Patient #2: DMPA
A 21-year-old G0P0 presents with amenorrhea for 6 months using intramuscular (IM) DMPA, which was started for menorrhagia. She is not sexually active and tells you she “doesn’t want a foreign object in my body.” Her friend was recently diagnosed with deep vein thrombosis after a car accident and leg fracture. Although your patient doesn’t have any other personal risk factors for VTE, she is concerned about her own VTE risk on an upcoming trip while using DMPA.
You counsel your patient that a meta-analysis that found no increased VTE risk with other progestin-only agents did find a doubling in VTE risk with DMPA use.10 Despite this increased relative risk, the baseline risk of VTE is 1 to 10 per 10,000 yearly in a young, healthy population,2 so her absolute risk of VTE remains low on the order of 2 to 20 per 10,000. MEC guidelines are category 2 (benefits generally outweigh risks) for DMPA use in women with current VTE, history of VTE, or risk factors for it.5 You discuss with your patient that estrogen-containing options including COC pills would also be an option for her, however, they increase VTE risk 3-5 fold,11 which is a greater risk compared to progestin-only agents.
A 2012 Dutch metaanalysis in women at low risk of VTE found no increased risk of VTE among overall users of a progestin-only contraceptive compared to non-users (relative risk 1.03; 95% CI 0.76 to 1.39). Importantly, the subgroup analysis of DMPA users demonstrated that, unlike other progestin-only options like the LNG-IUS and norethindrone, DMPA was associated with a doubling in VTE risk compared to that in non-users of hormones (relative risk 2.67; 95% CI 1.29 to 5.53).10
Two studies assessed VTE risk with DMPA use in populations at higher VTE risk. The first found a trend toward an increased risk of VTE in smokers using DMPA (OR 7.0; 95% CI 0.4–138) compared to smokers not using hormones (OR 1.3; 95% CI 0.97–1.6), however, the confidence intervals were wide and the results were not statistically significant.4 The second is a case control study of women with Factor V Leiden mutations, which found no increased risk of VTE in women using other progestin-only agents, however, an increased risk of VTE was found in users of DMPA (OR 2.2; 95% CI 1.3-4.0).14
- Committee on Practice Bulletins—Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012 Jul;120(2):197-206..
- Eichinger S, Evers JLH, Glasier A, et al.Venous thromboembolism in women: a specific reproductive health risk. Hum Reprod Update 2013;19:471-482.
- Trenor CC 3rd, Chung RJ, Michelson AD, et al.Hormonal contraception and thrombotic risk: a multidisciplinary approach. Pediatrics 2011;127:347-357.
- Curtis KM, Tepper NK, Jatlaoui TC, et al.U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep2016;65:1-103.
- Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception 1998;57(5):315-324.
- US Food and Drug Administration. Levonorgestrel-releasing intrauterine system. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021225s019lbl.pdf.
- Gaspard UJ, Romus MA, Gillain D, Duvivier J, Demey-Ponsart E, Franchimont P. Plasma hormone levels in women receiving new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel. Contraception 1983;27:577-590.
- Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ2009;339:b2890.
- Tepper NK, Whiteman MK, Marchbanks PA, James AH, Curtis KM. Progestin-only contraception and thromboembolism: A systematic review. Contraception 2016;94:678-700.
- Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ 2012;345:e4944.
- Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, Politou M. Oral Contraceptives and HRT Risk of Thrombosis. Clin Appl Thromb Hemost 2018;24:217-225.
- US Food and Drug Administration. Depo-provera. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020246s036lbl.pdf.
- US Food and Drug Administration. Oral provera. US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011839s071lbl.pdf.
- Bergendal A, Persson I, Odeberg J, et al.Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes. Obstet Gynecol 2014;124:600-609.
- US Food and Drug Administration. Norethindrone. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf.
- Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA. Formation of ethinyl estradiol in women during treatment with norethindrone acetate. J Clin Endocrinol Metab 2007;92:2205-2207.
- Klehr-Bathmann I, Kuhl H. Formation of ethinylestradiol in postmenopausal women during continuous treatment with a combination of estradiol, estriol and norethisterone acetate. Maturitas 1995;21:245-250.
- Reed MJ, Ross MS, Lai LC, Ghilchik MW, James VH. In vivo conversion of norethisterone to ethynyloestradiol in perimenopausal women. J Steroid Biochem Mol Biol 1990;37:301-303.
- Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K. In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women. Contraception 1997;56:379-385.
- Barsoum MK, Heit JA, Ashrani AA, Leibson CL, Petterson TM, Bailey KR. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res 2010;126:373-378.
- US Food and Drug Administration. Megestrol acetate. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020264s017lbl.pdf.
- Muneyyirci-Delale O, Gupta A, Abraham C, Chandrareddy A, Bowers CH Jr, Cutler JB. Management of dysfunctional uterine bleeding based on endometrial thickness. Int J Womens Health 2010;2:297-302.
- Ruiz-García V, López-Briz E, Carbonell-Sanchis R, Bort-Martí S, Gonzálvez-Perales JL. Megestrol acetate for cachexia-anorexia syndrome. A systematic review. J Cachexia Sarcopenia Muscle 2018;9:444-452.
- Incidence of Venous Thromboembolism (VTE) in Patients Prescribed Megestrol for Appetite Stimulation | January 2017 | ACP. https://www.acponline.org/membership/medical-students/acp-impact/archive/january-2017/incidence-of-venous-thromboembolism-vte-in-patients-prescribed-megestrol-for-appetite-stimulation (accessed Oct 12, 2019).
- Bolen JC, Andersen RE, Bennett RG. Deep vein thrombosis as a complication of megestrol acetate therapy among nursing home residents. J Am Med Dir Assoc 2000;1:248-252.
- Ordu C, Pilanci KN, Koksal UI, et al.Can megestrol acetate induce thrombosis in advanced oncology patients receiving chemotherapy? Asian Pac J Cancer Prev 2014;15:10165-10169.
- Thürlimann B, Castiglione M, Hsu-Schmitz SF, et al.Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Swiss Group for Clinical Cancer Research (SAKK). Eur J Cancer 1997;33:1017-1024.