Reassessing Use of Depot Medroxyprogesterone Acetate in Select Groups of Women: Applying the 2024 U.S. Centers for Disease Control and Prevention Medical Eligibility Criteria for Contraceptive Use Guidelines

Case History

A 32-year-old woman presents for contraceptive counseling. She has been using depot medroxyprogesterone acetate (DMPA) for the past year and is due for her next injection. Her previous medical history is significant for anemia due to heavy menstrual bleeding and an unprovoked proximal deep vein thrombosis (DVT) 9 months ago. She completed only 6 months of anticoagulation, rather than indefinite therapy, due to her increased bleeding risk with anemia. She is otherwise healthy and does not smoke. She is satisfied with her current contraceptive method and requests to continue DMPA. She is not currently on anticoagulation.

Which of the following is the most appropriate next step in contraceptive management? A.

Discontinue DMPA and switch to a combined oral contraceptive pill.

DMPA Background

DMPA was approved by the Food and Drug Administration (FDA) as an injectable progestin-only contraceptive agent in 1992. ¹ It is available as a 104 mg subcutaneous injection (DMPA-SC) and a 150 mg intramuscular injection, both administered at 12–14 week intervals. Injections may be delayed up to 15 weeks with no need for backup contraception. ² DMPA-SC can be self-injected (FDA approved for contraception but off-label for self-administration) and has been shown to improve contraceptive continuation rates without increasing pregnancy risk when compared with clinician administration.^2–4

DMPA is a highly effective contraceptive option. ¹ In a large prospective cohort study evaluating the effectiveness of long-acting reversible contraceptives (LARCs), compared with other contraceptive methods, DMPA failure rates were comparable to LARCs (including the levonorgestrel intrauterine device [IUD], copper IUD, and subdermal implant) at 0.1%, 0.7%, and 0.7% in years 1, 2, and 3, respectively (p = 0.96). When measured as failure rates per 100 participant-years, rates were similarly low among perfect users of DMPA injections (0.22, p < 0.001) and users of IUDs or subdermal implants (0.27, p < 0.001) and substantially lower than rates observed among users of the combined hormonal pill, patch, or ring (4.55).^2,5

Common side effects of DMPA use (≥5% of users) include menstrual irregularities, weight gain, headache, nervousness, abdominal pain, dizziness, and asthenia. DMPA is associated with greater weight gain than other contraceptive methods, such as combined oral contraceptives and subdermal implants.^1,6 DMPA is associated with a predominantly reversible reduction in bone mineral density (BMD), with greater loss observed with longer duration of use, prompting the FDA black box warning issued in 2004. ⁷ Studies in both adolescents and adults demonstrate partial to complete recovery of BMD following discontinuation, though the extent of recovery varies based on the duration of exposure, age at initiation, and the specific skeletal sites affected.

The U.S. Medical Eligibility Criteria for Contraceptive Use

The U.S. MEC provides evidence-based contraceptive guidelines regarding the safety and use of all FDA-approved methods of contraception to guide clinical practice in the United States. The guidelines are updated every 5–6 years and published by the Centers for Disease Control and Prevention (CDC) based on current scientific literature and systematic reviews.^4,7,8 Contraceptive safety is scaled from one to four with the following definitions: •

U.S. MEC 1: A condition for which there is no restriction for the use of a contraceptive method.

The only absolute Category 4 contraindication to DMPA use is active breast cancer. Examples of Category 3 conditions include decompensated cirrhosis and hepatocellular adenoma; history of stroke or ischemic heart disease; and solid organ transplant (SOT) with increased risk for fracture, such as those on immunosuppressive therapies. In addition, some Category 2 conditions include obesity, gallbladder disease, active VTE on therapeutic anticoagulation, and SOT without increased fracture risk.^4,7

Thrombogenic Risk Category Changes

A 2025 systematic review of progestin-only contraceptives found statistically significant increases in odds of venous thromboembolism (VTE) with DMPA use in women without known thrombogenic conditions such as factor V Leiden mutation (FVL), history of VTE, women in the postpartum period, diabetic patients, active smokers, and lupus patients. A case-control study of women with known FVL mutation showed a significant increase in VTE risk with DMPA use (OR: 16.7, 95% CI: 2.4–714). Similarly, in a cohort study of postpartum women, there was a statistically significant increase in VTE risk among women using DMPA compared with nonusers (IRR: 1.9, 95% CI: 1.4–2.7). In a retrospective cohort study of women with diabetes using DMPA, there was also a statistically significant increase in VTE or arterial thromboembolism risk when compared with IUD users (aHR: 4.7, 95% CI: 2.5–8.8). While there is an increased VTE risk in women with inherited or acquired thrombophilia using DMPA, other progestin-only methods do not confer this risk. ⁹

The August 2024 USMEC update recommends increased caution with DMPA use in patients with prior VTE who are at high risk of recurrence and in those with thrombophilia due to elevated VTE risk.^8,10 High-risk features include thrombophilia (e.g., Factor V Leiden, prothrombin mutation, protein C/S or antithrombin deficiency, and antiphospholipid syndrome), active cancer, or a history of recurrent VTE. ⁷ Accordingly, DMPA has been reclassified to USMEC Category 3 for high-risk patients not on anticoagulation or those on prophylactic-dose anticoagulation, representing a change from Category 2 in 2016. DMPA remains Category 2 for patients on therapeutic anticoagulation or those at low risk of recurrence. ⁸

Solid Organ Transplant Category Changes

Women who are recipients of SOTs are vulnerable to reductions in BMD due to pre-transplant factors such as malnutrition, vitamin D deficiency, and secondary hyperparathyroidism. Post-transplant use of steroids and prolonged immunosuppressive drugs further compound this vulnerability. Although data examining DMPA use in these groups is limited, its established detrimental effects on BMD raise concern for further increasing fracture risk. ¹¹

The 2024 guideline update reflects growing evidence that DMPA accelerates BMD decline and increases fracture risk, particularly among patients receiving chronic immunosuppression. ¹⁰ Longitudinal studies indicate that BMD reductions with DMPA may be only partially reversible, with transplant recipients inherently facing a higher baseline risk for osteoporosis and fragility fractures. Consequently, DMPA was reclassified from Category 2 to Category 3 for long-term use in this population, signifying that the risks now outweigh the benefits. As a result, alternative contraceptive options are preferred. ⁴

In summary, DMPA remains a safe contraceptive option for individuals with a single thrombotic event and low recurrence risk as well as those on therapeutic anticoagulation. However, individuals with thrombophilia or at high risk for recurrent thrombosis should be counseled on contraceptive options with a more favorable safety profile. DMPA should also be avoided in SOT recipients due to increased fracture risk. While DMPA is considered overall safe, clinicians should discuss the potential adverse effects and theoretical harms with patients and engage in shared decision-making to ensure informed contraceptive choice.

Correct Answer: B

According to the U.S. MEC guidelines, DMPA may be continued if a patient has a history of DVT with a low risk of recurrence. In her case, her DVT was unprovoked, and she is no longer on anticoagulation, indicating a high risk of recurrence. This is defined as U.S. MEC Category 3—theoretical or proven risks usually outweigh the advantages. However, as with each medication, other risk factors should be considered, and shared decision-making should be used on whether or not to continue the medication.

Answer A is incorrect, as in women with a history of DVT, estrogen-containing contraceptives are contraindicated due to the increased risk of thromboembolism.

Option C is overly restrictive and not evidence-based; other progestin-only and nonhormonal methods are generally safe.

Option D is incorrect as there is an increased risk of thrombosis with DMPA.