100 woman-years. However, significant heterogeneity was detected. Hormonal injectable, intra-uterine device (IUD) or implants or sterilization, older age, more years of education and condom use were associated with lower pregnancy. On the other hand, living with a man, history of pregnancy, self and partner desire for future baby, oral contraceptive use, increased number of unprotected sexual acts and inconsistent use of condoms were associated with higher pregnancy.

Conclusions

The incidence rate of pregnancy in microbicide trials is high and strategies for its reduction are urgently required in order to improve the sample size and power of these trials.     

Venous thromboembolism and anticoagulant therapy in pregnancy

Background:Venous thromboembolism (VTE) is a leading cause of maternal mortality in western countries. Many of these deaths could be prevented by optimal prophylaxis and management.Objective:The aim of this study was to examine the current literature to assess the risk of VTE in pregnant women and to identify the most effective and safe anticoagulant therapy.Methods:A search was conducted using the major electronic databases of PubMed and MEDLINE 1996–October 2005 using the following key words: Pregnancy, venous thrombosis, thrombophilia, prosthetic heart valves, anticoagulants, heparin, low-molecular-weight heparin, coumarin, and warfarin.Results:The common risk factors for VTE during pregnancy are age >35 years, obesity, operative delivery, thrombophilia, and a family or personal history of VTE. Coumarins are unsuitable for use during pregnancy because of embryopathy and risk of fetal bleeding. Low-molecular-weight heparins (LMWHs), such as enoxaparin and dalteparin, are safer and more convenient than unfractionated heparin (UFH). LMWH is now the agent of choice for pharmacologic thromboprophylaxis and treatment of VTE during pregnancy. Women with a suspected VTE should receive anticoagulant therapy until an objective diagnostic test is performed, unless there is a clear contraindication to anticoagulation. If a VTE is confirmed, anticoagulant treatment should be continued throughout pregnancy. These patients usually, require at least 6 months of anticoagulation, and treatment should be continued until at least 6 weeks postpartum. Management of women with prosthetic heart valves in pregnancy is controversial; while coumarin treatment is more effective than UFH for thromboprophylaxis in the mother, UFH is associated with a better outcome for the fetus. Coumarin embryopathy can be avoided if heparin is substituted by 6 weeks' gestation. The limited data on LMWH in women with prosthetic heart valves suggest that it compares favorably with UFH.Conclusions:LMWH is now the anticoagulant of choice for the treatment and prevention of VTE in pregnancy. However, the management of women with prosthetic heart valves requiring anticoagulation in pregnancy remains controversial as coumarins appear safer for the mother, but heparin is associated with less fetal morbidity and data on LMWH are limited.     

A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases

Introduction

We performed a meta-analysis to investigate the risk of deep vein thrombosis (DVT) and/or pulmonary embolisms (PEs) in patients with inflammatory arthritis, vasculitis and connective tissue diseases (CTDs) (systemic lupus erythematosus (SLE), Sjögren’s syndrome, inflammatory myositis and systemic sclerosis (SSc)).

Methods

PubMed, Embase, the Cochrane databases and MEDLINE were searched to identify full-text English-language publications about adult patients with rheumatologic inflammatory diseases and venous thromboembolisms (VTEs). Data regarding rates of DVTs and PEs were extracted. Using random-effects models, pooled estimates for VTEs in individual and pooled diseases were compared with matched populations where possible. Studies were excluded if VTEs were described in the setting of pregnancy, postoperative outcomes or solely antiphospholipid antibody syndrome.

Results

Most of the 5,206 studies were excluded because they did not state the rate or incidence of VTEs. In total, 25 studies remained for analysis. Ten studies that included rheumatoid arthritis comprised an aggregate of 5,273,942 patients and 891,530,181 controls with a cumulative VTE incidence of 2.18% (95% confidence interval (CI): 1.82% to 2.54%) and an odds ratio of 2.23 (95% CI: 2.02 to 2.47) compared to age- and sex-matched populations. Ten studies comprised an aggregate of 54,697 SLE patients with a cumulative VTE incidence of 7.29% (95% CI: 5.82% to 8.75%). Four Sjögren’s syndrome studies comprising an aggregate of 25,100 patients demonstrated a cumulative VTE incidence of 2.18% (95% CI: 0.79% to 3.57%). Four studies of inflammatory myositis comprising an aggregate of 8,245 patients yielded a cumulative VTE incidence of 4.03% (95% CI: 2.38% to 5.67%). The SSc- and antineutrophil cytoplasmic antibody vasculitis–related cumulative VTE rates (four studies each) were 3.13% and 7.97%, respectively.

Conclusions

The inflammatory rheumatologic diseases studied were all associated with high rates of VTEs—more than three times higher than in the general population.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0435-y) contains supplementary material, which is available to authorized users.     

Venous thromboembolism risk and management in women with cancer and thrombophilia

Background:Venous thromboembolism (VTE) and its complications result in a high rate of morbidity and mortality.Objective:The aim of this study was to review the risk of VTE in women with cancer and other predisposing risk factors, as well as the management of these patients.Methods:Data for this review were identified by searches of MEDLINE, Current Contents, and references from relevant articles using the search terms venous thrombosis, venous thromboembolism, pulmonary embolism, anticoagulation, risk factors, cancer, thrombophilia, heparin, and warfarin. Abstracts and reports from meetings were included only when they directly related to previously published work. Only papers published in English between 1960 and 2005 were included.Results:VTE risk is increased in patients with cancer, with 15% of these patients developing VTE or disseminated intravascular coagulation. Understanding a patient's thromboembolic risk is essential because it affects the type and duration of antithrombotic therapy. The incidence of VTE is dependent on a number of factors, including tumor type, mode of treatment, surgical procedures, patient immobility, and thrombophilia. Progression and recurrence of VTE can be prevented by therapy with unfractionated or low-molecular-weight heparin (LMWH_ followed by warfarin for at least three months. In selected women with advanced cancer disease, a long-term course of LMWH in therapeutic doses is the treatment of choice.Conclusions:In women with cancer, the clinical course is often complicated by VTE episodes. The risk of VTE increases in association with either inherited or acquired thrombophilic conditions. Appropriate management of throemboembolism in women with cancer has the potential to reduce the negative clinical outcomes related to these complications.     

Minimizing Venous Thromboembolism in Feminizing Hormone Therapy: Applying Lessons From Cisgender Women and Previous Data

ObjectiveTo review he impact of estrogen-containing feminizing hormone regimens on transgender individuals’ risk for VTE.MethodsWe evaluated VTE risk by screening 1170 relevant studies published from 1994 to 2020, focusing on meta-analysis data.ResultsThe type of oral estrogen, route of administration, patient demographics, and comorbidities may affect the risk of VTE. Venous thrombosis is the most common vascular complication associated with HT.ConclusionConjugated equine estrogens and 17-β estradiol appear to be safer than oral ethinyl estradiol. Transdermal estrogen formulations appear to be the least thrombogenic estrogens. Estrogens used concomitantly with progestins increase the risk of VTE compared to estrogens alone.To date, there are no data to demonstrate the benefit of holding HT prior to vaginoplasty or other gender affirming surgeries. For most young, healthy transgender women, there is little risk of VTE with HT, while older patients with risk factors should be discussed case by case.     

Pregnancy in women with prosthetic heart valves

Pregnancy in women with mechanical valve prostheses has a high maternal complication rate including valve thrombosis and death. Coumarin derivatives are relatively safe for the mother with a lower incidence of valve thrombosis than un-fractionated and low-molecular-weight heparin, but carry the risk of embryopathy, which is probably dose-dependent. The different anticoagulation regimens are discussed in this review. When valve thrombosis occurs during pregnancy, thrombolysis is the preferable therapeutic option. Bioprostheses have a more favourable pregnancy outcome than mechanical prostheses but due to the high re-operation rate in young women they do not constitute the ideal alternative. When women with native valve stenosis need pre-pregnancy intervention, mitral balloon valvuloplasty is the best option in mitral stenosis, while the Ross operation or homograft implantation may be the preferable surgical regimen in aortic stenosis. (Neth Heart J 2008;16:406-11.)     

Thrombosis in pregnancy and maternal outcomes

Pregnancy increases the risk of thrombosis four‐ to five‐fold. Seventy‐five to eighty percent of pregnancy‐related thrombotic events are venous and twenty to –twenty‐five percent are arterial. The main reason for the increased risk is hypercoagulability. Women are hypercoagulable because they have evolved so that they are protected against the bleeding challenges of pregnancy, miscarriage, or childbirth. Both genetic and acquired risk factors can further increase the risk of thrombosis. The maternal consequences of thrombosis of pregnancy include permanent vascular damage, disability, and death. While the maternal outcomes of thrombosis can be modified by anticoagulation therapy, management of thrombosis during pregnancy is the subject of another paper in this issue (see paper by B. Konkle). This review will focus on the epidemiology, pathophysiology, risk factors, and maternal consequences of thrombosis in pregnancy. Birth Defects Research (Part C) 105:159–166, 2015. © 2015 Wiley Periodicals, Inc.     

Incident HIV during Pregnancy and Postpartum and Risk of Mother-to-Child HIV Transmission: A Systematic Review and Meta-Analysis

Background

Women may have persistent risk of HIV acquisition during pregnancy and postpartum. Estimating risk of HIV during these periods is important to inform optimal prevention approaches. We performed a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy/postpartum and to compare mother-to-child HIV transmission (MTCT) risk among women with incident versus chronic infection.

Methods and Findings

We searched PubMed, Embase, and AIDS-related conference abstracts between January 1, 1980, and October 31, 2013, for articles and abstracts describing HIV acquisition during pregnancy/postpartum. The inclusion criterion was studies with data on recent HIV during pregnancy/postpartum. Random effects models were constructed to pool HIV incidence rates, cumulative HIV incidence, hazard ratios (HRs), or odds ratios (ORs) summarizing the association between pregnancy/postpartum status and HIV incidence, and MTCT risk and rates. Overall, 1,176 studies met the search criteria, of which 78 met the inclusion criterion, and 47 contributed data. Using data from 19 cohorts representing 22,803 total person-years, the pooled HIV incidence rate during pregnancy/postpartum was 3.8/100 person-years (95% CI 3.0–4.6): 4.7/100 person-years during pregnancy and 2.9/100 person-years postpartum (p = 0.18). Pooled cumulative HIV incidence was significantly higher in African than non-African countries (3.6% versus 0.3%, respectively; p<0.001). Risk of HIV was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6) than among non-pregnant/non-postpartum women in five studies with available data. In African cohorts, MTCT risk was significantly higher among women with incident versus chronic HIV infection in the postpartum period (OR 2.9, 95% CI 2.2–3.9) or in pregnancy/postpartum periods combined (OR 2.3, 95% CI 1.2–4.4). However, the small number of studies limited power to detect associations and sources of heterogeneity.

Conclusions

Pregnancy and the postpartum period are times of persistent HIV risk, at rates similar to “high risk” cohorts. MTCT risk was elevated among women with incident infections. Detection and prevention of incident HIV in pregnancy/postpartum should be prioritized, and is critical to decrease MTCT. Please see later in the article for the Editors'' Summary     

Impact of D-Dimer for Prediction of Incident Occult Cancer in Patients with Unprovoked Venous Thromboembolism

BackgroundUnprovoked venous thromboembolism (VTE) is related to a higher incidence of occult cancer. D-dimer is clinically used for screening VTE, and has often been shown to be present in patients with malignancy. We explored the predictive value of D-dimer for detecting occult cancer in patients with unprovoked VTE.MethodsWe retrospectively examined data from 824 patients diagnosed with deep vein thrombosis or pulmonary thromboembolism. Of these, 169 (20.5%) patients diagnosed with unprovoked VTE were selected to participate in this study. D-dimer was categorized into three groups as: <2,000, 2,000–4,000, and >4,000 ng/ml. Cox regression analysis was employed to estimate the odds of occult cancer and metastatic state of cancer according to D-dimer categories.ResultsDuring a median 5.3 (interquartile range: 3.4–6.7) years of follow-up, 24 (14%) patients with unprovoked VTE were diagnosed with cancer. Of these patients, 16 (67%) were identified as having been diagnosed with metastatic cancer. Log transformed D-dimer levels were significantly higher in those with occult cancer as compared with patients without diagnosis of occult cancer (3.5±0.5 vs. 3.2±0.5, P-value = 0.009, respectively). D-dimer levels >4,000 ng/ml was independently associated with occult cancer (HR: 4.12, 95% CI: 1.54–11.04, P-value = 0.005) when compared with D-dimer levels <2,000 ng/ml, even after adjusting for age, gender, and type of VTE (e.g., deep vein thrombosis or pulmonary thromboembolism). D-dimer levels >4000 ng/ml were also associated with a higher likelihood of metastatic cancer (HR: 9.55, 95% CI: 2.46–37.17, P-value <0.001).ConclusionElevated D-dimer concentrations >4000 ng/ml are independently associated with the likelihood of occult cancer among patients with unprovoked VTE.     

来那度胺致多发性骨髓瘤患者静脉血栓形成的机制

来那度胺是一种新型的免疫调节药物,已被广泛应用于治疗多发性骨髓瘤,但其所致静脉血栓形成的副作用也越来越明显。当单独使用来那度胺治疗多发性骨髓瘤时,患者静脉血栓的发生率比较低,而其与地塞米松、化疗药物等联合使用治疗多发性骨髓瘤时,静脉血栓的发生率明显高于单独使用。来那度胺致多发性骨髓瘤患者静脉血栓形成的机制目前尚未完全阐明,国内外研究显示,其主要与内皮细胞功能紊乱、组织因子与磷脂酰丝氨酸暴露增加及体内的高凝状态相关。本文主要就来那度胺致多发性骨髓瘤患者静脉血栓形成的机制进行了简要综述。     

Diet as prophylaxis and treatment for venous thromboembolism?

Background

Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored.

Methods and Findings

The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment. Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial.

Conclusions

Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials.     

Risk of Venous Thromboembolism in Patients with Cancer: A Systematic Review and Meta-Analysis

Background

People with cancer are known to be at increased risk of venous thromboembolism (VTE), and this risk is believed to vary according to cancer type, stage of disease, and treatment modality. Our purpose was to summarise the existing literature to determine precisely and accurately the absolute risk of VTE in cancer patients, stratified by malignancy site and background risk of VTE.

Methods and Findings

We searched the Medline and Embase databases from 1 January 1966 to 14 July 2011 to identify cohort studies comprising people diagnosed with one of eight specified cancer types or where participants were judged to be representative of all people with cancer. For each included study, the number of patients who developed clinically apparent VTE, and the total person-years of follow-up were extracted. Incidence rates of VTE were pooled across studies using the generic inverse variance method. In total, data from 38 individual studies were included. Among average-risk patients, the overall risk of VTE was estimated to be 13 per 1,000 person-years (95% CI, 7 to 23), with the highest risk among patients with cancers of the pancreas, brain, and lung. Among patients judged to be at high risk (due to metastatic disease or receipt of high-risk treatments), the risk of VTE was 68 per 1,000 person-years (95% CI, 48 to 96), with the highest risk among patients with brain cancer (200 per 1,000 person-years; 95% CI, 162 to 247). Our results need to be considered in light of high levels of heterogeneity, which exist due to differences in study population, outcome definition, and average duration of follow-up between studies.

Conclusions

VTE occurs in greater than 1% of cancer patients each year, but this varies widely by cancer type and time since diagnosis. The absolute VTE risks obtained from this review can aid in clinical decision-making about which people with cancer should receive anticoagulant prophylaxis and at what times. Please see later in the article for the Editors'' Summary.     

The epidemiological significance of Chagas' disease in women.

Little is known about the risks associated with Trypanosoma cruzi infection in non-pregnant and pregnant women. From a limited number of studies it appears that in rural areas, parasite rates and rates of serological positivity are similar in both sexes. Abnormal ECG tracings are consistently more frequent in men suggesting that immunity to T. cruzi may be different in females. Complications arising from Chagas' disease in pregnancy are only infrequently reported. Evidence for increased risk of abortion or prematurity is inconclusive except in cases of congenital infection. Most cases of congenital Chagas' disease have been reported from non-endemic areas and there is a suggestion that parasitemic episodes during pregnancy may influence pregnancy outcome. Preliminary evidence indicates that chronic infection can result in in-utero sensitization via passively acquired maternal antibodies. The review concludes that maternal T. cruzi infection carries risks for the child and these warrant systematic research because of their public health significance.     

Risk Factors for Venous Thromboembolism in 1.3 Million Pregnancies: A Nationwide Prospective Cohort

Objective

To quantify risk factors for venous thromboembolism during pregnancy and the puerperal period.

Design

In a nationwide prospective cohort study we followed pregnant and puerperal women in Denmark from 1995 to 2009 for venous thromboembolism. Information on risk factors and confounders was retrieved from national registries. The diagnosis of venous thromboembolism was confirmed through medical charts. We calculated adjusted incidence rates per 10,000 women years and used Poisson regression to estimate effects during pregnancy and the puerperal period.

Results

We studied 1,297,037 pregnancies and related puerperal periods, during which there were 748 venous thromboembolisms. The incidence rate for venous thromboembolism during a pregnancy with and without hospitalization for hyperemesis was 15.2/10,000 yr and 6.3/10,000 yr, respectively, (adjusted rate ratio: 2.5 (95%-confidence interval; 1.4–4.5)). The incidence rate among women with multiple pregnancies was 18.2/10,000 yr and 6.3/10,000 yr in singletons (adjusted rate ratio: 2.8 (1.9–4.2)). Increased risk was found with hospitalization during pregnancy or the puerperal period with incidence rates of 42.1/10.000 and 54.7/10.000, respectively, (rate ratios: 12.2 (8.7–17) and 5.9 (4.0–8.8)). Women hospitalized with infections during pregnancy had incidence rates of 25.9/10,000 yr and 29.3/10,000 yr during pregnancy and the puerperal period, respectively, and of 62.7/10,000 yr if hospitalized with infection in the puerperal period. Puerperal venous thromboembolism was associated with hospitalization for preeclampsia and intrauterine growth restriction/fetal death with incidence rates of 45.8/10,000 yr and 18.3/10,000 yr, respectively (rate ratio: 5.0 (3.1–7.8) and 1.9 (0.9–4.4)). Additionally puerperal venous thromboembolism was associated with obesity, elective and acute caesarean sections and major postpartum bleeding with incidence rates of 25.5/10,000 yr, 23.2/10,000 yr, 34.0/10,000 yr and 20.3/10,000 yr, respectively (rate ratios 1.7 (1.1–2.7), 2.1 (1.4–3.1), 3.0 (2.3–4.0) and 1.4 (1.0–2.1)).

Conclusions

Important risk factors for venous thromboembolism during pregnancy or the puerperal period were hospitalization, infection, hyperemesis, multiple pregnancies, preeclampsia, obesity, caesarean section, major postpartum bleeding, and intrauterine growth restriction or fetal death.     

Nonclinical aspects of venous thrombosis in pregnancy

Pregnancy is a hypercoagulable state which carries an excess risk of maternal venous thrombosis. Endothelial injury, alterations in blood flow and activation of the coagulation pathway are proposed to contribute to the hypercoagulability. The risk for thrombosis may be accentuated by certain drugs and device implants that directly or indirectly affect the coagulation pathway. To help ensure that these interventions do not result in adverse maternal or fetal outcomes during pregnancy, gravid experimental animals can be exposed to such treatments at various stages of gestation and over a dosage range that would identify hazards and inform risk assessment. Circulating soluble biomarkers can also be evaluated for enhancing the assessment of any increased risk of venous thrombosis during pregnancy. In addition to traditional in vivo animal testing, efforts are under way to incorporate reliable non‐animal methods in the assessment of embryofetal toxicity and thrombogenic effects. This review summarizes hemostatic balance during pregnancy in animal species, embryofetal development, biomarkers of venous thrombosis, and alterations caused by drug‐induced venous thrombosis. Birth Defects Research (Part C) 105:190–200, 2015. © 2015 Wiley Periodicals, Inc.     

An Economic Evaluation of Venous Thromboembolism Prophylaxis Strategies in Critically Ill Trauma Patients at Risk of Bleeding

Background

Critically ill trauma patients with severe injuries are at high risk for venous thromboembolism (VTE) and bleeding simultaneously. Currently, the optimal VTE prophylaxis strategy is unknown for trauma patients with a contraindication to pharmacological prophylaxis because of a risk of bleeding.

Methods and Findings

Using decision analysis, we estimated the cost effectiveness of three VTE prophylaxis strategies—pneumatic compression devices (PCDs) and expectant management alone, serial Doppler ultrasound (SDU) screening, and prophylactic insertion of a vena cava filter (VCF)—in trauma patients admitted to an intensive care unit (ICU) with severe injuries who were believed to have a contraindication to pharmacological prophylaxis for up to two weeks because of a risk of major bleeding. Data on the probability of deep vein thrombosis (DVT) and pulmonary embolism (PE), and on the effectiveness of the prophylactic strategies, were taken from observational and randomized controlled studies. The probabilities of in-hospital death, ICU and hospital discharge rates, and resource use were taken from a population-based cohort of trauma patients with severe injuries (injury severity scores >12) admitted to the ICU of a regional trauma centre. The incidence of DVT at 12 weeks was similar for the PCD (14.9%) and SDU (15.0%) strategies, but higher for the VCF (25.7%) strategy. Conversely, the incidence of PE at 12 weeks was highest in the PCD strategy (2.9%), followed by the SDU (1.5%) and VCF (0.3%) strategies. Expected mortality and quality-adjusted life years were nearly identical for all three management strategies. Expected health care costs at 12 weeks were Can$55,831 for the PCD strategy, Can$55,334 for the SDU screening strategy, and Can$57,377 for the VCF strategy, with similar trends noted over a lifetime analysis.

Conclusions

The attributable mortality due to PE in trauma patients with severe injuries is low relative to other causes of mortality. Prophylactic placement of VCF in patients at high risk of VTE who cannot receive pharmacological prophylaxis is expensive and associated with an increased risk of DVT. Compared to the other strategies, SDU screening was associated with better clinical outcomes and lower costs. Please see later in the article for Editors'' Summary     

Incidence,trends, and risks of ectopic pregnancy in a population of women.

In a 20-year longitudinal study on ectopic pregnancy in a defined population of women aged 15-39 years the rate of ectopic pregnancy per 1000 diagnosed conceptions increased from 5.8 during 1960-4 to 11.1 during 1975-9. The mean annual incidence of ectopic pregnancy per 1000 women increased from 0.6 to 1.2 during the same period. The numbers of ectopic pregnancies per 1000 diagnosed conceptions increased with increasing age of the women and were 4.1, in the teenage group 6.9, in women aged 20-29 years, and 12.9 in women aged 30-39. Among 20- to 29-year-old sexually active women at risk of pregnancy who had never had acute salpingitis the rates of ectopic pregnancy per 100 woman-years were the same in those who did not use contraceptives as in those using non-medicated or copper-medicated intrauterine contraceptive devices (IUCDs; 0.3/100 woman years). The risk of an ectopic pregnancy increased sevenfold after acute salpingitis. These findings confirm the increased risk of ectopic pregnancy after salpingitis and suggest that the increase in the incidence of ectopic pregnancy in Lund from 1960 to 1979 was partly accounted for by the use of IUCDs.