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Association of Progestogens and Venous Thromboembolism Among Women of Reproductive Age - PubMed

  • ️Sat Jan 01 2022

Association of Progestogens and Venous Thromboembolism Among Women of Reproductive Age

Richard H Cockrum et al. Obstet Gynecol. 2022.

Abstract

Objective: To evaluate associations between use of seven progestogens and incident acute venous thromboembolism (VTE) among women of reproductive age.

Methods: This nested matched case-control study identified women aged 15-49 years from January 1, 2010, through October 8, 2018, in the IBM MarketScan databases, a nationwide sample of private insurance claims in the United States. After exclusions, 21,405 women with incident acute VTE (case group), identified by diagnosis codes, were matched 1:5 by year of birth and index date through risk set sampling to 107,025 women without prior VTE (control group). From lowest to highest systemic dose based on a modified hierarchy, progestogens studied were levonorgestrel-releasing intrauterine device (LNG-IUD), oral norethindrone, etonogestrel implant, oral progesterone, oral medroxyprogesterone acetate, oral norethindrone acetate, and depot medroxyprogesterone acetate (DMPA). Conditional logistic regression models adjusted for 16 VTE risk factors were used to estimate odds ratios and 99% CIs for incident acute VTE associated with current progestogen use compared with nonuse. The primary analysis treated each progestogen as a binary exposure. Dose, which varied for oral formulations, and chronicity were explored separately. Significance was set at P <.01 to allow for multiple comparisons.

Results: Current use of higher-dose progestogens was significantly associated with increased odds of VTE compared with nonuse (oral norethindrone acetate: adjusted odds ratio [aOR] 3.00, 99% CI 1.96-4.59; DMPA: aOR 2.37, 99% CI 1.95-2.88; and oral medroxyprogesterone acetate: aOR 1.98, 99% CI 1.41-2.80). Current use of other progestogens was not significantly different from nonuse (LNG-IUD, etonogestrel implant, and oral progesterone) or had reduced odds of VTE (oral norethindrone). Sensitivity analyses that assessed misclassification bias supported the primary findings.

Conclusion: Among reproductive-aged women using one of seven progestogens, only use of norethindrone acetate and medroxyprogesterone acetate-considered higher-dose progestogens-was significantly associated with increased odds of incident acute VTE. The roles of progestogen type, dose, and indication for use warrant further study.

Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Conflict of interest statement

Financial Disclosure Kenneth S. Cohen received travel reimbursement from the Japan Cancer Society for an awards ceremony in 2019. He received payment from the American Medical Forum for independent CME talks in 2019, and honoraria for streaming lectures in 2020. He also received honoraria from Bioascend for a lecture at the International Ultmann Chicago Lymphoma Symposium 2022. The other authors did not report any potential conflicts of interest.

Figures

Figure 1.
Figure 1.

Case and matched control selection flow diagram. VTE, venous thromboembolism.

Figure 2.
Figure 2.

Current use of progestogens and odds of venous thromboembolism (VTE). *Exposures are listed using a progestogen dose hierarchy by Bergendal et al, modified to incorporate noncontraceptive progestogens (lowest to highest: levonorgestrel intrauterine device [LNG-IUD], oral norethindrone [NET], etonogestrel implant [implant], oral progesterone [prog], oral medroxyprogesterone acetate [MPA], oral norethindrone acetate [NETA], DMPA, depot medroxyprogesterone acetate [DMPA]). †Referent group for each conditional logistic regression model is noncurrent users of any progestogen (ie, no progestogen use within 28 days before index date), n=125,027 (cases: n=20,554; controls: n=104,473). The crude model was adjusted for year of birth and index date by study design. The fully adjusted model additionally included 16 VTE risk factors: obesity (body mass index >30 mg/kg2), history of smoking, atherosclerotic cardiovascular disease, hypertension, congestive heart failure, chronic kidney disease, rheumatoid arthritis, systemic lupus erythematous, inflammatory bowel disease, cancer (with exclusions), hemiplegia or paraplegia, hypercoagulable state, superficial venous thrombosis, varicose veins, history of surgery or lower extremity fracture within 180 days before index date, and history of hospitalization within 180 days of index date. ‡P<.01. §P<.001. OR, odds ratio.

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