Anti-beta2-glycoprotein I antibodies in women with recurrent spontaneous abortion, unexplained fetal death, and antiphospholipid syndrome.

OBJECTIVE: Studies in rheumatologic and hematologic populations suggest that anti-beta(2)-glycoprotein I antibodies are more specific for the clinical manifestations of antiphospholipid syndrome than anticardiolipin antibodies. However, the association between anti-beta(2)-glycoprotein I and pregnancy loss remains uncertain. We sought to determine whether anti-beta(2)-glycoprotein I is associated with the obstetric features of antiphospholipid syndrome. STUDY DESIGN: Sera from 4 groups of women were studied: (1) 152 healthy fertile control subjects, (2) 141 subjects with unexplained recurrent spontaneous abortions, (3) 58 subjects with unexplained fetal deaths, and (4) 73 subjects with well-characterized antiphospholipid syndrome. Serum anticardiolipin and anti-beta(2)-glycoprotein I levels were determined by enzyme-linked immunoassay. RESULTS: Patients with antiphospholipid syndrome had significantly higher levels of immunoglobulin G and immunoglobulin M anticardiolipin and anti-beta(2)-glycoprotein I than the other 3 groups (P <.0001). However, women in the recurrent spontaneous abortion, fetal death, and fertile control groups had similar levels of each antibody. Similarly, there were no differences in the proportion of women with positive test results for each autoantibody in these 3 groups. Linear regression analysis showed significant correlation between anticardiolipin immunoglobulin G and beta(2)-glycoprotein I immunoglobulin G (R (2) = 0.544786, P =.0001) and anticardiolipin immunoglobulin M and beta(2)-glycoprotein I immunoglobulin M (R (2) = 0.525048, P =.0001). CONCLUSION: Both anticardiolipin and anti-beta(2)-glycoprotein I are associated with antiphospholipid syndrome. However, testing for anti-beta(2)-glycoprotein I does not identify additional patients with either recurrent spontaneous abortions or unexplained fetal deaths who initially have negative test responses for anticardiolipin. This is likely because of the strong correlation between the 2 autoantibodies. Our data do not support routine testing for anti-beta(2)-glycoprotein I in addition to testing for antiphospholipid antibodies in women with recurrent pregnancy loss and unexplained fetal death.     

Immunoglobulin A anti-beta2-glycoprotein antibodies in women who experience unexplained recurrent spontaneous abortion and unexplained fetal death

OBJECTIVE: Studies in rheumatologic populations suggest that immunoglobulin A antiphospholipid antibodies are strongly associated with the clinical manifestations of antiphospholipid syndrome. However, the association between immunoglobulin A antiphospholipid antibodies and pregnancy loss is uncertain. We determined whether immunoglobulin A antiphospholipid antibodies, specifically anti-beta(2)-glycoprotein I and anticardiolipin, are associated with the obstetric features of antiphospholipid syndrome. STUDY DESIGN: Sera from 4 groups of women were studied: (1) 133 women who experienced unexplained recurrent spontaneous abortion, (2) 48 women who experienced unexplained fetal death, (3) 145 healthy fertile control subjects, and (4) 67 women with well-characterized antiphospholipid syndrome. Serum immunoglobulin A, immunoglobulin G, and immunoglobulin M anti-beta(2)-glycoprotein I and anticardiolipin antibodies were determined by enzyme-linked immunoassay. RESULTS: Groups of women who experienced unexplained recurrent spontaneous abortion and unexplained fetal death had a higher proportion of women who had positive test results for immunoglobulin A anti-beta(2)-glycoprotein I antibodies than fertile control subjects (P < .01, chi-square test); these subjects also had higher levels of autoantibody (P = .001, Kruskal-Wallis). Women who experienced recurrent spontaneous abortion had a higher proportion of women with positive test results for immunoglobulin A anticardiolipin antibodies compared to fertile control subjects (P < .05, chi-square test); this group also had higher levels of autoantibody (P = .0065, Kruskal-Wallis test). Linear regression analysis showed significant correlation between anti-beta(2)-glycoprotein I immunoglobulin A and anti-beta(2)-glycoprotein I immunoglobulin G (R = .609; P =.0001) and less correlation between anticardiolipin immunoglobulin A and anticardiolipin immunoglobulin G (R = .093; P = .065). CONCLUSION: Immunoglobulin A anti-beta(2)-glycoprotein I antibodies are more common in women who experience unexplained recurrent spontaneous abortion and unexplained fetal death whose initial test results are negative for lupus anticoagulant and immunoglobulin G anticardiolipin antibodies compared to fertile control subjects. Therefore, these antibodies may identify additional women with clinical features of antiphospholipid syndrome who are not identified through traditional testing. It is unclear whether these antibodies are directly pathogenic, a result of the pregnancy losses, or markers for an underlying, yet uncharacterized autoimmune disorder.     

The detection of anti-beta2-glycoprotein I antibodies is associated with increased risk of pregnancy loss in women with threatened abortion in the first trimester

OBJECTIVE: This study was designed to evaluate whether the detection of serum antiphospholipid autoantibodies may be useful in predicting pregnancy outcome in women with threatened abortion in the first trimester. STUDY DESIGN: A group of 77 pregnant women of between 8 and 12 weeks' gestation with vaginal bleeding was tested for serum antiphospholipid, lupus anticoagulants, anticardiolipin, antinuclear antibodies, and anti-beta2-glycoprotein I antibodies, and was followed up until the spontaneous end of pregnancy. A control group composed of 15 healthy women with uncomplicated gestation was tested contemporarily for the same antibody panel. RESULTS: Of the 77 patients with threatened abortion, 32 (41.5%) progressed to deliver at term and 45 (58.5%) experienced early pregnancy loss. Among the antibodies evaluated, only anti-beta2-glycoprotein I was significantly more frequent in those women whose pregnancy resulted in spontaneous abortion (22/45, 49%) than in those who progressed to term (6/32, 19%) or in the control group (2/15, 13%; p=0.004). This difference was specific to the IgM isotype (p=0.001). After adjustment by multivariate analysis, the odds ratio for pregnancy loss associated with a positive beta2-glycoprotein I antibody test was 5.18 (p=0.001). CONCLUSION: The detection of anti-beta2-glycoprotein I antibodies is associated with an increased risk of pregnancy loss in women with threatened abortion in the first trimester.     

Effects of third-generation oral contraceptives on high-sensitivity C-reactive protein and homocysteine in young women

OBJECTIVE: To evaluate the effect of third-generation oral contraceptives on high-sensitivity C-reactive protein (CRP), homocysteine, and lipids levels in a population of young, fertile, nonobese women. METHODS: Blood markers were evaluated in 277 healthy white women (mean age 23 years and mean body-mass index 21 kg/m(2)). Seventy-seven oral contraceptive users were compared with 200 non-oral contraceptive users. Progressive cutoffs of high-sensitivity CRP and homocysteine levels were examined. RESULTS: Levels of high-sensitivity CRP posing a high risk of cardiovascular disease (3.0 to less than 10.0 mg/L) were found in 27.3% of oral contraceptive users and in 8.5% of non-oral contraceptive users (odds ratio 4.04; 95% confidence interval [CI] 1.99-8.18). Levels of high-sensitivity CRP at intermediate risk (1.0 to less than 3.0 mg/L) were found in 32.5% of oral contraceptive users and in 11.0% of non-oral contraceptive users (odds ratio 3.89; 95% CI 2.03-7.46). Notably, non-oral contraceptive users were 8.65 (95% CI 4.39-17.1) times as likely to demonstrate a protective level of high-sensitivity CRP (less than 0.5 mg/L) compared with oral contraceptive users. Oral contraceptive use increased serum triglycerides (P<.001) and total cholesterol P=.001); however, high-density lipoprotein, not low-density lipoprotein, contributed to this increase. A decreased ratio of low-density lipoprotein to high-density lipoprotein cholesterol was observed in oral contraceptive users compared with nonusers (P=.016). Oral contraceptive use did not affect homocysteine levels. CONCLUSION: Third-generation oral contraceptive use increases low-grade inflammatory status measured by high-sensitivity CRP concentrations. Alteration of inflammatory status in oral contraceptive users could affect the risk of venous thromboembolism, cardiovascular disease, and other oral contraceptive-associated adverse conditions in young women.     

Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism?

BACKGROUND: Major concern was raised by an earlier study regarding oral contraceptive use in women with the factor V Leiden mutation. A more than 30-fold increase in relative risk for venous thromboembolism was reported; for homozygotes, the relative risk was as much as 100-fold or more. OBJECTIVE: To replicate the reported risk estimates with a new population-based case-control study. METHODS: Eighty women with a diagnosis of venous thromboembolism were consecutively identified and compared with population-based controls (n = 406). Factor V Leiden mutation was identified by genotype analysis. The evaluation was performed with conditional logistic regression (matched for 5-year age group). RESULTS: Matched, adjusted odds ratios (OR) for idiopathic venous thromboembolism in women without and with the factor V Leiden mutation who used oral contraceptives were 4.1 (95% confidence interval (CI) 2.1-7.8) and 10.2 (95% CI 1.2-88.4), respectively. The adjusted OR for factor V Leiden carriers was 2.0 (95% CI 1.0-4.4). The OR for women with the factor V Leiden mutation and oral contraceptive use versus no factor V Leiden mutation and no oral contraceptive use was 10.2 (95% CI 3.8-27.6). CONCLUSION: The results confirm the increased relative risk of idiopathic venous thromboembolism for users of oral contraceptives and factor V Leiden carriers. However, we suspect that the true risk for women who are factor V Leiden carriers may be increased two- to four-fold rather than seven-fold or more, and that the risk for the combination of factor V Leiden and oral contraceptive use may be increased in the order often- to 15-fold rather than over 30-fold.     

Beta 2-glycoprotein I is a good indicator of certain adverse pregnancy conditions.

OBJECTIVE: To compare levels of beta2-glycoprotein I antibodies with six different antiphospholipid antibodies (aPL) in sera from patients with certain adverse pregnancy conditions. PATIENTS AND METHODS: aPL levels were examined in pregnant women with anti-phospholipid syndrome (26), pre-eclampsia (32), autoimmune disease (12), or diabetes mellitus (23) and in a group with physiological pregnancy (38). A commercial ELISA was used to determine the serum levels of anti-beta2-GPI (Immunotech) in isotypes IgG and IgA, and anti-cardiolipin levels (Milenia) in IgG and IgM. aPL screening also included L-alpha-phosphatidic acid, L-alpha-phosphatidylethanolamine, L-alpha-phosphatidyl-DL-glycerol, L-alpha-phosphatidylinositol, and L-alpha-phosphatidyl-serine (Sigma, U.S.A.) in IgG and IgM. Statistical analysis of all aPL levels was made by cut-off levels for Ig isotypes by using 3 SD or 95th percentile calculated using STATGRAPHICS. RESULTS: Positive levels of antibodies against beta2-GPI in IgA are more frequently associated with a diagnosis of anti-phospholipid syndrome, pre-eclampsia, and autoimmune disease in pregnant women than with diabetes mellitus in pregnancy. Very high interindividual differences in aPLs (against inositol, L-serine, cardiolipin, and beta2-glycoprotein in IgG and IgA) were found in serum from women with pregnancy complicated by anti-phospholipid syndrome, pre-eclampsia, and autoimmune disease. Pregnant patients with diabetes mellitus had higher serum levels in aPLs to DL-glycerol, inositol, L-serine, and beta2-glycoprotein. Positive aPL levels predominate in isotype IgG. Very low levels of aPLs to phosphatidic acid and phosphatidyl-ethanolamine were detected in all groups studied. CONCLUSION: Serum levels of anti-beta2-GPI could serve as a better prognostic marker in complicated pregnancy than the panel of seven different anti-phospholipid antibodies. Detection of anti-beta2-GPI is proposed as a first step of the screening for aPLs.     

Erroneous clinical diagnosis of leg vein thrombosis in women on oral contraceptives

Most studies demonstrating an increased risk of venous thromboembolism in women on oral contraceptives are based on clinical manifestations of the disease. Because of the fallibility of the clinical diagnosis of suspected leg vein thrombosis, Doppler ultrasonic evaluation (with a 93% accuracy compared to venography) was performed for clinical manifestations in deep vein thrombosis in 54 women taking birth control pills and 75 women of similar age who were not on contraceptives. The clinical diagnosis was confirmed by Doppler in only 16.7% of the women taking contraceptives and 30.7% of women not taking contraceptives (P = 0.052). This study suggests that the clinical diagnosis of leg vein thrombosis is frequently erroneous, particularly in women taking oral contraceptives. Future investigations reporting venous thromboembolism associated with oral contraceptives should be based on diagnoses validated by accurate objective techniques.     

Oral contraceptives increase deep venous thrombosis in smoking women

There is consistent evidence that the use of oral contraceptives and is associated with increased risk of deep vein thrombosis. The study objective was to assess age specific incidence of deep venous thrombosis and pulmonary embolism in women 20 to 50 years of age associated with the use of oral contraceptives, and smoking habit. A case-control study of vein thrombosis was conducted in National Heart Hospital in Sofia. The study consists of studies for vascular events (peripheral vascular disease) during hormonal therapy. We found that cigarette smoking aggravates venous thromboembolism and pulmonary embolism the in women using oral contraceptives, v. The effect of smoking alone on venous tromboembolism was not found significant. Most probably different factors that increase the incidence of vascular narrowing or occlusion might explain the association between deep venous thrombosis, complicated pulmonary thromboembolism oral contraceptives use and smoking in women in pre-menopausal age.     

The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives.

OBJECTIVES: To investigate the factors associated with idiopathic venous thromboembolism in combined oral contraceptive users and to estimate the crude and age-specific incidence rates ofidiopathic venous thromboembolism among this population. METHODS: The UK MediPlus Database and the General Practice Research Database were searched to identify women with evidence of venous thromboembolism while exposed to combined oral contraceptives. Cohort and nested case-control studies were carried out using the same methodology on both databases. We conducted a meta-analysis using the individual data for the cases and controls from the two case-control studies to identify factors associated with idiopathic venous thromboembolism in women using combined oral contraceptives. RESULTS: The incidence rate of idiopathic venous thromboembolism among oral contraceptive users was 39.4 per 100,000 exposed woman-years. The age-specific incidence rates were found to rise sharply after the age of 39 years. Factors identified as being significantly associated with idiopathic venous thromboembolism in women using combined oral contraceptives were: body mass index of 25 kg/m2 and over, the association rising dramatically in women with a body mass index of 35 kg/m2 or more; smoking; general ill health; and asthma. CONCLUSION: We believe that, before prescribing combined oral contraceptives, the venous as well as the arterial factors need to be considered and, in addition, age, obesity and smoking are all relevant when assessing an individual patient's risk.     

Contraceptive choices in women with coagulation disorders

When compared with older reports on the thromboembolic effects of high-dose oral contraceptives, new studies with low-dose oral contraceptives have a significantly reduced risk of thromboembolism. In the absence of risk factors such as smoking or inherited disorders predisposing to thrombosis, the modern low-dose oral contraceptive (< 50 μg of estrogen) is a safe and effective choice for contraception in women without symptoms who have family histories of sporadic thromboembolism. An intrauterine device or some form of barrier method is recommended for women who have a personal history of venous thrombus disease. The low-dose oral contraceptive may be a good choice in women taking oral anticoagulants because of the risk of teratogenic effects of anticoagulants and the risks of intraperitoneal bleeding associated with ovulation. In addition, oral contraceptives help diminish the excessive menstrual bleeding often seen in these women. (Am J Obstet Gynecol 1993;168:1990-3.)     

Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women.

BACKGROUND: The risk of cardiovascular disease associated with progestogen-only pills has rarely been studied so far. METHODS: In the Transnational case-control study we were looking for a potential cardiovascular disease risk with oral progestogen-only pills in women aged 16-44 years. A total of 1058 cases of myocardial infarction, thromboembolic cerebrovascular accident or venous thromboembolism, and 3808 controls unaffected by these diseases, were enrolled. The group of women who had either used oral progestogen-only pills or no oral contraceptives included 394 cardiovascular disease cases (123 cases of myocardial infarction, 90 cases of thromboembolic cerebrovascular accident and 181 cases of venous thromboembolism) and 2366 controls. RESULTS: The adjusted (matched) odds ratio (OR) for all cardiovascular diseases combined for women using progestogen-only pills compared with non-users of oral contraceptives was 0.84 (95% confidence interval (CI), 0.45-1.58). The adjusted ORs for myocardial infarction, thromboembolic cerebrovascular accidents and venous thromboembolism for users of progestogen-only pills were 0.94 (95% CI, 0.31-2.91), 1.60 (95% CI, 0.24-0.72) and 0.68 (95% CI, 0.28-1.66), respectively. Hence, there was no significant increase in cardiovascular disease risk associated with progestogen-only pill use. The association between cardiovascular disease and established risk factors (smoking and hypertension) was confirmed. CONCLUSION: Although limited by the small number of exposed cases, our data suggest that there is no convincing evidence for an increased risk of cardiovascular disease associated with progestogen-only pill use.     

The effects of age,body mass index,smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives

Objectives To investigate the factors associated with idiopathic venous thromboembolism in combined oral contraceptive users and to estimate the crude and age-specific incidence rates of idiopathic venous thromboembolism among this population.

Methods The UK MediPlus Database and the General Practice Research Database were searched to identify women with evidence of venous thromboembolism while exposed to combined oral contraceptives. Cohort and nested case-control studies were carried out using the same methodology on both databases. We conducted a meta-analysis using the individual data for the cases and controls from the two case-control studies to identify factors associated with idiopathic venous thromboembolism in women using combined oral contraceptives.

Results The incidence rate of idiopathic venous thromboembolism among oral contraceptive users was 39.4 per 100 000 exposed woman-years. The age-specific incidence rates were found to rise sharply after the age of 39 years. Factors identified as being significantly associated with idiopathic venous thromboembolism in women using combined oral contraceptives were: body mass index of 25 kg/m² and over, the association rising dramatically in women with a body mass index of 35 kg/m² or more; smoking; general ill health; and asthma.

Conclusion We believe that, before prescribing combined oral contraceptives, the venous as well as the arterial factors need to be considered and, in addition, age, obesity and smoking are all relevant when assessing an individual patient's risk.     

Pregnancy outcome is not affected by antiphospholipid antibody status in women referred for in vitro fertilization

OBJECTIVE: To determine the prevalence of antiphospholipid (aPL) and anti-beta 2 glycoprotein I (anti-beta2-GPI) antibodies in women referred for IVF and to prospectively evaluate the effect of these antibodies on IVF outcome. DESIGN: Prospective observational study. SETTING: A university hospital and IVF unit. PATIENT(s): Three hundred eighty consecutive women referred for IVF. INTERVENTION(s): Blood samples taken before commencement of IVF cycles were tested for the presence of aPL (lupus anticoagulant [LA], anticardiolipin [aCL], and antiphosphatidyl serine antibodies [aPS]) and anti-beta2-GPI antibodies. MAIN OUTCOME MEASURE(s): Antibody prevalence, pregnancy rates, and live birth rates. RESULT(s): Of the total 380 women, 89 tested persistently positive for aPL (23.4%). None of 176 women tested for IgG aPS antibodies had a positive titer. Only 3.3% (11 of 329) tested positive for anti-beta2-GPI antibodies. Pregnancy rate, live birth rate, gestational age at delivery, and birth weight were not affected by aPL status. CONCLUSION(s): Although women referred for IVF have a high prevalence of aPL, these antibodies do not affect the outcome of treatment. Screening women undergoing IVF for aPL is not justified.     

Venous thromboembolism in relation to oral contraceptive use

The relation of the risk of venous thromboembolism to the use of oral contraceptives was assessed in a hospital-based study of 61 women suffering from a first episode of idiopathic deep vein thrombosis or pulmonary embolism (cases) and 1278 women admitted for trauma or respiratory infections (controls). Twenty (33%) of the cases and 121 (9%) of the controls had used oral contraceptives within the previous month, yielding an age-adjusted relative risk estimate of 8.1 (95% confidence interval 3.7 to 18) for recent users relative to never-users. For women using oral contraceptives containing less than 50 micrograms estrogen, the relative risk estimate was 11 (3.7 to 22); for preparations with 50 micrograms estrogen, it was 5.5 (2.1 to 15); and for preparations with more than 50 micrograms estrogen, it was 11 (3.9 to 30). Past use of oral contraceptives was not associated with an increased risk. The data suggest that the risk of venous thromboembolism is increased for recent oral contraceptive users relative to nonusers, even if women use oral contraceptives containing low doses of estrogen. Confidence intervals were wide, however, so that a reduction in the risk for users of lower dose formulations relative to users of higher dose formulations cannot be ruled out. Selection bias, if present, would have resulted in overestimation of the relative risk, but should not have distorted the comparisons according to dosage.     

The effects of oral estrogen-progestin compounds on blood coagulation factors

Oral contraceptives increase the levels of coagulation Factors II (prothrombin), VII (proconvertin), IX (plasma thromboplastin component), and X (Stewart factor) which form the prothrombin complex or vitamin-K-dependent factors. These factors occur in the progressive clotting process initiated by ruptured endothelium (intrinsic mechanism) or by tissue thromboplastin (extrinsic). Although Factors I (fibrinogen), VII, VIII (antihemophilic), IX, X, and platelets are increased in pregnancy, thromboembolism is more likely to occur in the postpartum period. During 1966-1967, 51 deaths and 183 nonfatal cases of thromboembolism among pill users were reported to the U.S. Food and Drug Administration. Several women known to have experienced a thromboembolism while using oral contraception had a second thromboembolic episode when the pill was resumed. In one of these women, coagulation factors were observed to rise during the second course of steroids when the second thromboembolism occurred. Further evidence associating thromboembolism and oral contraceptives comes from British case-controlled retrospective data and from studies with oral estrogens and progestins for menstrual indications. Research on animal models and screening tests is underway.     

Anticardiolipin and anti-beta2-glycoprotein-I antibodies in preeclampsia

OBJECTIVE: To estimate whether antiphospholipid antibodies, specifically anticardiolipin and anti-beta(2)-glycoprotein-I antibodies, are associated with preeclampsia. METHODS: Plasma was prospectively obtained from four groups of pregnant women: those with 1) mild preeclampsia (n = 109); 2) severe preeclampsia (n = 134); 3) hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (n = 57); and 4) normotensive controls (n = 100). Anticardiolipin and anti-beta(2)-glycoprotein-I levels were determined by enzyme-linked immunoassay. RESULTS: Subjects with mild preeclampsia, severe preeclampsia, and HELLP syndrome did not have significantly elevated levels of immunoglobulin G (IgG) and IgM anticardiolipin and anti-beta(2)-glycoprotein-I antibodies compared with normotensive controls (P >.05, Kruskal-Wallis). Similarly, subjects with mild preeclampsia, severe preeclampsia, and HELLP syndrome did not have a significantly higher proportion of women testing positive for each autoantibody compared with normotensive controls (chi(2)). The proportion of patients testing positive for anticardiolipin and anti-beta(2)-glycoprotein-I antibodies were similar in patients with preeclampsia developing before and after 34 weeks' gestation (chi(2)). CONCLUSION: Circulating levels of both anticardiolipin and anti-beta(2)-glycoprotein-I antibodies were not increased in patients with mild preeclampsia, severe preeclampsia, or HELLP syndrome compared with normotensive controls. Our data do not support routine testing for anticardiolipin and anti-beta(2)-glycoprotein-I antibodies in women with preeclampsia.     

Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation

OBJECTIVE: To examine the effect of raloxifene on major adverse events that occur with postmenopausal estrogen therapy or tamoxifen. METHODS: The Multiple Outcomes of Raloxifene Evaluation, a multicenter, randomized, double-blind trial, enrolled 7,705 postmenopausal women with osteoporosis. Women were randomly assigned to raloxifene 60 mg/d or 120 mg/d or placebo. Outcomes included venous thromboembolism, cataracts, gallbladder disease, and endometrial hyperplasia or cancer. RESULTS: During a mean follow-up of 3.3 years, raloxifene was associated with an increased risk for venous thromboembolism (relative risk [RR] 2.1; 95% confidence interval [CI] 1.2-3.8). The excess event rate was 1.8 per 1,000 woman-years (95% CI -0.5-4.1), and the number needed to treat to cause 1 event was 170 (95% CI 100-582) over 3.3 years. Risk in the raloxifene group was higher than in the placebo group for the first 2 years, but decreased to about the same rate as in the placebo group thereafter. Raloxifene did not increase risk for cataracts (RR 0.9; 95% CI 0.8-1.1), gallbladder disease (RR 1.0; 95% CI 0.7-1.3), endometrial hyperplasia (RR 1.3; 95% CI 0.4-5.1), or endometrial cancer (RR 0.9; 95% CI 0.3-2.7). CONCLUSION: Raloxifene was associated with an increased risk for venous thromboembolism, but there was no increased risk for cataracts, gallbladder disease, endometrial hyperplasia, or endometrial cancer. LEVEL OF EVIDENCE: I