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The objective of the study was to determine whether women with significant left common iliac vein stenosis who also use combined oral contraceptives (COCs) have a combined likelihood of deep vein thrombosis (DVT) greater than each independent risk.
Study Design
This was a case-control study comparing 35 women with DVT against 35 age-matched controls. Common iliac vein diameters were measured from computed tomography and magnetic resonance imaging. Logistic regression modeling was used with adjustment for risk factors.
Results
DVT was associated with COC use (P = .022) and with increasing degrees of common iliac vein stenosis (P = .004). Compared with women without venous stenosis or COC use, the odds of DVT in women with a 70% venous stenosis who also use COCs was associated with a 17-fold increase (P = .01).
Conclusion
Venous stenosis and COC use are independent risk factors for DVT. Women concurrently exposed to both have a multiplicative effect resulting in an increased risk of DVT. We recommend further studies to investigate this effect and its potential clinical implications.
According to the 1995 National Survey of Family Growth, approximately 1 in 5 American women between the ages of 15 and 44 years were using COCs, and 82.4% had used them at some point in their lifetime.
Although COCs are an effective means of birth control, their use have been associated with several risks. Various observational studies over the last several decades have reported an increased risk of deep vein thrombosis (DVT) in patients after starting COCs.
Without COC use, the baseline risk of DVT in normal, healthy women aged 15-44 years is approximately 1-3 cases per 10,000 person-years. In the first year of COC use, the risk of DVT increases by 3- to 6-fold.
Given the small absolute risk of DVT in nonpregnant, reproductive-age women, screening strategies to identify who is at greatest risk for DVT prior to starting COCs are currently not recommended.
However, women who possess an underlying thrombophilia can experience exacerbation of their prothrombotic state during COC use. Studies focusing on factor V Leiden mutations and deficiencies in protein C, protein S, and antithrombin have established an additive risk of COC use in contributing to DVT in these patients.
Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication The GTH Study Group on Natural Inhibitors.
However, these studies have not investigated the anatomic stasis component of Virchow's triad as an added risk factor for DVT, which we believe is important in the development of venous thrombus among women using COCs.
Currently, the clinically accepted definitions of venous stasis include recent travel and lower-extremity immobility.
However, reduced venous velocity can also occur because of anatomically narrowed vasculature that may impede flow. Cadaveric studies by May and Thurner
described naturally occurring compression of the left common iliac vein (LCIV) against the lumbar spine by the overlying right common iliac artery resulting in slow turbulent flow through the vein. This May-Thurner syndrome or iliac vein compression syndrome (IVCS) has been associated with ipsilateral DVT, especially those involving the proximal venous segments. Anatomic studies have shown that an underlying stenosis (>50%) of the LCIV is present in 22-24% of the healthy population.
It is likely that the risk of DVT increases with the degree of venous stenosis. This hypothesis is supported by a study showing that patients with left iliofemoral DVT had a 74% mean stenosis of the LCIV compared with a 28% mean stenosis in an age-matched asymptomatic control group.
We have previously reported that 84% of COC-induced lower extremity DVTs occurred in the left leg, and in these patients there is an iliac vein mean stenosis of 71%.
Similarly, studies of acute DVT during pregnancy demonstrated that approximately 90% of pregnancy-induced DVTs occurred in the left lower extremity, with a propensity also toward the proximal veins.
Therefore, we hypothesized that significant LCIV stenosis could be a risk factor for a first-time DVT episode in young women taking COCs. The goal of our study was to determine whether COC users with LCIV stenosis are at a higher risk for left-sided DVT than those without venous stenosis and, if so, to what degree.
Materials and Methods
A retrospective case-control study was conducted at an academic hospital under institutional review board approval. Hospital records from Jan. 1, 2002, to Dec. 31, 2008, were searched to identify women between the ages of 18 and 45 years who were diagnosed with DVT using International Classification of Diseases, ninth revision (ICD-9) codes (451.1, 451.2, 453.41, 453.40). Cross-sectional imaging was necessary for venous stenosis measurements, and all patients without computed tomography (CT) or magnetic resonance (MR) imaging of the lower abdomen or pelvis were excluded.
The case subjects were defined as those with a first-time, acute presentation of a lower-extremity DVT that was visually confirmed by ultrasound, CT, or MR imaging. Exclusion criteria were then used to minimize misclassification of outcomes within these case subjects. Patients were excluded if no DVT was found on imaging or if they had a history of chronic venous disease or previous lower-extremity surgical or endovascular vascular procedures that may have distorted the iliac vein anatomy. Furthermore, because nearly all cases of IVCS occur on the left, only subjects with unilateral left-sided DVT were included.
The control subjects consisted of women between the ages of 18 and 45 years who presented to the emergency room from January 2002 to December 2008 with a chief complaint of abdominal pain (ICD-9 codes 789.01-789.09) and who were evaluated with CT imaging of the abdomen and pelvis. Subjects were excluded from the control population if they had a prior history of DVT or lower-extremity surgical or endovascular procedure.
The electronic medical record for all subjects was reviewed to assess whether combination oral contraceptives were used at the time of presentation. Patients using any form of progestin-only or nonhormonal contraceptives were considered as nonusers of COCs. Additional prothrombotic risks were also identified, including smoking, active malignancy, pregnancy, self-described inherited thrombophilia or that confirmed by hypercoagulability testing, and recent prolonged travel or immobilization. A patient with any of these risk factors was considered as having an additional hypercoagulable state in our statistical modeling.
CT scans were performed on either an 8 row or 16 row multidetectors (General Electric Medical Systems, Milwaukee, WI). MR imaging was performed on a 1.5-Tesla systems (General Electric Medical Systems) and included gradient-echo sequences and dynamic time-of-flight spoiled gradient-echo sequences. Axial CT and MR images of 5 mm thickness or less were reviewed, and the minor diameter of the LCIV measured at the point at which the right common iliac artery crosses anterior to the left iliac vein. The cross-sectional minor axis diameter of the right common iliac vein was measured 1 cm below the inferior vena cava bifurcation. Measurements were performed independently by 2 reviewers (K.T.C. and L.V.H.) who were blinded to the subject's clinical presentation. The percent stenosis was calculated by dividing the LCIV minor diameter by the right common iliac vein minor diameter then subtracting this percentage from 100.
Simplified assumptions were made to determine the sample size needed in this case-control study. Based on the population frequencies of 17.3% women using COCs and 20% with iliac vein compression, we calculated approximately 3.5% of the population would concurrently have both conditions. We hypothesized that stenosis-induced stasis would have a prothrombotic effect independent from COC-related thrombophilia, and therefore, the relative risks of DVT for COC use and significant venous stenosis would be multiplicative. Compared with the patient with no risk factors, prior studies have estimated COC use and significant venous stenosis increased the relative risk of DVT by 3 and 7, respectively, resulting in a combined relative risk of both factors to be 21 times above baseline. With these assumptions, we calculated a sample size of 17 subjects was necessary to detect a significant effect (α = 0.05, β = 0.20).
We then conservatively doubled this sample size to include the first 35 cases and controls that met our inclusion criteria.
Statistical analysis was performed using SAS version 9.1 (SAS Institute, Inc, Cary, NC). The likelihood of venous thromboembolism with the primary factors of COC use and venous stenosis was assessed using logistic regression models adjusted for age and a variable representing the presence of additional hypercoagulable states. The effect of venous compression on DVT was reported for each percent increase in stenosis. A subgroup analysis was also performed to compare the odds of DVT for patients with and without COC use and with and without a clinically significant amount of IVCS (defined as ≥70% stenosis, based the anatomical measurements from Oguzkurt et al
). The odds ratios and 95% confidence intervals were calculated, and statistical significance was set at an alpha level of 0.05.
Results
Between 2002 and 2008, 131 women between the ages of 18 and 45 years were diagnosed with DVT and had appropriate CT or MR imaging at our academic hospital. Ninety-two patients (70%) had unilateral left-sided DVT. Case subjects were then randomly chosen until the first 35 cases were found who met the exclusion criteria. In the same 6 year period, 853 total control subjects presented to the emergency room with abdominal pain, from which 35 controls were picked randomly. These control subjects consisted of genitourinary (23%) and gastrointestinal (19%) diagnoses, motor vehicle accidents (13%), back injuries (6%), infections including postsurgical dehiscence (6%), and idiopathic abdominal pain (33%).
Subjects in both cohorts were of similar age (Table 1). Compared with the controls, the cases of DVT had higher incidences of COC use and reported more hypercoagulable risk factors. Right venous diameters were similar between the cases and controls (12.6 mm vs 13.2 mm, respectively), but the former had a smaller average LCIV diameter that resulted in a greater average degree of venous stenosis. Among all 70 subjects, 30 had a 70% or greater degree of venous stenosis, and 8 of these were COC users. Nine patients used COCs but had less than 70% venous stenosis. Among all COC users, 7 patients had additional hypercoagulable risk factors (3 with factor V Leiden heterozygosity including 1 also with prolonged travel, 2 with anticardiolipin antibodies, 1 with prothrombin G20210 mutation, and 1 with antithrombin-III deficiency).
TABLE 1Population characteristics of cases and controls
Among the patients who did not use COCs, 6 were pregnant, and 8 had an active malignancy. Thirty-one patients neither used COC nor had a significant venous stenosis. Smoking was confirmed in 6 patients. Ten of the 35 controls (29%) had venous stenosis exceeding 70%. All cases of left iliac venous stenosis were due to external compression by the right common iliac vein. No significant pregnancy-related venous compression was observed.
The logistic regression model showed the primary effect of COC use increased the odds of DVT 5-fold (odds ratio [OR], 4.58; 95% confidence interval [CI], 1.32–15.93; P = .017). Every 1% increase in venous stenosis was associated with an increased risk of DVT (OR, 1.05; 95% CI, 1.01–1.08; P = .005). The estimated effect of COC use was not significantly changed by the addition of venous stenosis and indicated these 2 primary factors were statistically independent. After fully adjusting for age and additional hypercoagulable risks, both COC use and every 1% increase in venous stenosis remained statistically significant with ORs of 5.46 (95% CI, 1.28–23.33; P = .022) and 1.05 (95% CI, 1.02–1.08; P = .004), respectively (Table 2). The presence of an additional hypercoagulable risk was also a significant factor and increased the odds by 7.5-fold (P = .002).
TABLE 2Multivariate logistic regression model for risk of DVT
Predicted likelihoods of DVT from the regression model for COC users and nonusers are graphed in the Figure. The likelihood of DVT was positively correlated to increasing venous stenosis, regardless of COC use but was consistently greater in COC users than nonusers. Based on these modeled data, the probability for venous thromboembolism becomes greater than 50% for COC users with venous stenosis above 45%. In comparison, the same probability occurs in COC nonusers once venous stenosis exceeds 70%.
FIGUREModel probability of DVT vs venous stenosis as a function of COC use
The odds of DVT are compared among subgroups with COC use alone, with greater than 70% venous stenosis alone, and with both COC use and venous stenosis against those with neither risk factor (see Table 3). Individually, the use of COC and greater than 70% venous stenosis were associated with statistically significant increased odds of DVT by factors of 4.89 and 3.53, respectively. Concurrent exposure to both COCs and greater than 70% venous stenosis was associated with a 17.11-fold increase in the odds of DVT compared with baseline.
TABLE 3Risk of DVT among subgroups with oral contraceptive use or 70% venous stenosis
The risk of estrogen-associated venous thrombosis has been extensively studied since the introduction of oral contraceptives in the 1960s. This risk is further increased in women with underlying hereditary thrombophilic conditions. Research in patients with multiple risk factors has shown that COC use in the presence of factor V Leiden heterozygosity and prothrombin G20210 mutation resulted in 35- and 16-fold increases in DVT risk, respectively.
In our study population, COC use increased the odds of venous thromboembolism by 5-fold. This estimate is similar to the magnitude of risk identified in prior studies. Each percentage increase in common iliac vein stenosis was also associated with a small but statistically significant increase in the odds of developing DVT. When venous stenosis exceeded 70%, which occurred in 29% of our controls, the associated risk of DVT increased 3.5 times. In comparison, factor V Leiden, which is the most common inherited thrombophilia, has a global incidence of less than 5%. Subjects with greater than 70% venous stenosis, if also taking COCs, were associated with a risk of DVT that is 17-fold above the baseline population. This risk was comparable with our pretest estimate of a 21-fold increase.
We also hypothesized the effects of venous thrombosis from combined oral contraceptive use and venous stenosis work independently. The combined risk of COC use and greater than 70% venous stenosis was multiplicative, possibly because of biologically independent mechanisms underlying these 2 risk factors. Combined oral contraceptives are believed to induce a prothrombotic state through resistance to activated protein C.
In comparison, the reason through which flow stasis leads to thrombosis is less known but may include hypoxia-induced endothelial activation and the accumulation of prothrombotic substances in flow voids without adequate circulation.
The threshold degree of venous stenosis needed to cause such an effect is currently unknown, but from our data, the likelihood of DVT is positively correlated with increasing amounts of stenosis.
Our models predict the amount of stenosis necessary for DVT is less among COC users than nonusers. Although it is believed that 22-24% of the general population have iliac vein stenoses exceeding 50%, the true incidence of those with stenoses above 70% is currently unknown. In 1 small study, the incidence of a 70% stenosis in the general population was 2%.
Further research may elucidate how these suggested thrombogenic mechanisms vary with increasingly stenotic venous flow, and ultimately, in whom COC use would be contraindicated.
Despite the common incidence of venous stenosis, the absolute risk of venous thromboembolism in women aged 18-45 years remains low. Along with hereditary thrombophilias, effective screening of the general population for those with IVCS is difficult to justify prior to starting COCs. Currently the diagnosis of IVCS requires imaging modalities that are costly and can pose risks of radiation exposure. Unfortunately, patients with undiagnosed IVCS have a significantly higher likelihood of ileofemoral DVT.
Compared with DVT in the popliteal or calf veins, these proximal thrombi are associated with higher likelihoods of pulmonary embolism and post-thrombotic syndrome.
Based on our study findings and these possible complications of IVCS, if a young woman using COCs develops left-sided DVT in the absence of other risk factors, the possibility of common iliac vein stenosis should be considered, and she may benefit from further evaluation with diagnostic imaging.
There is a paucity of prospective studies that investigate the impact of common iliac vein stenosis on venous thromboembolism in large populations. We believe this study illustrates the possible prothrombotic effect of a significant venous stenosis. Although we can not draw conclusions from this study that may affect clinical practice, we propose additional research to identfy cost-effective methods to diagnose IVCS and its associated annual risk of DVT among oral contraceptive users. Furthermore, corrective treatment may soon be possible for venous stenosis.
Endovascular stenting of stenosed iliac veins have shown encouraging results in several small clinical studies,
Methodology for antithrombotic and thrombolytic therapy guideline development: American College of Chest Physicians evidence-based clinical practice guidelines, 8th ed.
but given that long-term data are retrospective and available from only a few centers, this approach is recommended only at centers with appropriate expertise.
A larger National Institutes of Health–funded, multicenter prospective study is now underway to definitively compare endovascular thrombolysis against medical management of these proximal culprit lesions in patients with acute DVT.
If diagnosed, IVCS may possibly be treated with stent placement, which might then reduce the long-term risk of DVT and potentially allow resumed COC use in the absence of other DVT risk factors. This would be a radical change in current practice and would require the proper prospective studies to justify such a change.
Our study has several important limitations. Most importantly, the data were subject to all the limitations of a retrospective analysis. Additionally, the number of identified hypercoagulable risk factors was higher in the case population than vs the control group. Not surprisingly, these factors are more likely to be assessed and identified when venous thrombosis is clinically suspected. However, even among these patients, these factors were not fully documented. Therefore, to model the available information and minimize the impact of missing data, we grouped all hypercoagulable risks into a binary term to account for any additional known risks. Although this surrogate approach allows for adjustment of confounders in the statistical models, it limits our ability to differentiate between the magnitude or number of underlying thrombophilias.
The third limitation was the size of our study. A larger sample size would result in more precise statistical calculations and would allow a sensitivity analysis at different degrees of stenosis for greater clinical utility.
Finally, selection bias was another limitation. Patients in this study were selected from a single institution based on availability of CT or MR imaging and for having unilateral lower extremity DVT. Twenty-nine percent of our control population was found to have a 70% or greater iliac vein stenosis, which is higher than that seen in prior studies.
Although we can not exclude possible selection bias, we utilized this high incidence of stenosis within our statistical analysis in an attempt to elucidate its possible role in causing DVT that could be further investigated in prospective studies. It was also encouraging that our calculated 5-fold increase in risk of DVT from COC use was consistent with results from other studies.
In conclusion, LCIV stenosis is a relatively common but underrecognized condition associated with an increased risk of ipsilateral DVT. In a young woman with 70% iliac vein stenosis or greater, the risk of DVT was associated with a 3.5-fold increase. This risk is even greater if combined with combined oral contraceptive use, resulting in a multiplicative effect that is 17-fold above the baseline.
We believe larger prospective studies are warranted to further assess the actual annual risk of DVT in patients with significant venous stenosis and to evaluate the safety of COC use in such patients. Until those data are available, we believe that if a young woman using COCs presents with left-sided venous thrombosis in the absence of other hypercoagulable conditions, venous stenosis should be considered as a possible underlying condition. An ongoing prospective National Institutes of Health–funded randomized trial may provide guidance as to the best treatment options for these patients.
Methodology for antithrombotic and thrombolytic therapy guideline development: American College of Chest Physicians evidence-based clinical practice guidelines, 8th ed.
Cite this article as: Chan KT, Tye GA, Popat RA, et al. Common iliac vein stenosis: a risk factor for oral contraceptive-induced deep vein thrombosis. Am J Obstet Gynecol 2011;205:537.e1-6.
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