Contraception: Depot Medroxyprogesterone Acetate
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers.
Educational grant provided by Women's Health and Education Center (WHEC).
An unintended pregnancy represents a lost opportunity for preconceptional care for the fetus and a higher risk of pregnancy-related morbidity in the mother. Unintended pregnancies have been also associated with higher rates of unhealthy behaviors, such as smoking or alcohol use, and the lower rates of prenatal vitamin use, which increase the risk of low-birth weight infants and other adverse pregnancy outcomes. A woman's use of her contraceptive method is affected by features of the method itself (dosing frequency, ease of use, cost and availability) as well as by her perceptions about the method. A patient's perception can be influenced by her own personal experiences with various methods in addition to her fears and misinformation and those of her family, friends, and the media. By providing counseling and information, as well as offering methods that may help reduce women's chances for inconsistent or incorrect contraceptive use, clinicians can help to overcome many of the barriers to successful contraception that women face. Depot medroxyprogesterone acetate (DMPA) is a reversible contraceptive method. It is a progestin-only contraception and it is an option for women in whom estrogen-containing contraceptive is contraindicated or causes additional health concerns.
The purpose of this document is to describe advantages and disadvantages of depot medroxyprogesterone acetate (DMPA) use by individual adolescent and adult women. It also evaluates evidence regarding short- and long-term effects of DMPA on skeletal health. Counseling of all reproductive-age women, about the importance of maintaining a healthy lifestyle to minimize risks of osteoporotic fractures later in life, is essential. The review utilizes an evidence-based approach to the recently approved black box changes in DMPA product labeling.
Depot medroxyprogesterone acetate (DMPA) is an injectable, progestin-only contraception that provides highly effective, private, reversible contraception and avoids both the need for user action daily or near the time of sexual intercourse and need for partner cooperation. The 2002 National Survey of Family Growth reported that 5.3% of all U.S. women aged 15 through 44 currently using contraception used DMPA (1). Among contraception users, 13.9% of those aged 15 to 19 and 10.1% of those aged 20 to 24 currently used DMPA compared with 1.6% of those aged 40 to 44. Decreasing rates of adolescent pregnancy between 1995 and 2002 are considered to be due in part to increased use of some method of contraception, including DMPA, by this age group (2). DMPA is available in two formulations: 150 mg/1 mL for intramuscular injection (IM) and 104 mg/0.65 mL for subcutaneous (SC) injection. The injections can be given every three months because low solubility of the microcrystals at the injection site allows pharmacologically active drug levels to persist for several months. Following a single 150 mg IM dose of DMPA, drug levels increase for approximately three weeks, reaching a peak concentration of 1 to 7 ng/mL (3). The levels then decrease exponentially until they become undetectable (less than 100 pg/mL) between 120 and 200 days following the injection, but considerable inter-individual variability in serum levels exists.
The relatively new 104 mg formulation provides slower and more sustained absorption of the progestin than conventional DMPA, which allows for a 30% lower dose of progestin, but with the same duration of effect as conventional DMPA. Administration via the SC route is less painful than IM injection and potentially may allow patient self-administration. Intramuscular DMPA is available as a generic formulation, which is less costly than DMPA-SC. Otherwise the benefits and risks are similar for IM and SC administration. Serum progesterone levels are low (<0.4 ng/mL) for several months following an injection of DMPA since ovulation is suppressed. Estrogen levels vary, but most women have lower levels than normally cycling women (2, 3). Women who have used DMPA for several years have serum estradiol levels between 10 and 92 pg/mL (mean about 40 pg/mL). Although the endometrium becomes atrophic, vasomotor symptoms are uncommon and the vaginal epithelium remains moist and well rugated.
Mechanism of Action and Efficacy:
DMPA primarily acts by inhibition of gonadotropin secretion, thereby inhibiting follicular maturation and ovulation; a hypoestrogenic state also results (4). Another contraception effect is progestin's ability to cause changes in cervical mucus and tubal motility that are hostile to sperm migration.
For the 150 mg IM injection, failure rates in clinical trials ranged from 0.0 to 0.7/100 woman years (5). The typical-user failure rate is 3/100 woman years, reflecting that some users do not return for their injections as scheduled. Because progestin levels are high, efficacy is not reduced by high body weight or use of concurrent medications. For the 104 mg SC injection, no contraceptive failures were reported in phase III clinical trials (6). This formulation is relatively new; typical-user failure rates are not yet available, but would be expected to be similar to the IM preparation.
Advantages of DMPA Use:
DMPA provides high contraceptive effectiveness, with a first-year pregnancy rate of 0.3%. Contraceptive effectiveness begins within 24 hours after injection. However, women can still ovulate in the first 24 hours; therefore, back-up protection is needed for the first 3 days of DMPA use (6). The contraceptive efficacy of DMPA is maintained for at least 14 weeks after administration, providing a margin of protection if reinjection is delayed (4, 6). Use of DMPA is required only once every 3 months, the injection site is invisible, and the long-acting contraception provided by DMPA is not dependent on user action or partner cooperation at the time of intercourse. The reversible contraceptive action of DMPA is inhibition of ovulation, with ovulation resuming between 14 weeks to 9 months after method discontinuation. In addition, since DMPA is a progestin-only method, it is appropriate for many women in whom estrogen use is contraindicated. Ovarian estradiol production is reduced with DMPA use. For about one third of DMPA users, mean estradiol levels are similar to those in normal-cycling women during the early- to mid-follicular phase of the menstrual cycle, approximately 40 to 50 pg/mL (4). However, in most DMPA users estradiol levels vary after the DMPA injection and may reach levels found in postmenopausal women (mean 18.9 pg/mL). Vasomotor symptoms and vaginal dryness occur uncommonly in DMPA users. High-dose progestins suppress vasomotor symptoms.
The timing of injections is summarized in the table below. Inadvertent administration of DMPA during pregnancy does not increase the risk of congenital anomalies (7). In the US Planned Parenthood National Database for 1994 to 1998, 402 DMPA users became pregnant and many of these women received more than one dose of DMPA while pregnant (7). No fetal anomalies were reported, but birth outcome data were incomplete.
Benefits of DMPA:
DMPA has been used to manage a variety of gynecologic and non-gynecologic disorders. The tendency of DMPA to cause amenorrhea makes it a particularly appropriate contraceptive choice for women with menorrhagia, dysmenorrhea, or iron-deficiency anemia. DMPA transforms proliferative endometrium into secretory type, thus it protects against development of endometrial hyperplasia. Progestins inhibit endometriotic tissue growth by directly causing initial decidualization and eventual atrophy and by inhibiting pituitary gonadotropin secretion and ovarian estrogen production. Randomized trials have shown that DMPA is more effective than oral contraceptives and danazol, and as effective as leuprolide for treatment of pain associated with endometriosis (4, 10). DMPA is a useful means of suppressing menstrual bleeding and managing menstrual hygiene in individuals with special needs (eg, cognitive impairment, military personnel). Use of DMPA has been associated with hematologic improvement (fewer painful crises) in women with sickle cell disease. The efficacy of DMPA's contraceptive protection does not appear attenuated by the use of enzyme-inducing anticonvulsants, and DMPA may have intrinsic anticonvulsant properties. For these reasons, DMPA might be a good contraceptive of choice for many women with seizure disorders. DMPA offers effective treatment of menopausal vasomotor symptoms in women who need to avoid estrogen therapy.
Effect on cancer risk -- the World Health Organization (WHO) examined the risk of endometrial, ovarian, liver and cervical carcinoma in DMPA-users. In large case control studies, DMPA decreased the prevalence of endometrial cancer by 80%, and was associated with a greater protective effect against endometrial cancer than oral contraceptives. DMPA did not increase the risk of ovarian, cervical or liver cancer. Additional data from New Zealand, South Africa and the United States showed no increase in risk of breast cancer in DMPA users. Theoretically, it is possible that prolonged ovulation suppression associated with DMPA might provide protection against ovarian cancer, as seen with oral contraceptives.
Effect on cardiovascular risk -- DMPA use reduces plasma high-density lipoprotein levels and peripheral arterial hyperemia-induced flow-mediated dilatation, but does not increase production of coagulation factors, and has no adverse effect on blood pressure. Epidemiological studies have shown no adverse cardiovascular effects related to use of DMPA. Based on these findings, the American College of Obstetricians and Gynecologists (ACOG) stated that DMPA and other progestin-only contraceptives may be appropriate contraceptive options for women with a history of venous thromboembolism (VTE) and those in whom use of combination estrogen-progestin contraceptive is contraindicated (17). This recommendation differs from package labeling of DMPA, which indicates that a prior history of VTE is a contraindication to DMPA use. In women with multiple risk factors for cardiovascular disease (eg, smoking, older age, hypertension, diabetes), the World Health Organization (WHO) classifies DMPA as Category 3, indicating that the risks of use may exceed the benefit (19). This classification may reflect theoretical concerns related to the reduction in plasma high-density lipoprotein levels associated with DMPA use. However, lipid changes associated with use of hormonal contraceptives have not been linked to adverse clinical cardiovascular outcomes (4).
Side Effects of DMPA:
Intensive counseling regarding the side effects of DMPA and the need for timed injections should be provided. In a clinical trial in which over 3,900 women used DMPA for contraception for up to seven years, the following side effects were reported by more than 5% of subjects: menstrual irregularities (bleeding or amenorrhea), weight changes, headache, abdominal pain or discomfort, nervousness, dizziness, and asthenia (3,4,5).
Menstrual Changes -- It occurs in all women using DMPA and is the most frequent cause for discontinuation. The frequency and duration of such unscheduled bleeding decrease with increasing duration of use. In fact, after one year (four DMPA injections), 50% of women experience amenorrhea, and with ongoing use, the rate of amenorrhea increases to 75%. Amenorrhea (along with a reduction or elimination of menstrual cramps) can be viewed as one of the advantages of using this method (8). If persistent spotting or unscheduled bleeding in the first few months of use is unacceptable to a DMPA user who otherwise wishes to continue using this method, one option is to administer oral or transdermal estrogen supplements (eg, 1.25 mg of oral conjugated estrogen, estropipate, or esterified estrogens; 1 to 2 mg of oral micronized estradiol; 0.1 mg estradiol patches). If bothersome spotting and/or unscheduled bleeding persist after several injections of DMPA, we suggest evaluation to look for anatomic causes of abnormal bleeding unrelated to DMPA use, such as uterine fibroids or endometrial polyps.
Weight Changes -- Observational studies have reported variable effects of DMPA on weight gain. Some studies found non-significant changes in weight among women who used DMPA for up to one year. Others describe weight gain ranging from 3 to 6 kg (9); however, these trials were conducted in postpartum adolescents, Navajo Indians, African Americans, which are groups that may be prone to weight gain irrespective of progestin use. Thus, the weight gain changes reported with DMPA use in these studies may have resulted from demographic differences in the study populations and the differing susceptibilities of these populations for weight gain. Two randomized trials comparing a subcutaneous formulation of DMPA and leuprolide in women with symptomatic endometriosis found no difference in the impact of these drugs on weight (10). The potential for excessive weight gain with DMPA use is probable for some women, but weight gain is not a certainty for all users. For those women who experience at or below 5% body weight gain with DMPA use in the first 6 months, excessive future weight gain is unlikely and continued DMPA use provides a convenient, highly effective, and relatively inexpensive method of birth control. Most DMPA users who gain excessive weight experience more than a 5% weight increase within 6 months (24). These data help physicians predict who is at risk of excessive gain and counsel them appropriate. With close monitoring and counseling from clinicians, women who choose DMPA can avoid long-term weight changes that may result in obesity-related health problems.
Mood Changes -- Observational studies have not reported any consistent effects of DMPA on mood. We feel that progestins may cause or exacerbate depressive symptoms in certain subpopulations of women, including those with a history of premenstrual syndrome or mood disorders. Therefore, we suggest that clinicians follow such women closely when any progestin-based therapy is initiated, but we do not feel a history of depression is a contraindication to use of DMPA.
Headache -- DMPA can trigger as a side effect in susceptible patients, but progestins prevent migraine in others (11).
DMPA Use and Bone Mineral Density (BMD):
BMD decreases during DMPA use -- The decreased endogenous serum estradiol levels produced by DMPA use may increase the rate of bone resorption. A primary concern regarding the safety of long-term use of DMPA is the effect on bone density. Observations of reduced BMD in current DMPA users have led to concerns that DMPA-induced bone loss might increase the long-term risk of fractures years after discontinuation of the drug, particularly in two groups of women: young women, who have not yet attained their peak bone mass; perimenopausal women, who may be starting to lose bone mass and who may have reached menopause by the time of DMPA discontinuation, with no opportunity to regain the lost bone mass. Many studies have found that, in adult DMPA users, BMD decreases from baseline levels and in current adolescent DMPA users BMD levels are reduced compared with non-users (12). Methodology and study population demographics, as well as BMD levels and the extent of BMD decrease found in DMPA users vary among studies. A systematic review of DMPA found that, in longitudinal studies of adult DMPA users, the rates of BMD reduction changed over the period of use and differed among studies, with most studies reporting overall BMD decreases of less than 1% per year of use (13). The same review found that, in adolescents, differences in BMD reflected both decreased BMD in DMPA users and increased BMD in non-users. Other studies of women initiating DMPA use found BMD decreases of about 2% to 3% per year during the first 2 years of use; however, almost all of the decrease in BMD occurs in the first 2 years of DMPA use, with little incremental BMD loss during additional years of use. There are no data on postmenopausal fracture rates in women who used DMPA as adolescents or adults; therefore, the clinical significance of DMPA-associated declines in BMD is unknown.
BMD recovers after DMPA discontinuation -- Most studies find that women regain BMD after discontinuation of DMPA use (13). Adults -- studies of adult DMPA users have found that decreases in BMD are reversed after discontinuation of DMPA use. The seven-year prospective study found that at 1.8 years after DMPA discontinuation, total hip BMD had returned almost to baseline levels (-0.20%) and lumbar spine BMD levels showed only partial recovery (-1.19%). A cross sectional study of postmenopausal former-users of DMPA and never-users found no significant differences between the groups (14). Overall, the evidence indicates that former-users of DMPA post-menopausally have BMD nearly identical to that of never-users. Adolescents -- because adolescence is a critical period of bone accretion, recent evidence of BMD recovery in adolescents following discontinuation of DMPA use is also reassuring. In a population based, prospective cohort study of DMPA users aged 14 to 18 (the only study of BMD changes following DMPA discontinuation by adolescents), mean BMD measured at all anatomic sites reached or exceeded the levels of never-users by 12 months after DMPA discontinuation (15). This finding indicates that there is a faster rate of BMD recovery after stopping DMPA use in adolescents than that observed in adult DMPA discontinuers. Mean annualized gains in BMD by adolescents following discontinuation of DMPA use in this study also were greater than those occurring in an older cohort (18 to 39 years) prospectively studied by the same investigators (hip 1.34% vs 1.04% per year, respectively; spine 2.86% vs 1.41%, respectively). Modified lifestyle factors may help increase BMD in all adolescents, including DMPA users. All adolescents should be encouraged to perform weight-bearing exercise, not to smoke, and to follow an adequately nutritious diet including sufficient dietary calcium (1,300 mg/day) and vitamin D (200-400 IU) daily.
Hypoestrogenemia normally occurs in postpartum and is associated with decrease in BMD. In the first 45 days of postpartum period, women have lower BMD than age-matched non-pregnant controls. During 3 months or more of lactation, breastfeeding women experience progressive declines in BMD compared with non-breastfeeding women, who progressively regain BMD. The changes in BMD -- both decline and recovery -- associated with DMPA use demonstrate similarities to the BMD changes that occur in postpartum during and after breastfeeding. The magnitude of BMD decrease is greater with lactation than with DMPA, but the patterns of BMD recovery are parallel. Prolonged duration of breastfeeding has not to be associated with an elevated risk of postmenopausal fractures. The decrease in BMD associated with DMPA use is similarly transient, and BMD in adults has been found to be at least as high in former adolescent DMPA users as in never-users (14, 15).
DMPA Black Box Warning:
In 2004, the US Food and Drug Administration (FDA) mandated that a black box warning be added to DMPA labeling, stating that (16), women who use DMPA may lose significant BMD; that bone loss is greater with increasing duration of use and may not be completely reversible; that it is unknown whether use of DMPA during adolescence or early adulthood will reduce peak bone mass or increase risk for osteoporotic fracture later in life; and that DMPA should be used as birth control for longer than 2 years only if other contraceptive methods are inadequate.
Professional Society Recommendations:
After publication of these FDA labeling changes, and after review of the available evidence, the American College of Obstetricians and Gynecologists (ACOG), the Society for Adolescent Medicine (SAM), and the World Health Organization (WHO) endorsed guidelines differing from the DMPA product labeling.
ACOG Guidelines: ACOG recommends that skeletal health concerns should not restrict use of DMPA in adult women. In adolescents, the advantages of DMPA use outweigh the theoretical concerns regarding BMD and fractures. Consideration of long-term use in adolescents should be individualized (17).
SAM Position Paper: SAM states that, for the majority of adolescents, the benefits of DMPA use (ie, prevention of physical, social, and economic adverse of unintended pregnancy including possible attendant effects on bone) outweigh potential risks. The use of DMPA in adolescents can be continued without any restriction on duration of use. Counseling about the risks and benefits of DMPA use should be provided (18).
WHO Recommendations: The WHO recommends that there should be no restriction on use or duration of use of DMPA in adult women otherwise eligible to use this method. Among adolescents, the advantages of DMPA use generally outweigh theoretical concerns regarding fracture risk. Overall risks and benefits for continuing DMPA use should be reconsidered over time with individual adolescent users (19).
Are BMD Tests or Interventions Appropriate?
It should be axiomatic in clinical practice that testing of any type is not indicated if the test results will not influence management. The WHO provided diagnostic criteria for osteoporosis and low bone density (osteopenia) in postmenopausal Caucasian women based upon BMD values by dual energy x-ray absorptiometry. For determining the future probability of osteoporotic fractures, BMD is combined with other clinical risk factors, most importantly age and prior fracture history. Much confusion surrounds the use of these WHO criteria in young women. The International Society for Clinical Densitometry has stated that the WHO criteria -- which were developed for use in postmenopausal white women -- cannot be applied to premenopausal women, who by definition cannot have postmenopausal osteoporosis (20). Moreover, the use of T-scores is not appropriate for young women who have not reached skeletal maturity (20). BMD testing is recommended only in adolescents or premenopausal women who have had fragility fractures or who have medical problems known to be associated with significant skeletal consequences (20). The results of BMD tests in prospective or current DMPA users provide no more useful information than they would in lactating women. Therefore, in the absence of other indications, bone densitometry should not be performed either at initiation or for follow-up in apparently healthy women or adolescents using DMPA for contraception. Even more uncertain is the role or effectiveness for young women of drugs approved to treat women with postmenopausal osteoporosis. There is no evidence that bisphosphonate therapy for young women with low BMD reduces fracture risk, and there is concern about the use of these agents in women who might subsequently become pregnant (15). The selective estrogen-receptor modulator raloxifene is contraindicated in women who might become pregnant and would likely induce bone loss in premenopausal women as has been observed with tamoxifen.
With teriparatide injection in adolescents, there would be concern about osteosarcoma. None of these agents has been studied in healthy premenopausal women or in DMPA users. In the absence of a strong clinical rationale (eg, long-term glucocorticoid therapy), no justification exists for prescribing drugs that treat osteoporosis to current DMPA users. Regardless of use or non-use of any contraceptive method, the US Recommended Adequate Intake daily for all adolescents to maximize bone formation is 1,300 mg of calcium and 5 mcg (200 IU) of vitamin D. However, many clinicians recommend 400 IU daily for adolescents. With rare exceptions (eg, immobilized adolescent), estrogen supplementation is not recommended for DMPA users because the required daily user action and estrogenic side effects may complicate correct DMPA use.
Long-Term DMPA Use:
Studies of long-term up to 27 years current or former DMPA users, including postmenopausal women, have found little or no difference in BMD these women and similarly aged controls (21), and there are data reporting an increased incidence of fractures in these women. It is therefore reasonable for women who wish to do so to continue using DMPA until their mid-50s, when contraception is no longer necessary. Subcutaneous DMPA is approved for management of endometriosis-associated pain, and intramuscular DMPA also has been found to be effective for this purpose (off-label application). In clinical trials, DMPA has been found equivalent to leuprolide acetate in reducing endometriosis-associated pain with less short-term impact on BMD. With this chronic disease, clinicians also may use DMPA until menopause (22). In addition to enhancing quality of life by allowing couples to choose whether or not, and when they wish to bear children, effective contraception saves healthcare costs. An analysis of nine contraceptive methods found that, over a five-year period, DMPA and intrauterine devices were most cost-effective reversible contraceptives.
The controversy surrounding the use of DMPA prompted the National Institute of Public Health of Quebec to organize a scientific meeting in 2008 with representatives from Canadian medical associations involved in family planning, obstetrics and gynecology, and specialties interested in bone health to develop a consensus position. This group emphasizes that DMPA remains a valid contraceptive option for women and that its potential impact on BMD should be balanced against significant individual, familial, and social consequences of unintended pregnancy. This consensus position encourages women to be informed that the use of DMPA is a cost-effective contraceptive option, associated with a slight decrease in BMD that is largely, if not completely, reversible. It recommends that no absolute limit be placed on the duration of DMPA use and that measuring BMD is not recommended (23). Although this is not level 1 evidence, this position statement is supported by literature and most consensus statements; it reaffirms and evidence-based approach to contraceptive decision making that can be adopted by clinicians.
Potential Drug Interactions:
The contraceptive efficacy of DMPA in women taking hepatic enzyme inducers has not been explicitly studied; however, physicians with substantial experience prescribing DMPA (150 mg every three months) for women taking anticonvulsants have not reported contraceptive failure among such patients.
Other potential drug interactions are (17): Medications that decrease steroid levels in women taking oral contraceptive
Antibiotics -- Rifampin
Anticonvulsants -- Barbiturates (including phenobarbital and primidone); carbamazepine and oxcarbazepine; felbamate; phenytoin; topiramate; vigabatrin.
Antidepressant (over the counter botanical) -- St. John's Wort.
Summary and Recommendations:
Depot medroxyprogesterone acetate (DMPA) injection is an excellent method of contraception for women who desire a long-term, reversible contraceptive method. It is highly effective, private, and avoids the need for compliance daily or near the time of sexual intercourse. It primarily acts by inhibiting follicular maturation and ovulation through inhibition of gonadotropin secretion; it also affects cervical mucus. DMPA is available in two formulations: 150 mg/1 mL for intramuscular injection (IM) and 104 mg/0.65 mL for subcutaneous (SC) injection. The ideal time to initiate DMPA is within five days of the onset of menses, so as to assure absence of pregnancy. The dose is repeated each three months, with a two-week grace period. We suggest performing a pregnancy test before administering DMPA in women more than two weeks late for their injection. Although DMPA does not permanently impact endocrine function, return of fertility may be delayed. Within 10 months of last injection, 50% of women who discontinued DMPA to become pregnant will conceive; in a small proportion of women, however, fertility is not reestablished until 18 months after the last injection. Thorough candid counseling about side effects is important. Women who are well-informed when they choose this method of contraception are much more likely to become highly satisfied users with high continuation rates. Menstrual changes occur in all women using DMPA and are the most frequent cause for discontinuation. During the first months of use, episodes or irregular bleeding and spotting lasting seven days or longer are common. The frequency and duration of such bleeding decrease with increasing duration of use. After one year of use, 50% of women experience amenorrhea, and with ongoing use, the rate of amenorrhea increases to 75%.
Because DMPA induces amenorrhea, it can be used for managing a variety of gynecologic and non-gynecologic disorders, such as menorrhagia, dysmenorrhea, and iron deficiency anemia. There is no high quality evidence that use of DMPA increases risk of developing cancer, cardiovascular disease, or sexually transmitted infection. DMPA use significantly reduces the risk of developing endometrial cancer. There is an association between current DMPA use and decreased bone mineral density; losses in bone mineral density are temporary and reverse after discontinuation of DMPA. There is no evidence of an increase in risk of fractures. We believe that, in all age groups, the advantages of DMPA use as a contraceptive generally outweigh the theoretical concerns regarding skeletal harm. We suggest not avoiding DMPA as a contraceptive option in adolescent girls and older reproductive age women. In contrast to package labeling, we suggest not avoiding DMPA as a contraceptive option in women at increased risk of thrombosis.