Patient #1: LNG-IUS
A 25-year-old G0P0 with systemic lupus erythematosus (SLE) and positive anti-phospholipid antibodies presents to discuss management of heavy periods, a hemoglobin of 10.5 g/dL and a need for contraception. She denies a personal or family history of VTE. The woman doesn’t remember to take her other medications regularly and desires an option that lightens her cycle, while also providing longer-term effective contraception.
You counsel your patient that the Centers for Disease Control and Prevention Medical Eligibility Criteria (CDC-MEC)1 guidelines characterize the LNGIUS as category 3 (risks generally outweigh benefits) in patients with SLE and positive antiphospholipid antibodies. However, you also educate her that citations behind the MEC recommendation are mostly based on a theoretical risk of VTE rather than studies of LNG-IUS use in her specific situation. Based on this patient’s positive antiphospholipid antibodies, the MEC guidelines recommend only one option for her: the copper IUD;5 however, with her heavy bleeding and mild anemia, it is not an ideal option. You counsel her that the literature does not demonstrate any increased risk of VTE with LNG-IUS use, in both low- and high-risk populations, and engage in shared decision-making.
The LNG-IUS is available in several versions, with its active progestin component levonorgesterol ranging from 13.5 to 52 mg. With use of the device, the stable plasma level of levonorgestrel is at most approximately 3% of the level seen with a levonorgestrel-containing combination oral contraceptive (COC) pill.6,7 The 52-mg LNG-IUS is approved by the US Food and Drug Administration (FDA) for contraception for up to 5 years and for heavy menstrual bleeding. There is no FDA warning for VTE risk on the package insert.6
Multiple studies have evaluated use of the 52-mg LNG-IUS and VTE risk in a low-risk population.8-9 The largest was a 2009 national registry cohort study in Denmark involving non-pregnant women aged 15 to 49, with no history of cardiovascular disease or malignancy.8 The study evaluated 10.4 million woman-years and reported 4,214 VTE episodes. The authors concluded that compared to non-use of hormones, use of the 52-mg LNG-IUS was not associated with increased risk of VTE (RR 0.90; 95% CI 0.64-1.26).8 Two systematic reviews were conducted, one prior to and one including this article,9,10 both of which concluded that the 52-mg LNG-IUS does not increase VTE risk in low-risk populations.
The relationship between the 52-mg LNG-IUS and VTE risk also has been evaluated in populations at higher VTE risk. A 2016 systematic review included nine studies of the the device in high-risk women with SLE, hypertension, smoking, thrombophilia, and history of VTE. The study concluded that there was no statistically significant increased risk of VTE in women using the 52-mg LNG-IUS in these high-risk populations.9
- 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.