DMPA: Battered and Bruised but Still Needed and Used in the USA

Anita L Nelson

Disclosures

Expert Rev of Obstet Gynecol. 2010;5(6):673-686. 

In This Article

Abstract and Introduction

Abstract

Depot medroxyprogesterone acetate (DMPA; Depo-Provera®, Merck & Co., Inc., NJ, USA) is a very safe and effective method of birth control that can be used by virtually every woman. However, DMPA has not achieved its full potential for pregnancy protection. With correct and consistent use, the first-year pregnancy rate should be 0.3%, but in typical use, the first-year pregnancy rate is 7.4%. This gap is due to interrupted use and high discontinuation rates. Responding to patient complaints of side effects and adopting new practice protocols that enhance prompt access to DMPA may improve continuation rates and lower failure rates. Newer information about the long-term safety of DMPA on bone health and sexually transmitted disease risk may encourage more clinicians to more enthusiastically support the use of DMPA, particularly among women who would benefit from its noncontraceptive health applications.

Introduction

The 3-month injectable depot medroxyprogesterone acetate (DMPA) was registered for use as a contraceptive in 1979. It is the fifth most commonly used contraceptive method worldwide.[201] In sub-Saharan Africa, it is used by one-third of women employing contraception.[1] However, DMPA has had a tumultuous history in the USA over the last four decades. The first US FDA-approved application for DMPA was with very high doses of DMPA (1000 mg/week), followed by lower maintenance doses given for 1–3 weeks to treat endometriosis and endometrial carcinoma.[2] At the time, medroxyprogesterone acetate (MPA) was also used off-label in high doses to treat breast cancer. Response rates of 45% were attained in patients with estrogen receptor- and progesterone receptor-positive lesions. DMPA is known to turn on the metastasis suppressor gene Nm23-H1 and to reduce soft agar colonization of metastatic breast cancer cell lines by almost 50%.[3] However, as a contraceptive version of DMPA was being developed, new testing regulations were put in place by the FDA to ensure product safety in the wake of the thalidomide disaster. In animal safety testing of DMPA for contraception, female beagle dogs developed breast cancer when treated with massive doses of DMPA. Rhesus monkeys developed endometrial cancer with doses 50-times higher than the contraceptive dose.[2] The FDA denied approval in 1978 and again in 1983 owing to those health issues, coupled with deeply held concerns by some women's advocacy groups that injectable contraceptives could be used to involuntarily control the fertility of specific groups of women.

During the intervening years, those problems were resolved. It was learned that all progestins at high doses, even progesterone, cause breast tumors in beagles, and that beagles are not appropriate test animals for any steroid hormones. Extensive clinical experience with women in international studies demonstrated the neutrality of DMPA on the long-term risk of breast cancer,[4–6] ovarian carcinoma[7] and cervical cancer,[8] and the protective effect DMPA had on preventing endometrial cancer.[9] Residual concerns regarding DMPA's potential as an involuntary contraceptive dissolved when physicians refused to use Norplant in that way. The FDA approved DMPA 150-mg intramuscular (IM) injection for contraception in October 1992.

Since most US practitioners already had extensive off-label experience using DMPA for contraception in the intervening years, its introduction was reasonably straightforward. Studies showed that DMPA and Norplant accounted for a significant share of the decline that was seen in adolescent pregnancy rates in the 1990s. DMPA was an especially good choice for at-risk teenagers because it was very convenient and very private. With the loss of Norplant contraceptive implants late in the 1990s, injectable contraception became the only long-acting contraception felt at the time to be suitable for teens. Teenager use of DMPA increased from 4% in 1994 to 17% in 1997; by 2002, 400,000 teenagers in the USA relied on the method.[10]

However, at the turn of the century, new safety concerns were raised about the possibility that the use of DMPA might thin the vaginal epithelium[11] and influence cervical ectopy, thereby increasing the vulnerability of users to acquiring or transmitting HIV infection or other sexually transmitted diseases (STDs), especially chlamydia.[12,13] Later, concern was raised that DMPA use might increase the progression of HIV infection.[14]

The popularity of DMPA was even more severely diminished by product labeling changes made in 2004. A Black Box warning was added to alert clinicians to the possible loss of bone-mineral density (BMD) with extended DMPA use and to advise clinicians to limit use DMPA use to 2 years unless other methods were inadequate. The new labeling also recommended that BMD be evaluated in women who used DMPA for longer than 24 months.[202]

A lower dose formulation, DMPA-SQ (Pfizer, NY, USA) 104 mg given subcutaneously, was introduced around this time. It had been hoped that the lower dose might be associated with the risk of BMD loss and that the subcutaneous (SQ) administration might enable self-administration. Unfortunately, BMD losses with DMPA-SQ 104 mg at 3 years were found to be no different from those seen with IM DMPA,[15] although the potential for self-administration has not been totally dismissed.

This classic boom-and-bust story of DMPA has, unfortunately, been experienced by virtually every other safe and effective contraceptive method introduced into the USA, including intrauterine devices and Norplant, the contraceptive patch and many birth-control pills.[16] However, the original DMPA is still available and has garnered consistent professional support for both its short- and long-term use.[17,18] The latest data from the National Survey on Family Growth (NSFG) reported that 22.2% of US women aged 15–44 years who have ever been sexually active have ever used DMPA;[19] that is an increase from 4.5% in 1995. DMPA is more likely to have been used by African–American (29.5%) or Hispanic women (26.2%) than by Caucasian (19.0%) or Asian women (16.6%). Among the 61.9% of US women currently on contraception, only 2.0% of women in the 2006–2008 NSFG were currently using DMPA, which was down from 3.3% in 2002. DMPA was used by 9.4% of contracepting women aged 15–19 years, and by 5.2% of contracepting women aged 25–29 years. Again, African–American women were almost three times as likely to use injectable contraception as were Caucasian women. The NSFG also showed that DMPA tended to be used more by women with lower education who had incomes below the poverty level, and by those who intended to have more children. In every category measured, use of DMPA had declined dramatically between the 2002 survey and the 2006–2008 survey, reflecting the impact of the Black Box warning.

This article will highlight some of the current issues surrounding the use of DMPA in the USA. The most important issues affecting patient attitudes relate to potential side effects of changes in bleeding patterns, weight changes and mood changes. On the other hand, clinicians are also concerned about potential adverse impacts on bone mineralization and STD susceptibility. Other issues that influence DMPA success include practice protocols that facilitate women's timely access to injections and important counseling messages, including information about noncontraceptive benefits.

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