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Early release, published at www.cmaj.ca on December 3, 2012. Subject to revision.
Risk of venous thromboembolism in women with polycystic
ovary syndrome: a population-based matched cohort analysis
Steven T. Bird PharmD MS, Abraham G. Hartzema PhD PharmD, James M. Brophy PhD MD, Mahyar Etminan PharmD MS, Joseph A.C. Delaney PhD Competing interests:
Abraham Hartzema has
Background: There is an increased risk of
controls was 10.9/10 000 person-years.
Women with PCOS taking combined oral con- ing oral contraceptives. However, whether traceptives had an RR for venous thromboem- there is an additional risk among women with bolism of 2.14 (95% confidence interval [CI] polycystic ovary syndrome (PCOS) is unknown.
1.41–3.24) compared with other contraceptiveusers. The incidence of venous thromboem- Methods: We developed a population-based
cohort from the IMS LifeLink Health Plan Claims women with PCOS not taking oral contracep- Database, which includes managed care organi- Correspondence to:
tives; the incidence was 4.1/10 000 person- 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 CMAJ 2012. DOI:10.1503
with PCOS not taking oral contraceptives was matched, based on a propensity score, to con- /cmaj.120677
trol women (n = 43 506) taking oral contracep-tives. Venous thromboembolism was defined Interpretation: We found a 2-fold increased
using administrative coding and use of antico- agulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous oral contraceptives with and without PCOS.
taking oral contraceptives. Physicians should Results: The incidence of venous thromboem-
consider the increased risk of venous throm- boembolism when prescribing contraceptive 10 000 person-years, while that for matched Polycystic ovary syndrome (PCOS) is the ApoB ratios) are doubled among women with Combined oral contraceptives are the main- Institutes of Health criteria estimates its preva- stay treatment for PCOS. However, they are also lence in the United States to be between 6% and known to elevate the risk of venous thromboem- 10%, while the Rotterdam criteria estimates the bolism and cardiovascular disease.6 To date, con- prevalence to be as high as 15%.1 Although its traceptive studies involving women with PCOS cause is not entirely known, the diagnostic cri- have focused mainly on efficacy, evaluating the teria include oligo- or anovulation, clinical effect of combined oral contraceptives on the and/or biochemical signs of hyperandrogenism, reduction of hirsutism and hyperandrogenism.7,8 and polycystic ovaries.2 Women often present Two studies assessed the metabolic effects of with clinical manifestations of high androgen combined oral contraceptives in PCOS, but these levels, including facial hair growth (hirsutism), studies had small sample sizes and could not acne vulgaris and hair loss on the scalp. Previ- ous studies reported the prevalence of impaired glucose tolerance to be 31.1%–35.2% and the crease in both cardiovascular risk factors and prevalence of type 2 diabetes to be 7.5%–9.8% subclinical cardiovascular disease,11 recent among women with PCOS.3,4 A recent consensus guidelines have concluded there are no data in workshop reported that the prevalence of several the literature assessing the association between known risk factors for cardiovascular disease the use of oral contraceptives and cardiovascular (hypertension, diabetes, abdominal obesity, psy- chological factors, smoking, altered apoA1/ combined oral contraceptives are the mainstay 2012 Canadian Medical Association or its licensors
treatment, our objective was to determine ceptive users. We also examined whether women with PCOS not taking oral contraceptives had an oral contraceptives have a greater risk of venous increased risk of venous thromboembolism com- thromboembolism compared with other contra- Materials and methods
Table 1: Health care and combined oral contraceptive use at baseline
Data source
The IMS LifeLink Health Plan Claims Databasecontains paid claims data from over 102 man- aged care plans in the US. This database contains fully adjudicated medical and pharmacy claims Health care use, % of women
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 Combined oral contraceptive use
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.12–14 The LifeLink database is subject to quality checks to ensure data quality and to mini- This study was approved by the University of Florida Gainsville Health Science Institutional Combined oral contraceptive, % of women
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 enrollment in the IMS database. We also excluded women with a history of cancer, cerebrovascular disease, car- Norethindrone acetate, µg ethinyl estradiol diovascular disease, venous thromboembolism orprior 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 enrollment, and the end of the study period. Because venous thromboembolism risk varies substantially between person-timeexposed to and unexposed to combined oral con- traceptives, the exposure cohort was limited strictly to exposed person-years to increase inter- *Defined as a claim for polycystic ovary syndrome (International Classification of Disease, 9th nal validity of the study and to reduce concern revision, clinical modification [ICD-9-CM] 256.4) †Initiated combined oral contraceptive therapy after the polycystic ovary syndrome claim. for confounding by contraceptive use.
‡Evidence of combined oral contraceptive use during the 365-day period before the within the combined oral contraceptive cohort), women were also required to have a diagnosis of our case ascertainment. Women with a claim for PCOS (ICD-9-CM 256.4). The index date was PCOS (ICD-9-CM 256.4), a claim for a diag- the first dispensing for a combined oral contra- nostic criteria (anovulation [ICD-9-CM 628.0] ceptive after the PCOS claim. Those with com- and hirsutism [ICD-9-CM 704.1]), or a prescrip- bined oral contraceptive use during the 365-day tion for antiandrogen treatment (i.e., spironolac- period before the index date were considered to tone) were included as having PCOS. Spirono- be prevalent users, while we considered women with no prior combined oral contraceptive use tobe new users. We used a logistic regression Table 2: Comparison of medication use and comorbidities at cohort entry
model to develop a propensity score as the prob- ability for developing PCOS. This score wasformed from prescription and medical claims, demographics and health care utilization dataduring the 365 days before the index date, in addition to the calendar year of diagnosis(formed from covariates at cohort entry in Medication use, % of women
Table 1 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 with similar baseline comorbidities (who werealso taking combined oral contraceptives).
Outcome measure
The outcome of nonfatal venous thromboem- Comorbidities, % of women
bolism was a combined outcome of pulmonary 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 toavoid 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 viouslyshown 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 using a modified Poisson regression with a robust error variance, resulting in a risk ratio (RR).18 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 more inclusive definition of PCOS to improve sensitivity and to evaluate the impact of includ- *Defined as a claim for PCOS (International Classification of Disease, 9th revision, clinical modification [ICD-9-CM] 256.4) ing PCOS diagnostic criteria and treatment in treatment of hyperandrogenism and not as an cessfully match 43 506 (92.8%) of these women, independent risk factor for venous thromboem- producing a patient population of 87 012 for our 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, assessed during the one year before a claim for and we used Cox proportional hazard models to PCOS, creating populations with nearly identical estimate the association between PCOS and characteristics at cohort entry (Table 1). Women venous thromboembolism. All additional PCOS with a PCOS claim, however, were more likely to criteria were also evaluated in similar separately develop nearly every study covariate after base- line, when compared with the matched controls(Table 2). Noteworthy differences at study end Comparison to women with PCOS not
include the use of diabetic medications (PCOS: using combined oral contraceptives
42.88% v. controls: 21.55%), despite similar rates We did not conduct a direct comparison of the of diabetes (14.87% v. 12.23%, respectively), risk of venous thromboembolism among women hyperlipidemia (27.10% v. 20.15%, respectively), with PCOS using, compared to those not using, hypertension (18.70% v. 14.75%, respectively), combined oral contraceptive therapy; if the deci- menstrual irregularity (72.07% v. 54.15%, sion to treat or not to treat PCOS with combined respectively) and obesity (33.11% v. 21.04%, oral contraceptives is an indication of disease severity, then this analysis would be subject to To provide an assessment of baseline venous person- years, while that for matched controls PCOS compared to among women without this PCOS who were taking combined oral contra- 2 million women not taking combined oral con- bolism of 2.14 (95% confidence interval [CI] 1.41–3.24). Our secondary analysis found an described above, with the exception that a 1:4 RR of 2.12 (95% CI 1.40–3.21) (Table 3). match was conducted to ensure adequate power In our sensitivity analysis, a more inclusive def- based on the lower prevalence of PCOS among inition of PCOS also included women who met a women who do not use combined oral contra- diagnostic criteria for PCOS (anovulation or hir- sutism) or treatment for PCOS (spironolactone).
We evaluated proportionality of hazards using The characteristics of this population are shown in analysis included 89 555 women (5.5% of the totalpopulation) with PCOS, and 84 632 (94.5%) were We included 1 632 678 combined oral contracep- successfully matched, defining a second cohort tive users who met our inclusion criteria. Of with 169 264 women. In this second analysis, the these, 46 867 women (2.9% of the total popula- incidence of venous thromboembolism among tion) had a claim for PCOS. We were able to suc- women with PCOS was 24.1/10 000 person-years,while that for matched controls was 10.8/10 000person-years. In this analysis, women with PCOS Table 3: Risk of venous thromboembolism in women with polycystic ovary
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 HR1.72 (95% CI 0.75–3.98), hirsutism HR 2.49 (95% CI 1.35–4.59) and spironolactone HR 1.89 (95% was 6.3/10 000 person-years among women with PCOS not taking contraceptives, while the inci- *Claims for PCOS, anovulation, hirsutism, spironolactone treatment, or PCOS-related dence among matched controls was 4.1/10 000 person-years. Among women not taking com- bined oral contraceptives, women with PCOS Limitations
had an HR for venous thromboembolism of 1.55 Because combined oral contraceptives are rou- (95% CI 1.10–2.19) and a RR of 1.63 (95% CI 1.13–2.34) compared with matched controls.
drugs are known to increase the risk of venous The characteristics of this population are shown thromboembolism, including only users of these drugs limits both confounding by indication and contraindication. However, we do not have anaccurate measure for many potential con- Interpretation
founders (e.g., diet, exercise and family historyof venous thromboembolism), and some residual We found a 2-fold increased risk of venous confounding is likely present. Claims for obesity were similar between women with (13.35%) and taking combined oral contraceptives compared without (13.32%) PCOS at study entry, suggest- with matched controls. We found a similar ing that unmeasured obesity would not be differ- increased risk when we expanded the definition ent between groups; however, we did not have of PCOS by including its symptoms and treat- access to body mass index values, and residual ment. We also found a 1.5-fold increased relative risk of venous thromboembolism among women with PCOS who were not taking contraceptives based on the presence of 2 of the following 3 symptoms: oligo- or anovulation, clinical and/or Our findings are consistent with the previously biochemical signs of hyperandrogenism, and reported 2-fold increase in most of the risk factors polycystic ovaries.1 This regimented clinical for venous thromboembolism among women with diagnostic criteria likely makes a claim for PCOS.1 Among users of combined oral contracep- PCOS very specific, reducing potential bias from tives, the incidence of venous thromboembolism exposure misclassification. However, the sensi- for matched controls was comparable to that of tivity and specificity of PCOS claims are un - users in the general population (7–11/10 000 per- known, and the use of ICD-9-CM codes to iden- son-years),17,19 while the incidence among women tify participants with PCOS may underreport the true prevalence of this condition. Thus, we women not using oral contraceptives, the incidence developed a second definition based on diagnos- of venous thromboembolism among those without tic criteria and medication treatment in order to PCOS was close to previously reported baseline perform a second analysis with an improved sen- rates,17 while those with PCOS had increased risk.
sitivity. This inclusive definition gave a preva- The absolute rate of venous thromboembolism lence of PCOS of 5.5% in the study population, among women with PCOS taking combined oral which is comparable to the known prevalence of contraceptives (23.7/10 000 person-years) was 6%–10%, as defined using the National Institute substantially higher than that among women with this condition not taking contraceptives (6.3/10000 person-years).
Conclusion
Although the covariates at cohort entry were Women with PCOS taking combined oral con- nearly identical between the groups, women with traceptives had a 2-fold increased risk of venous PCOS were more likely to experience nearly thromboembolism, while such women not taking every comorbidity during follow-up. Covariates these drugs had a 1.5-fold increased risk. This is reported at end of the study had a longer period of consistent with previous finding of increased car- assessment and thus were better captured; how- diovascular risk factors and subclinical vascular ever, the differential development of these condi- disease among women with this syndrome.1,5 tions supports the finding that women with PCOS Physicians should be aware of a potentially syn- are at risk of many additional comorbidities.1 ergistic increase in venous thromboembolism The use of contraceptive products by women risk in women with PCOS taking combined oral with PCOS is thought to improve cycle regula- tion and benefit both acne and hyperandro-genism.20 Previous studies have found that com- References
bined oral contraceptives are effective for the Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on reduction of androgen levels and hirsutism in women’s health aspects of polycystic ovary syndrome (PCOS):the Amsterdam ESHRE/ASRM-sponsored 3rd PCOS consensus women with PCOS; these studies have mainly workshop group. Fertil Steril 2012;97:28-38.
focused on drospirenone, desogestrel and cypro- Rotterdam ESHRE/ASRM-sponsored PCOS consensus work- terone acetate.8,9,19 These studies were small in shop group. Revised 2003 consensus on diagnostic criteria andlong-term health risks related to polycystic ovary syndrome. Fer- size and not powered to assess thrombotic events.
Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and thromboembolism from use of oral contraceptives containing predictors of risk for type 2 diabetes mellitus and impaired glu- different progestogens and oestrogen doses: Danish cohort cose tolerance in polycystic ovary syndrome: a prospective, con- trolled study in 254 affected women. J Clin Endocrinol Metab Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159:702-6.
Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of Seeger JD, Loughlin J, Eng PM, et al. Risk of thromboembolism impaired glucose tolerance and diabetes in women with polycys- in women taking ethinyestradiol/drospirenone and other oral tic ovary syndrome. Diabetes Care 1999;22:141-6.
contraceptives. Obstet Gynecol 2007;110:587-93.
Moran LJ, Misso ML, Wild RA, et al. Impaired glucose toler- Nader S, Diamanti-Kandarakis E. Polycystic ovary syndrome, ance, type 2 diabetes and metabolic syndrome in polycystic oral contraceptives and metabolic issues: new perspectives and a ovary syndrome: a systematic review and meta-analysis. Hum unifying hypothesis. Hum Reprod 2007;22:317-22.
Reprod Update 2010;16:347-63.
Baillargeon JP, McClish DK, Essah PA, et al. Association between Affiliations: Department of Health and Human Services
the current use of low-dose oral contraceptives and cardiovasculararterial disease: a meta-analysis. J Clin Endocrinol Metab 2005; (Bird), Food and Drug Administration, Center for Drug Evaluation and Research, Office of Management and Acade- Kriplani A, Periyasamy AJ, Agarwal N, et al. Effect of oral contra- mic Collaboration Program; Department of Pharmaceutical ceptive containing ethinyl estradiol combined with drospirenone Outcome and Policy (Bird, Delaney, Hartzema), University vs. desogestrel on clinical and biochemical parameters in patients of Florida College of Pharmacy, Gainesville, FL; Depart- with polycystic ovary syndrome. Contraception 2010;82:139-46.
ment of Medicine and Epidemiology (Brophy), McGill Uni- Batukan C, Muderris II. Efficacy of a new oral contraceptive versity, Montréal, Que.; Pharmaceutical Outcomes Pro- containing drospirenone and ethinyl estradiol in the long-term gramme (Etminan), School of Medicine, University of treatment of hirsutism. Fertil Steril 2006;85:436-40.
Falsetti L, Pasinetti E. Effects of long-term administration of an oral contraceptive containing ethinylestradiol and cyprteroneacetate on lipid metabolism in women with polycystic ovary Contributors: All authors took part in the study design and
syndrome. Acta Obstet Gynecol Scand 1995;74:56-60.
the analysis and interpretation of the data. The manuscript Pasquali R, Gambineri A, Anconetani B, et al. The natural his- was drafted by Steven Bird and was critically revised for tory of the metabolic syndrome in young women with polycystic important intellectual content by all authors. The statistical ovary syndrome and the effect of long-term oestrogen-progesta- analysis was completed by Steven Bird, and the study guar- gen treatment. Clin Endocrinol (Oxf) 1999;50:517-27.
antor is Joseph Delaney. All authors approved the final ver- Meyer C, McGrath BP, Teede HJ. Overweight women with polycystic ovary syndrome have evidence of subclinical cardio-vascular disease. J Clin Endocrinol Metab 2005;90:5711-6.
Funding: This work was supported by an unrestricted oper-
Bird ST, Pepe SR, Etminan M, et al. The association between ating grant funded in part by the McGill University Health drospirenone and hyperkalemia. BMC Clin Pharmacol 2011; 11: 23.
Bird ST, Wei L, Brophy JM, et al. Irritable bowel syndrome and Center, Fonds de la Recherche en Santé du Québec, and the drospirenone-containing oral contraceptives; a comparative- Ministère de la Santé et des Services Sociaux. James Brophy safety study. Curr Drug Saf 2012;7:8-15.
is a physician scientist who receives financial support from le Etminan M, Delaney JA, Bressler B, et al. Oral contraceptives Fonds de la Recherche en Santé du Québec. Joseph Delaney and the risk of gallbladder disease: a comparative safety study.
receives financial support from Agency for Healthcare Research and Quality (grant no. R21 HS019516-01). Abra- Health IMS. LifeLink Health Plan Claims Database: overview ham Hartzema holds a grant from the National Institutes of and study design issues. Little Rock (AK): University of Health and is the principal investigator for the Observational Arkansas for Medical Sciences; 2010. Available: www.uams .edu/TRI /hsrcore/Lifelink_Health_Plan_Claims_Data_DesignIssues Medical Outcomes Partnership, a private–public partnership _wcost_April2010[1].pdf (accessed 2012 Nov. 15).
designed to help improve drug safety monitoring.
Shih W. Problems in dealing with missing data and informativecensoring in clinical trials. Curr Control Trials Cardiovasc Med Acknowledgement: Steven Bird is employed by the Food and
Drug Administration. This study represents the opinions of the 17. Lidegaard Ø, Nielsen LH, Skovlund CW, et al. Risk of venous authors and not those of the Food and Drug Administration.

Source: http://pop.pharmacy.ufl.edu/files/2012/12/PCOS-and-VTE_cmaj-120677-full-pdf.pdf