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Original Investigation
November 2018

Association of Risk for Venous Thromboembolism With Use of Low-Dose Extended- and Continuous-Cycle Combined Oral Contraceptives: A Safety Study Using the Sentinel Distributed Database

Author Affiliations
  • 1Division of Epidemiology, Office of Pharmacovigilance and Epidemiology, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
  • 2Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
JAMA Intern Med. 2018;178(11):1482-1488. doi:10.1001/jamainternmed.2018.4251
Key Points

Question  Is the risk for venous thromboembolism (VTE) higher with use of extended cyclic and continuous combined oral contraceptives (COCs) (84/7 or 365/0 days cycles) than traditional cyclic COC use (21/7 days cycle), while holding the progestogen type constant (levonorgestrel)?

Findings  This cohort study of 733007 in the US commercially insured population identified a slightly elevated VTE risk in association with continuous/extended COC use when compared with cyclic COC use. However, due to the small absolute risk difference and potential residual confounding, the findings did not show strong evidence supporting a VTE risk difference between continuous/extended and cyclic COC use.

Meaning  The VTE risk difference was small, which may not translate into a clinically significant difference between continuous/extended and traditional cyclic COCs.


Importance  Continuous/extended cyclic estrogen use (84/7 or 365/0 days cycles) in combined oral contraceptives (COCs) could potentially expose women to an increased cumulative dose of estrogen, compared with traditional cyclic regimens (21/7 days cycle), and may increase the risk for venous thromboembolism (VTE).

Objective  To determine, while holding the progestogen type constant, whether the risk for VTE is higher with use of continuous/extended COCs than with cyclic COCs among women who initiated a COC containing ethinyl estradiol and levonorgestrel.

Design, Setting, and Participants  Incident user retrospective cohort study of primarily commercially insured US population identified from the Sentinel Distributed Database. Participants were women aged 18 to 50 years at the time of initiating a study COC between May 2007 and September 2015. Using a propensity score approach and Cox proportional hazards regression models, we estimated the hazard ratios of VTE overall and separately by ethinyl estradiol dose and age groups.

Exposures  Initiation of continuous/extended or traditional cyclic COCs containing ethinyl estradiol or levonorgestrel of any dose.

Main Outcomes and Measures  First VTE hospitalization that occurred during the study follow-up, identified by an inpatient International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of 415.1, 415.1x, 453, 453.x, or 453.xx.

Results  We identified 210 691 initiators of continuous/extended COCs (mean [SD] age, 30.4 [8.6] years) and 522 316 initiators of cyclic COCs (mean [SD] age, 28.8 [8.3] years), with a mean of 0.7 person-years at risk among continuous/extended and cyclic users. Baseline cardiovascular and metabolic conditions (7.2% vs 4.7%), gynecological conditions (39.7% vs 32.3%), and health services utilization were slightly higher among continuous/extended cyclic than cyclic COC users. Propensity score matching decreased the hazard ratio estimates from 1.84 (95% CI, 1.53-2.21) to 1.32 (95% CI, 1.07-1.64) for continuous/extended use compared with cyclic COC use. The absolute risk difference (0.27 per 1000 persons) and the incidence rate difference (0.35 cases per 1000 person-years [1.44 vs 1.09 cases per 1000 person-years]) between the 2 propensity score–matched cohorts remained low, which may not translate into a clinically significant risk differences between cyclic and noncyclic estrogen use.

Conclusions and Relevance  Holding the progestogen type constant (levonorgestrel), we observed a slightly elevated VTE risk in association with continuous/extended COC use when compared with cyclic COC use. However, due to the small absolute risk difference and potential residual confounding, our findings did not show strong evidence supporting a VTE risk difference between continuous/extended and cyclic COC use.

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    1 Comment for this article
    Risks of venous thrombosis vary with type of progestin
    Ellen Grant |
    In 2015, Vinogradova et al collected 10,500 cases of VTE and 42,000 matched controls in UK general practice databases. 68% of cases and 57% of controls were analysed following exclusions mostly for pregnancy or hysterectomy. Any current use of combined OCs gave a 3-fold increased risk of idiopathic venous thromboembolism compared with no use in the past year. Newer third generation progestins doubled the risk compared with older progestins. Risks for desogestrel (x4.28), gestodene (x4.27), drospirenone (x4.12) and cyproterone (x4.27) were compared with levonorgestrel (x2.38), norethisterone (x2.56) and norgestimate (x2.53).1

    In 1969 I found, in the London oral contraceptive
    trial, that vein complaints, including painful distended veins, leg cramps, thrombophlebitis and thromboembolism, occurred in 3% to 50% of women taking oral contraceptives and related to dilated endometrial sinusoids, with or without stromal condensation. Norethisterone acetate (a progestin with inherent estrogenic activity) and ethynodiol diacetate combinations, caused more veins complaints than norgestrel, especially when combined with higher doses of estrogen.2 Norgestrel has inherent androgenic activity and most contemporary hormonal contraceptives are derived from, and act like, levonorgestrel.

    1 Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.BMJ 2015;350:h2135

    2 Grant ECG. Venous effects of oral contraceptives. BMJ 1969;2:73-7.