Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis.

There is an increased risk of venous thromboembolism among women tak- ing oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown.

We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organi- zations in the United States. Women aged 18– 46 years taking combined oral contraceptives and who had a claim for PCOS (n= 43 506) were matched, based on a propensity score, to con- trol women (n= 43506) taking oral contracep- tives. Venous thromboembolism was defined using administrative coding and use of antico- agulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS. Results:The incidence of venous thromboem- bolism among women with PCOS was 23.7/ 10000 person-years, while that for matched controls was 10.9/10000 person-years. Women with PCOS taking combined oral con- traceptives had an RR for venous thromboem- bolism of 2.14 (95% confidence interval [CI] 1.41–3.24) compared with other contraceptive users. The incidence of venous thromboem- bolism was 6.3/10 000 person-years among women with PCOS not taking oral contracep- tives; the incidence was 4.1/10000 person- years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10–2.19). Interpretation: We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking com- bined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous throm- boembolism when prescribing contraceptive therapy to women with PCOS.

© 2013 Canadian Medical Association or its licensors CMAJ, February 5, 2013, 185(2)E115 treatment, our objective was to determine whether women with PCOS taking combined oral contraceptives have a greater risk of venous thromboembolism compared with other contra- ceptive users. We also examined whether women with PCOS not taking oral contraceptives had an increased risk of venous thromboembolism com- pared with the general population.

Data source The IMS LifeLink Health Plan Claims Database contains paid claims data from over 102 man- aged care plans in the US. This database contains fully adjudicated medical and pharmacy claims for over 68 million patients, including inpatient and outpatient diagnoses and procedures (Inter- national Classification of Diseases, 9th Revision [Clinical Modification (ICD-9-CM)] in addition to retail and mail-order prescription records. The data are considered to be reasonably representa- tive of US residents with private health insurance in terms of geography, age and sex, and these data have been previously used to evaluate the comparative safety of combined oral contracep- tives. 12–14The LifeLink database is subject to quality checks to ensure data quality and to mini- mize error rates.15 This study was approved by the University of Florida Gainsville Health Science Institutional Review Board. Study population The study period was May 1, 2001, to Dec. 31, 2009. Women between the ages of 18 and 46 years were included in the analysis. The inception cohort was based on exposure to one of the fol- lowing combined oral contraceptives containing ≤0.035 mg ethinyl estradiol: desogestrel, dros pi - renone, levonorgestrel, norethindrone, norethin- drone acetate, norgestimate or norgestrel. Because we required a 1-year period for base- line covariate assessment, we excluded women who did not have 1 year of total enrolment in the IMS database. We also excluded women with ahistory of cancer, cerebrovascular disease, car- diovascular disease, venous thromboembolism or prior anticoagulation (warfarin and heparin). Censoring occurred at the outcome of venous thromboembolism, after a gap in combined oral contraceptive therapy of 30 or more days, dis- continuation of enrolment, and the end of the study period. Because venous thromboembolism risk varies substantially between person-time exposed to and unexposed to combined oral con- traceptives, the exposure cohort was limited strictly to exposed person-years to increase inter- nal validity of the study and to reduce concern for confounding by contraceptive use. For inclusion in the PCOS cohort (nested within the combined oral contraceptive cohort), Research E116 CMAJ, February 5, 2013, 185(2) Table 1: Health care and combined oral contraceptive use at baseline Characteristic Polycystic ovary syndrome* Matched controls Women, no. 43 506 43 506 Age, yr, mean 28.7 28.9 Health care use, % of women Admission to hospital 3.57 4.05 Emergency department visit 4.79 4.45 Physician office visit 51.31 50.08 Combined oral contraceptive use New user,† no. (%) of women 20 150 (46.32) 20 278 (46.61) Prevalent user,‡ no. (%) of women 23 356 (53.68) 23 228 (53.39) P r ior time on combined oral contraceptives, mean, d 103 103 Total time on combined oral contraceptives, mean, d 201 202 Number of combined oral contraceptives products used in the past, mean 0.6 0.6 Combined oral contraceptive, % of women Desogestrel, µg ethinyl estradiol 20 3.45 3.38 25 0.47 0.46 30 8.39 8.31 Drospirenone, µg ethinyl estradiol 20 7.46 8.45 30 20.81 21.02 Levonorgestrel, µg ethinyl estradiol 20 5.19 5.14 30 3.75 3.72 Triphasic 2.35 2.11 Norethindrone, µg ethinyl estradiol 35 10.53 10.28 Norethindrone acetate, µg ethinyl estradiol 20 4.60 4.48 30 2.74 2.66 35 1.51 1.55 Norgestimate, ethinyl-estradiol µg 25 5.78 5.68 35 18.31 18.21 Norgestrel, µg ethinyl estradiol 30 4.66 4.55 *Defined as a claim for polycystic ovary syndrome (International Classification of Disease, 9th Revision [Clinical Modification (ICD-9-CM)] 256.4). †Initiated combined oral contraceptive therapy after the polycystic ovary syndrome claim. ‡Evidence of combined oral contraceptive use during the 365-day period before the polycystic ovary syndrome claim. women were also required to have a diagnosis of PCOS (ICD-9-CM 256.4). The index date was the first dispensing for a combined oral contra- ceptive after the PCOS claim. Those with com- bined oral contraceptive use during the 365-day period before the index date were considered to be prevalent users, while we considered women with no prior combined oral contraceptive use to be new users. We used a logistic regression model to develop a propensity score as the prob- ability for developing PCOS. This score was formed from prescription and medical claims, demographics and health care utilization data during the 365 days before the index date, in addition to the calendar year of diagnosis (formed from covariates at cohort entry in Table1 and Table 2). This technique is com- monly used in large database studies to adjust for a large number of covariates without loss of sta- tistical precision. A 1:1 matching technique, based on the propensity score, was used to select a comparator group of women without PCOS with similar baseline comorbidities (who were also taking combined oral contraceptives). Outcome measure The outcome of nonfatal venous thromboem- bolism was a combined outcome of pulmonary embolism (ICD-9-CM 414.1) and deep vein thrombosis (ICD-9-CM 453, 451.1). Cases were women who had an event during or within 30 days after cessation of combined oral contracep- tive therapy. We included this 30-day window to avoid informative censoring bias, where women may stop taking combined oral contraceptives after having a venous thromboembolism. 16 All cases were also required to initiate anticoagulant treatment, with the first dose administered within 14 days of the venous thromboembolism claim. The case index date was 14 days after the venous thromboembolism claim to account for the antico- agulant assessment. This approach to identifying venous thromboembolism cases using subsequent anticoagulation therapy has been pre viously shown to have a 99% positive predictive value.17 Statistical analysis In the primary analysis, we used Cox proportional hazards models to estimate the hazard ratio (HR) for venous thromboembolism. We performed a secondary analysis to model the association between PCOS and venous thromboembolism using a modified Poisson regression with a robust error variance, resulting in a risk ratio (RR).18 We performed a secondary analysis with a more inclusive definition of PCOS to improve sensitivity and to evaluate the impact of includ- ing PCOS diagnostic criteria and treatment in our case ascertainment. Women with a claim for PCOS (ICD-9-CM 256.4), a claim for a diag- nostic criteria (anovulation [ICD-9-CM 628.0] and hirsutism [ICD-9-CM 704.1]), or a prescrip- tion for antiandrogen treatment (i.e., spironolac- tone) were included as having PCOS. Spirono- lactone was included as a proxy for the Research CMAJ, February 5, 2013, 185(2)E117 Table 2: Comparison of medication use and comorbidities at cohort entry and study end Variable Cohort entry Study end PCOS* Matched controls PCOS* Matched controls Medication use, % of women ACE inhibitor or ARB 2.18 2.57 5.06 5.10 Beta blocker 3.42 3.52 7.95 6.80 Benzodiazepine 8.93 8.06 20.77 16.95 Calcium-channel blocker 0.92 1.06 2.51 2.18 Diabetes medications 20.31 20.65 42.88 21.55 SSRI or tricyclic antidepressant 17.09 17.32 31.76 28.88 Statin or fibrate 2.45 2.79 5.79 5.23 Comorbidities, % of women Acne 11.04 10.92 24.15 19.65 Asthma 6.93 6.92 15.32 12.82 COPD 3.34 3.45 11.45 9.29 Diabetes 6.70 8.31 14.87 12.23 Dysmenorrhea 5.79 5.71 14.23 10.95 Endometriosis 2.71 2.82 7.42 4.88 Hyperlipidemia 10.47 10.91 27.10 20.15 Hypertension 7.82 8.40 18.70 14.75 Hypothyroid 8.23 8.32 17.23 12.67 Ovarian inflammation 1.74 1.83 5.72 3.84 Vaginal inflammation 12.56 12.52 31.22 27.64 Uterine leiomyoma 2.05 2.03 5.96 4.65 Irregular menstrual cycle 40.04 40.06 72.07 54.15 Migraine 5.53 5.67 15.10 12.33 Mood or anxiety disorder 15.96 16.26 34.09 29.65 Obesity 13.35 13.32 33.11 21.04 Peptic ulcer disease 0.40 0.42 1.32 1.03 Premenstrual tension syndrome (PMS or PMDD) 1.42 1.34 4.12 2.97 Sleep disorder 0.82 0.88 3.26 1.98 Smoking 2.57 2.71 7.31 6.85 Note: ACE = angiotensin-converting enzyme, ARB = angiotensin-receptor blocker, COPD = chronic obstructive pulmonary disorder, PCOS = polycystic ovary syndrome, PMDD = premenstrual dysphoric disorder, PMS = premenstrual syndrome, SSRI = selective serotonin reuptake inhibitor. *Defined as a claim for PCOS (International Classification of Disease, 9th Revision [Clinical Modification (ICD-9-CM)] 256.4). treatment of hyperandrogenism and not as an independent risk factor for venous thromboem- bolism. As in the main analysis, we used a 1:1 match, based on a propensity score to predict having PCOS to select a comparator population, and we used Cox proportional hazard models to estimate the association between PCOS and venous thromboembolism. All additional PCOS criteria were also evaluated in similar separately matched analyses. Comparison with women with PCOS not using combined oral contraceptives We did not conduct a direct comparison of the risk of venous thromboembolism among women with PCOS using, compared with those not using, combined oral contraceptive therapy; if the decision to treat or not to treat PCOS with combined oral contraceptives is an indication of disease severity, then this analysis would be sub- ject to confounding by indication. To provide an assessment of baseline venous thromboembolism risk among women with PCOS compared with women without this syn- drome, we obtained a random sample of 2mil- lion women not taking combined oral contracep- tives. We repeated all analyses as described above, with the exception that a 1:4 match was conducted to ensure adequate power based on the lower prevalence of PCOS among women who do not use combined oral contraceptives. We evaluated proportionality of hazards using the log–log survival curve.

We included 1632678 combined oral contracep- tive users who met our inclusion criteria. Of these, 46 867 women (2.9% of the total popula- tion) had a claim for PCOS. We were able to suc- cessfully match 43506 (92.8%) of these women, producing a patient population of 87012 for our primary analysis. We matched women based on comorbidities, assessed during the one year before a claim for PCOS, creating populations with nearly identical characteristics at cohort entry (Table 1). Women with a PCOS claim, however, were more likely to develop nearly every study covariate after base- line, when compared with the matched controls (Table 2). Noteworthy differences at study end include the use of diabetic medications (PCOS: 42.88% v. controls: 21.55%), despite similar rates of diabetes (14.87% v. 12.23%, respectively), hyperlipidemia (27.10% v. 20.15%, respectively), hypertension (18.70% v. 14.75%, respectively), menstrual irregularity (72.07% v. 54.15%, respectively) and obesity (33.11% v. 21.04%, respectively). The incidence of venous thromboembolism among women with PCOS was 23.7/10000 person- years, while that for matched controls was 10.9/10000 person-years. Women with PCOS who were taking combined oral contra- ceptives had an HR for venous thromboem- bolism of 2.14 (95% confidence interval [CI] 1.41–3.24). Our secondary analysis found an RR of 2.12 (95% CI 1.40–3.21) (Table 3). In our sensitivity analysis, a more inclusive def- inition of PCOS also included women who met a diagnostic criteria for PCOS (anovulation or hir- sutism) or treatment for PCOS (spironolactone). The characteristics of this population are shown in Appendix 1 (available at www.cmaj.ca /lookup /suppl /doi :10 .1503 /cmaj .120677/-/DC1). This analysis included 89555 women (5.5% of the total population) with PCOS, and 84632 (94.5%) were successfully matched, defining a second cohort with 169264 women. In this second analysis, the incidence of venous thromboembolism among women with PCOS was 24.1/10000 person-years, while that for matched controls was 10.8/10000 person-years. In this analysis, women with PCOS who were taking combined oral contraceptives had an HR for venous thromboembolism of 2.24 (95% CI 1.62–3.10) and an RR for venous thromboem- bolism of 2.23 (95% CI 1.61–3.08). In the strati- fied analyses, all additional measures of PCOS in this inclusive definition demonstrated increased risk of venous thromboembolism: anovulation HR 1.72 (95% CI 0.75–3.98), hirsutism HR 2.49 (95% CI 1.35–4.59) and spironolactone HR 1.89 (95% CI 1.15–3.10). The incidence of venous thromboembolism was 6.3/10000 person-years among women with PCOS not taking contraceptives, while the inci- dence among matched controls was 4.1/10000 person-years. Among women not taking com- bined oral contraceptives, women with PCOS Research E118 CMAJ, February 5, 2013, 185(2) Table 3: Risk of venous thromboembolism associated with PCOS in women taking the combined oral contraceptive pill Variable Cox proportional hazards models Relative risk regression PCOS claim 2.14 (1.41–3.24) 2.12 (1.40–3.21) Composite PCOS definition* 2.24 (1.62–3.10) 2.23 (1.61–3.08) PCOS symptoms and treatment Anovulation 1.72 (0.75–3.98) 1.70 (0.75–3.89) Hirsutism 2.49 (1.35–4.59) 2.43 (1.30–4.56) Spironolactone 1.89 (1.15–3.10) 1.86 (1.14–3.03) Note: PCOS = polycystic ovary syndrome. *Claims for PCOS, anovulation, hirsutism, spironolactone treatment, or PCOS-related procedures. had an HR for venous thromboembolism of 1.55 (95% CI 1.10–2.19) and a RR of 1.63 (95% CI 1.13–2.34) compared with matched controls. The characteristics of this population are shown in Appendix 2 (available at www.cmaj.ca /lookup /suppl /doi :10 .1503 /cmaj .120677/-/DC1). Interpretation We found a 2-fold increased risk of venous thromboembolism among women with PCOS taking combined oral contraceptives compared with matched controls. We found a similar increased risk when we expanded the definition of PCOS by including its symptoms and treat- ment. We also found a 1.5-fold increased relative risk of venous thromboembolism among women with PCOS who were not taking contraceptives compared with matched controls. Our findings are consistent with the previously reported 2-fold increase in most of the risk factors for venous thromboembolism among women with PCOS. 1 Among users of combined oral contracep- tives, the incidence of venous thromboembolism for matched controls was comparable to that of users in the general population (7–11/10000 per- son-years), 17,19while the incidence among women with PCOS was doubled. Similarly, among women not using oral contraceptives, the incidence of venous thromboembolism among those without PCOS was close to previously reported baseline rates, 17 while those with PCOS had increased risk. The absolute rate of venous thromboembolism among women with PCOS taking combined oral contraceptives (23.7/10000 person-years) was substantially higher than that among women with this condition not taking contraceptives (6.3/10 000 person-years). Although the covariates at cohort entry were nearly identical between the groups, women with PCOS were more likely to experience nearly every comorbidity during follow-up. Covariates reported at end of the study had a longer period of assessment and thus were better captured; how- ever, the differential development of these condi- tions supports the finding that women with PCOS are at risk of many additional comorbidities.1 The use of contraceptive products by women with PCOS is thought to improve cycle regula- tion and benefit both acne and hyperandro- genism.20 Previous studies have found that com- bined oral contraceptives are effective for the reduction of androgen levels and hirsutism in women with PCOS; these studies have mainly focused on drospirenone, desogestrel and cypro- terone acetate.8,9,19These studies were small in size and not powered to assess thrombotic events.

Because combined oral contraceptives are rou- tinely used by women with PCOS and these drugs are known to increase the risk of venous thromboembolism, including only users of these drugs limits both confounding by indication and contraindication. However, we do not have an accurate measure for many potential con- founders (e.g., diet, exercise and family history of venous thromboembolism), and some residual confounding is likely present. Claims for obesity were similar between women with (13.35%) and without (13.32%) PCOS at study entry, suggest- ing that unmeasured obesity would not be differ- ent between groups; however, we did not have access to body mass index values, and residual confounding is possible. Polycystic ovary syndrome is diagnosed based on the presence of 2 of the following 3 symptoms: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries. 1 This regimented clinical diagnostic criteria likely makes a claim for PCOS very specific, reducing potential bias from exposure misclassification. However, the sensi- tivity and specificity of PCOS claims are un - known, and the use of ICD-9-CM codes to iden- tify participants with PCOS may underreport the true prevalence of this condition. Thus, we developed a second definition based on diagnos- tic criteria and medication treatment in order to perform a second analysis with an improved sen- sitivity. This inclusive definition gave a preva- lence of PCOS of 5.5% in the study population, which is comparable to the known prevalence of 6%–10%, as defined using the National Institute of Health criteria.

Women with PCOS taking combined oral con- traceptives had a 2-fold increased risk of venous thromboembolism, while such women not taking these drugs had a 1.5-fold increased risk. This is consistent with previous finding of increased car- diovascular risk factors and subclinical vascular disease among women with this syndrome. 1,5 Physicians should be aware of a potentially syn- ergistic increase in venous thromboembolism risk in women with PCOS taking combined oral contraceptives.

1. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-sponsored 3rd PCOS consensus workshop group. Fertil Steril2012;97:28-38. 2. Rotterdam ESHRE/ASRM-sponsored PCOS consensus work- shop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fer- til Steril2004;1:19-25. Research CMAJ, February 5, 2013, 185(2)E119 3. Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glu- cose tolerance in polycystic ovary syndrome: a prospective, con- trolled study in 254 affected women. J Clin Endocrinol Metab 1999; 84:165-9. 4. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycys- tic ovary syndrome. Diabetes Care1999;22:141-6. 5. Moran LJ, Misso ML, Wild RA, et al. 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Effects of long-term administration of an oral contraceptive containing ethinylestradiol and cyprterone acetate on lipid metabolism in women with polycystic ovary syndrome. Acta Obstet Gynecol Scand1995;74:56-60. 10. Pasquali R, Gambineri A, Anconetani B, et al. The natural his- tory of the metabolic syndrome in young women with polycystic ovary syndrome and the effect of long-term oestrogen-progesta- gen treatment. Clin Endocrinol (Oxf)1999;50:517-27. 11. Meyer C, McGrath BP, Teede HJ. Overweight women with polycystic ovary syndrome have evidence of subclinical cardio- vascular disease. J Clin Endocrinol Metab2005;90:5711-6. 12. Bird ST, Pepe SR, Etminan M, et al. The association between drospirenone and hyperkalemia. BMC Clin Pharmacol2011; 11: 23. 13. Bird ST, Wei L, Brophy JM, et al. Irritable bowel syndrome and drospirenone-containing oral contraceptives; a comparative- safety study. Curr Drug Saf2012;7:8-15. 14. Etminan M, Delaney JA, Bressler B, et al. Oral contraceptives and the risk of gallbladder disease: a comparative safety study. CMAJ2011;183:899-904. 15. Health IMS. LifeLink Health Plan Claims Database: overview and study design issues . Little Rock (AK): University of Arkansas for Medical Sciences; 2010. Available: www.uams .edu /TRI /hsrcore/Lifelink_Health_Plan_Claims_Data_DesignIssues _wcost_April2010[1].pdf (accessed 2012 Nov. 15). 16. Shih W. Problems in dealing with missing data and informative censoring in clinical trials. Curr Control Trials Cardiovasc Med 2002;3:4. 17. Lidegaard Ø, Nielsen LH, Skovlund CW, et al. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ2011;343:d6423 18. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol2004;159:702-6. 19. Seeger JD, Loughlin J, Eng PM, et al. Risk of thromboembolism in women taking ethinyestradiol/drospirenone and other oral contraceptives. Obstet Gynecol2007;110:587-93. 20. Nader S, Diamanti-Kandarakis E. Polycystic ovary syndrome, oral contraceptives and metabolic issues: new perspectives and a unifying hypothesis. Hum Reprod2007;22:317-22. Affiliations: Department of Health and Human Services (Bird), Food and Drug Administration, Center for Drug Evaluation and Research, Office of Management and Acade- mic Collaboration Program; Department of Pharmaceutical Outcome and Policy (Bird, Delaney, Hartzema), University of Florida College of Pharmacy, Gainesville, Fla.; Depart- ment of Medicine and Epidemiology (Brophy), McGill Uni- versity, Montréal, Que.; and the Pharmaceutical Outcomes Programme (Etminan), School of Medicine, University of British Columbia, Vancouver, BC Contributors:All authors took part in the study design and the analysis and interpretation of the data. The manuscript was drafted by Steven Bird and was critically revised for important intellectual content by all authors. The statistical analysis was completed by Steven Bird, and the study guar- antor is Joseph Delaney. All authors approved the final ver- sion submitted for publication. Funding:This work was supported by an unrestricted oper- ating grant funded in part by the McGill University Health Centre, Fonds de la Recherche en Santé du Québec, and the Ministère de la Santé et des Services Sociaux. James Brophy is a physician scientist who receives financial support from le Fonds de la Recherche en Santé du Québec. Joseph Delaney receives financial support from Agency for Healthcare Research and Quality (grant no. R21 HS019516-01). Abra- ham Hartzema holds a grant from the National Institutes of Health and is the principal investigator for the Observational Medical Outcomes Partnership, a private–public partnership designed to help improve drug safety monitoring. Acknowledgement:Steven Bird is employed by the Food and Drug Administration. This study represents the opinions of the authors and not those of the Food and Drug Administration. Research E120 CMAJ, February 5, 2013, 185(2)