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

JAMA Intern Med. 2018 Nov 1;178(11):1482-1488. doi: 10.1001/jamainternmed.2018.4251.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Contraceptives, Oral, Combined / adverse effects*
  • Databases, Factual
  • Female
  • Humans
  • Incidence
  • Middle Aged
  • Retrospective Studies
  • Risk
  • Venous Thromboembolism / chemically induced*
  • Venous Thromboembolism / epidemiology*
  • Young Adult


  • Contraceptives, Oral, Combined