Tanya M. Petterson

Trends in the Incidence of Venous Thromboembolism during Pregnancy or Postpartum: A 30-Year Population-Based Study

Context The risk for venous thromboembolism during pregnancy and in the postpartum period has not been well defined by previous studies. Contribution Using 30 years of data, these investigators found that the risk for a first episode of venous thromboembolism is 5 times higher in the postpartum period than during pregnancy. The risk for pulmonary embolism is 15 times greater during the postpartum period than during pregnancy. Implications Women at high risk for venous thromboembolism may require special consideration for anticoagulation in the postpartum period. Cautions The ethnicity of the study population was 98% white. The findings may not be generalizable to other ethnic groups. The Editors Knowledge of the relative risk and incidence (absolute risk) of venous thromboembolism among pregnant and postpartum women is important for identifying patients who would benefit from prophylaxis. However, there are few data regarding the relative risk for venous thromboembolism during pregnancy (1), and the reported incidence of venous thromboembolism among pregnant or postpartum women varies widely. Previous studies reported incidence rates ranging from 18 to 95 events per 100000 woman-years during pregnancy and from 199 to greater than 1900 per 100000 woman-years during the postpartum period (2-7). Substantial variation also exists in the reported incidence of venous thromboembolism by trimester and by time after delivery (8-14). Given the markedly worse survival rate after pulmonary embolism compared with that after deep venous thrombosis alone (15), identification of those pregnant or postpartum women at high risk for pulmonary embolism is especially important. However, the incidence by type of venous thromboembolic event during pregnancy and during the postpartum period is uncertain (8, 10, 13, 14, 16-21). The wide variability in reported rates probably reflects differences in study design. For example, published studies identified cases from a variety of sources, including hospital inpatient databases (2, 3, 16, 22), the United Kingdoms National Health Service (4, 23), and hospital discharge and maternity registries (5, 6). Because of diagnostic uncertainty or misclassification, data from these sources possibly underestimated or overestimated the actual incidence rate. Incidence rates derived from hospital inpatient databases potentially missed venous thromboembolism events that occurred after discharge (2, 3, 5, 7, 22), and rates possibly varied when data were reported by selected strata (23) or when only patients referred to tertiary care centers were included (7). Moreover, most studies did not separate incident from recurrent events or include autopsy-discovered events (13, 24, 25). Finally, only a few studies reported trends in pregnancy-associated venous thromboembolism incidence over time (5, 6, 23). Because of these limitations, we performed a population-based study to estimate the relative risk and incidence of venous thromboembolism during pregnancy and the postpartum period within a well-defined geographic area, and we sought to describe trends in incidence over time. We examined the incidence of pregnancy-associated deep venous thrombosis and pulmonary embolism in women living in Olmsted County, Minnesota, between 1966 and 1995. We calculated incidence during pregnancy, incidence during the first 3 postpartum months, and total incidence. Methods Study Setting and Design Using the data resources of the Rochester Epidemiology Project (26), we identified the inception cohort of Olmsted County residents with a first lifetime deep venous thrombosis or pulmonary embolism diagnosed between 1966 and 1995. We included all female residents of Olmsted County who had a venous thromboembolism during pregnancy or the postpartum period; the postpartum period was defined as delivery of a newborn within 3 months before the deep venous thrombosis or pulmonary embolism event date, including delivery of a stillborn infant after the first trimester (27). The institutional review board of the Mayo Clinic approved the study. Definition of Deep Venous Thrombosis and Pulmonary Embolism A diagnosis of deep venous thrombosis was confirmed by venography, computed tomography, magnetic resonance imaging, impedance plethysmography, continuous-wave Doppler ultrasonography (performed in the Mayo Clinic Vascular Laboratory), compression venous duplex ultrasonography, radionuclide venography, radiolabeled fibrinogen leg scan, or pathologic examination of a thrombus removed at surgery or autopsy. A patient was also included when 1) the medical record indicated that a physician diagnosed deep venous thrombosis (or possible deep venous thrombosis); 2) signs and symptoms consistent with deep venous thrombosis were present; and 3) the patient received a course of anticoagulant therapy with heparin, warfarin, or a similar agent or underwent a surgical procedure for treatment of deep venous thrombosis (27). A diagnosis of pulmonary embolism was confirmed by pulmonary angiography, computed tomography, magnetic resonance imaging, a perfusion or ventilation-perfusion lung scan indicating high probability for pulmonary embolism, or pathologic examination of a thrombus removed at surgery or autopsy. A patient was also included when 1) the medical record indicated that a physician made a diagnosis of pulmonary embolism; 2) signs and symptoms consistent with pulmonary embolism were present; and 3) the patient received a course of anticoagulant therapy with heparin, warfarin, or a similar agent or underwent a surgical procedure for treatment of pulmonary embolism, such as placement of an inferior vena cava filter. We did not include patients who received only short-term anticoagulation while awaiting results of diagnostic evaluation for suspected deep venous thrombosis or pulmonary embolism. Statistical Analysis We also used the resources of the Rochester Epidemiology Project to calculate Olmsted County pregnancy rates. We determined the denominator by using Olmsted County census data from 1970, 1980, 1990, and 2000 for the population estimates, with linear interpolation for the years between censuses. Yearly counts of live births, fetal deaths, and neonatal deaths in Olmsted County from 1966 to 1995 were obtained from published documents from the Minnesota Department of Health (Minnesota Health Statistics Annual Summary). Counts were derived from the residence of the mother rather than the place of birth. We were able to obtain maternal ages for live births in Olmsted County but not for fetal or neonatal deaths. We restricted our study to pregnant women who did not have spontaneous or therapeutic abortions, but we did include stillbirths. We calculated age-specific rates of live births by using the number of live births as the numerator; for the denominator, we used age-specific census estimates of the female population of Olmsted County to estimate person-years at risk. Each mother who gave birth was assumed to have a single year of time within which to have a venous thromboembolism event (9 months during gestation and 3 months postpartum). Although the standard duration of the postpartum period is 6 weeks, we used a duration of 3 months for this analysis because we wished to include all venous thromboembolism events that could possibly be related to pregnancy. We were able to calculate age-specific woman-years for each year (for example, number of live births in Olmsted County); therefore, woman-years could be summed over the relevant time interval to calculate the correct denominator for the estimates of venous thromboembolism incidence. To calculate the incidence of venous thromboembolism during pregnancy and postpartum separately, we separated the denominator data by multiplying the total number of woman-years by 0.75 for pregnancies and by 0.25 for postpartum women. When determining incidence by trimester, half-trimester, and week, we multiplied by 0.25, 0.125, and 0.019, respectively (13 of 52 weeks, 6.5 of 52 weeks, and 1 of 52 weeks). We also calculated age-specific incidence rates for deep venous thrombosis alone and for pulmonary embolism (with or without deep venous thrombosis) among pregnant and postpartum women. Age-specific incidence rates were calculated overall (1966 to 1995) and for 3 time periods: 1966 to 1975, 1976 to 1985, and 1986 to 1995. Overall incidence rates over time were directly adjusted to the age distribution of total woman-years during the entire time period (1966 to 1995). Finally, we estimated the incidence of venous thromboembolism in Olmsted women of child-bearing years (age 15 to 45 years) that was not associated with pregnancy by subtracting pregnancy-related and postpartum-related venous thromboembolism cases from the total number of cases (numerator) and by subtracting the number of live births between 1966 and 1995 from the total person-years at risk for all Olmsted County women between the ages of 15 and 45 years (denominator). We estimated the relative risk (standardized incidence ratio) for venous thromboembolism among pregnant/postpartum Olmsted County women by dividing the observed number of venous thromboembolism events by the expected number of venous thromboembolism events determined using the incidence among nonpregnant Olmsted County women. We estimated the relative risk for venous thromboembolism during pregnancy or in the 3-month postpartum period by dividing the observed number of patients with venous thromboembolism during pregnancy or the postpartum period by the expected number with venous thromboembolism. The latter number was estimated by multiplying the age-specific incidence of venous thromboembolism attributable to other causes by the age-specific woman-years observed among the pregnant and postpartum women in Olmsted County between 1966 and 1995. We calculated exact 95% confidence intervals for all venous thromboembolism rates by assuming that the observed number of venous thromboemb

A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease.

There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory demyelinating diseases of the central nervous system who fail to recover after treatment with high‐dose corticosteroids. We conducted a randomized, sham‐controlled, double‐masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory demyelinating disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow‐up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelinating disease during 6 months of follow‐up. Moderate or greater improvement occurred during follow‐up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory demyelinating disease.

Bleeding and thromboembolism during anticoagulant therapy : a population-based study in Rochester, Minnesota

OBJECTIVE To estimate the incidence of and identify risk factors for hemorrhage and thromboembolism during long-term anticoagulant therapy. DESIGN We conducted a population-based retrospective cohort study of all residents of Rochester, Minnesota, in whom a course of warfarin therapy intended to last for more than 4 weeks was initiated between Sept. 1, 1987, and Dec. 31, 1989. METHODS Medical records were reviewed, and pertinent data were compiled. All bleeding complications were classified as minor or major on the basis of the bleeding severity index, and thromboembolic events were classified as major if they were fatal or life-threatening. Cumulative incidences of adverse events were analyzed statistically. RESULTS During the study period, 261 patients had incident courses of anticoagulation (52% were male, 61% were 65 years of age or older, and 31% were 75 years of age or older), with 221 patient-years of warfarin exposure. The primary indications for anticoagulation were venous thromboembolism (39%); stroke or transient ischemic attack (21%); atrial fibrillation (11%); and coronary artery disease, procedures for coronary artery disease, or cardiomyopathy (7%). The cumulative incidence of major hemorrhage at 1, 3, 12, and 24 months was 1.6%, 3.3%, 5.3%, and 10.6%, respectively, and of major or minor thromboembolic events was 2.3%, 5.0%, 7.4%, and 13.1%, respectively. In multivariate analysis, (1) a malignant condition was significantly associated with major hemorrhage; (2) malignant disease and history of peptic ulcer were significantly associated with the combined outcome of major or minor hemorrhage; and (3) malignant disease was significantly associated with any thromboembolism. Age, sex, atrial fibrillation, history of gastrointestinal hemorrhage, history of peptic ulcer, alcohol abuse, hypertension, stroke, and the Charlson comorbidity index were not significantly associated with major hemorrhage. CONCLUSION In this population-based study, including a high proportion of elderly patients, malignant disease at initiation of warfarin anticoagulation was significantly associated with both major hemorrhage and any thromboembolism. Advanced age is not a contraindication to anticoagulant therapy.

Incidence of Venous Thromboembolism in Hospitalized Patients vs Community Residents

OBJECTIVE To estimate the incidence rates of deep venous thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients and to compare these with incidence rates in community residents. PATIENTS AND METHODS We performed a retrospective review of the complete medical records from a population-based inception cohort of patients who resided in Olmsted County, Minnesota, and had an incident DVT or PE from 1980 through 1990. RESULTS From 1980 through 1990, 911 Olmsted County residents experienced their first lifetime event of definite, probable, or possible venous thromboembolism. Of these residents, 253 had been hospitalized for some reason other than a diagnosis of DVT or PE (in-hospital cases), and 658 were not hospitalized at onset of venous thromboembolism (community residents). The average annual age- and sex-adjusted incidence of in-hospital venous thromboembolism was 960.5 (95% confidence interval, 795.1-1125.9) per 10,000 person-years and was more than 100 times greater than the incidence among community residents at 7.1 (95% confidence interval, 6.5-7.6) per 10,000 person-years. The incidence of venous thromboembolism rose markedly with increasing age for both groups, with PE accounting for most of the age-related increase among in-hospital cases. Incidence rates in the 2 groups changed little over time despite a reduction in the average length of hospital stay between 1980 and 1990. CONCLUSIONS Venous thromboembolism is a major national health problem, especially among elderly hospitalized patients. This finding emphasizes the need for accurate identification of hospitalized patients at risk for venous thromboembolism and a better understanding of the mechanisms involved so that safe and effective prophylaxis can be implemented.

The Venous Stasis Syndrome After Deep Venous Thrombosis or Pulmonary Embolism: A Population-Based Study

OBJECTIVES To estimate the incidence and determine predictors of venous stasis syndrome and venous ulcers after deep venous thrombosis and pulmonary embolism. PATIENTS AND METHODS This population-based retrospective cohort study reviewed medical records of 1527 patients with incident deep venous thrombosis or pulmonary embolism between 1966 and 1990. We recorded baseline characteristics, event type (deep venous thrombosis with or without pulmonary embolism or pulmonary embolism alone), leg side and site of deep venous thrombosis (proximal with or without distal deep venous thrombosis vs distal deep venous thrombosis alone), and venous stasis syndrome and venous ulcer. RESULTS Two hundred forty-five patients developed venous stasis syndrome. One-year, 5-year, 10-year, and 20-year cumulative incidence rates were 7.3%, 14.3%, 19.7%, and 26.8%, respectively. By 20 years the cumulative incidence of venous ulcers was 3.7%. Patients with deep venous thrombosis with or without pulmonary embolism were 2.4-fold (95% confidence interval, 1.7-fold-3.2-fold) more likely to develop venous stasis syndrome than patients with pulmonary embolism and no diagnosed deep venous thrombosis. In patients aged 40 years or younger with proximal compared with distal-only deep venous thrombosis, venous stasis syndrome was 3.0-fold more likely (95% confidence interval, 1.6-fold-4.7-fold). In patients with unilateral leg deep venous thrombosis, venous stasis syndrome usually developed in the concordant leg (P < .001). There was a 30% (95% confidence interval, 2%-62%) increased risk for venous ulcer per decade of age at the incident venous thromboembolism. CONCLUSIONS The cumulative incidence of venous stasis syndrome continues to increase for 20 years after venous thromboembolism. Pulmonary embolism alone is less likely to cause venous stasis syndrome.

A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis.

Objective: To determine whether IV immunoglobulin (IVIg) reverses chronic visual impairment in MS patients with optic neuritis (ON). Methods: In this double-blind, placebo-controlled Phase II trial, 55 patients with persistent acuity loss after ON were randomized to receive either IVIg 0.4 g/kg daily for 5 days followed by three single infusions monthly for 3 months, or placebo. Results: The trial was terminated by the National Eye Institute because of negative results when 55 of the planned 60 patients had been enrolled. Fifty-two patients completed the scheduled infusions, and 53 patients completed 12 months of follow-up. Analysis of this data indicated that a difference between treatment groups was not observed for the primary outcome measure, improvement in logMAR visual scores at 6 months (p = 0.766). Exploratory secondary analyses suggested that IVIg treatment was associated with improvement in visual function (including logMAR visual scores at 6 months and visual fields at 6 and 12 months) in patients with clinically stable MS during the trial. Conclusions: IVIg administration does not reverse persistent visual loss from ON to a degree that merits general use.

IV immunoglobulin does not reverse established weakness in MS: A double-blind, placebo-controlled trial

Background: Immunoglobulin (Ig) administration induces remyelination in the Theiler’s virus model of MS. Methods: A randomized, double-blinded, placebo-controlled trial of IV immunoglobulin (IVIg) was performed in patients with MS who had persistent muscle weakness that had been stable for between 4 and 18 months to determine whether this would improve muscle strength (primary outcome: isometric muscle strength). Patients received either IVIg (0.4 g/kg) or placebo daily for 5 days, then single infusions every 2 weeks for 3 months (total, 11 infusions). Muscle groups identified by clinical measures to have unchanging significant weakness were the major targets for therapeutic response (targeted neurologic deficit [TND]). Results: IVIg was well tolerated. An interim analysis after 67 patients were enrolled indicated no difference in the degree of change in strength between treatment groups in either the TND or non-TND muscle groups at 6 months, and the trial was terminated. There was no apparent benefit in relapse behavior or impairment measures during the 6-month observation period. Nor was there apparent benefit in either patients who remained clinically stable or in those with evidence of disease activity. Patients with active MS during the trial worsened in both TND and non-TND muscle groups. This worsening was seen regardless of whether the clinical manifestations of disease activity involved the TND muscle groups. Conclusions: IVIg does not reverse established weakness in MS. Measurements of isometric muscle strength were reliable (reproducible) indices of strength and may be sensitive, objective methods to document functional changes in impairment in future MS trials.

Familial segregation of venous thromboembolism

Background: Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain. Objective: To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance. Patients and methods: In a family‐based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering age‐specific, non‐gender‐ and gender‐specific liability classes under Mendelian and non‐Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) non‐Mendelian. Results: Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first‐degree relatives. The sporadic model was rejected in both non‐gender‐ and gender‐specific liability class analyses. Among the remaining gender‐specific models, the unrestricted (non‐Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes. Conclusion: A multifactorial non‐Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.

Independent Association of High Blood Pressure and Aortic Atherosclerosis A Population-Based Study

BackgroundAtherosclerosis of the thoracic aorta is associated with stroke. The association between hypertension, a major risk factor for stroke, and aortic atherosclerosis has not been determined in the general population. Methods and ResultsTransesophageal echocardiography was performed in 581 subjects, a random sample of the Olmsted County (Minnesota) population aged ≥45 years participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. Blood pressure was assessed by multiple office measurements and 24-hour ambulatory blood pressure monitoring. The association between blood pressure variables and aortic atherosclerosis was evaluated by multiple logistic regression, adjusting for other associated variables. Among subjects with atherosclerosis, blood pressure variables associated with complex aortic atherosclerosis (protruding plaques ≥4 mm thick, mobile debris, or ulceration) were determined. Age and smoking history were independently associated with aortic atherosclerosis of any degree (P ≤0.001) and with complex atherosclerosis (P =0.002), whereas sex, diabetes mellitus, and body mass index were not. Multiple systolic and pulse pressure variables (office and ambulatory), but none of the diastolic blood pressure variables, were associated with atherosclerosis and complex atherosclerosis, adjusting for age and smoking. Among subjects with atherosclerosis, the odds of complex atherosclerosis increased as ambulatory out-of-bed systolic blood pressure increased (odds ratio 1.43 per 10 mm Hg increase, 95% CI 1.10 to 1.87) and with hypertension treatment, adjusting for age and smoking history. ConclusionsHigh blood pressure is independently associated with aortic atherosclerosis. Among subjects with atherosclerosis, high blood pressure is associated with complex atherosclerosis.

Relation of coronary artery disease and cerebrovascular disease with atherosclerosis of the thoracic aorta in the general population

The association between clinical coronary artery disease, cerebrovascular disease, and aortic atherosclerosis has not been examined in the general population. Transesophageal echocardiography was performed in 581 subjects, a random sample of the Olmsted County (Minnesota) population aged >/=45 years, participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. The frequency and severity of atherosclerosis of the thoracic aorta were determined in the population and the association between clinical coronary artery disease, cerebrovascular disease, and aortic atherosclerosis was examined. Previous myocardial infarction, angina pectoris, and coronary artery bypass surgery were significantly associated with aortic atherosclerosis, adjusting for age and gender (p </=0.01). Among subjects with atherosclerosis, these manifestations were associated with complex atherosclerosis (plaques >4-mm thick, ulcerated plaques, or mobile debris), adjusting for age and gender (p <0.05). Age, smoking, pulse pressure, previous myocardial infarction (odds ratio [OR] 4.67; 95% confidence interval [CI] 1.42 to 15.40), and coronary artery bypass surgery (OR 5.12; 95% CI 1.01 to 26.01) were independently associated with aortic atherosclerosis. Among subjects with atherosclerosis, age, smoking, pulse pressure, hypertension treatment, and coronary artery disease (OR 2.50; 95% CI 1.18 to 5.30) were independently associated with complex atherosclerosis. Weak associations were observed between previous ischemic stroke, transient ischemic attack, and aortic atherosclerosis, associations that were not significant after age- and gender-adjustment (p >0.2). Thus, coronary artery disease is strongly associated with aortic atherosclerosis and complex atherosclerosis in the general population. Cerebrovascular disease is weakly associated with aortic atherosclerosis, thereby questioning the overall importance of aortic atherosclerosis in the pathogenesis of cerebrovascular events in the general population.