Contraception 89 (2014) 331 – 334
Editorial
Injectable contraception: issues and opportunities☆,☆☆,★ Beginning in the 1960s, depot medroxyprogesterone acetate (DMPA) injectable contraception has been widely used in family planning programs abroad, especially in Africa and Southeast Asia [1]. Approved in the US for the treatment of endometrial cancer in the mid-1960s, it was also used offlabel for contraception [2]. In 1992, DMPA received Food and Drug Administration (FDA) approval for contraception and began to have a noticeable impact in preventing unintended pregnancies in the US, particularly among teens. By 2002, some 2 million US women used injectable contraception [3]. Whereas US teen births increased 23% from 1986, peaking in 1991, rates then declined 35% by 2005 [4]. The authors of the 2002 National Survey of Family Growth (NSFG) reported that “Teens were more likely in 2002 to use contraception at first sex and at most recent sex than in 1995 and were more likely to have used highly effective methods such as injectable contraception” [5]. 1. Effective contraception Among users who return for repeat injections, DMPA represents an effective contraceptive. The ‘perfect’ use firstyear failure rate for DMPA, reflecting the weighted average of the results from seven trials of intramuscular 150 mg IM formulation (available in the US as generic) and two trials of the 104 mg SC formulation, the first-year failure rate aggregated from clinical trials (‘perfect’ use) has been reported as two per 1,000 women [6]. In large Phase 3 trials of the 104 mg SC formulation, no pregnancies were reported [7], raising the possibility that the SC formulation (available in the US only as a branded formulation) may be even more effective than IM DMPA [6]. In the St. Louisbased Contraceptive Choice Project (CHOICE), in which women were offered at no cost their choice of contraceptive method, the three-year cumulative failure rate in women ☆
Disclosures: Dr. Kaunitz reports no disclosures regarding Pfizer, manufacturer of Depo-Provera and Depo SubQ-Provera. Dr. Kaunitz consults with Teva (which manufactures generic depot medroxyprogesterone acetate) regarding oral and intrauterine contraception. He also consults with Bayer, Merck and Watson/Actavis. ☆☆ Dr. Peipert serves as a consultant for Teva (which manufactures generic depot medroxyprogesterone acetate), Bayer, Merck, and Watson/ Activis, and receives research funding from Bayer and Merck. ★ Dr. Grimes reports no disclosures regarding injectable contraception. 0010-7824/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2014.03.014
who chose DMPA and returned consistently for injections was 0.7 percent, a failure rate comparable to that of women who chose intrauterine devices (IUDs) or the implant [8]. The typical use failure rate for DMPA is substantially higher [6], reflecting women who do not return for their injections as scheduled. More than a method’s inherent efficacy, compliance and continuation determine contraceptive effectiveness [9]. As with shorter-acting hormonal contraceptives (pills, patches, ring), suboptimal continuation rates impair effectiveness. In Trussell’s 2011 review, based on data from the 2002 NSFG, 56% of women using DMPA indicated they were continuing injections at one year [6]. This percentage is almost identical to data from the Contraceptive CHOICE project in St. Louis. In CHOICE, the 2-year continuation rate for DMPA use was 38%, compared with 43%, 78% and 69% for oral contraceptive, IUD and implant users, respectively. Twenty-eight percent of CHOICE DMPA users were still using the method at three years (unpublished data). Given the superior continuation rates of IUDs and implants, we agree with the CHOICE investigators' conclusion: “Given their effectiveness and high continuation rates, IUDs and implants should be first-line contraceptive options, and shorter-acting methods such as OCPs, patch, ring, and DMPA should be second tier” [10].
2. Improving convenience Improving convenience for users can increase continuation of injectable contraception, thereby reducing unintended pregnancies. Of note, the grace period for repeat injections is longer than previously thought. The Centers for Disease Control and Prevention (CDC) 2013 Selected Practice Recommendations for Contraceptive Use (SPR) [11] indicates that while routine repeat DMPA injections should be administered every 3 months or 13 weeks, injections can be provided before this time when needed, and repeat injections can be given up to 2 weeks late (15 weeks from the last injection) without requiring additional contraceptive protection [12]. The SPR goes on to state that women more than 2 weeks late (N 15 weeks from the last injection) can have the injection if it is reasonably certain she is not pregnant, and that such women should either abstain from
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sexual intercourse or use back-up contraception for the next 7 days [11]. Other approaches to facilitating repeat DMPA injections include administration by friends/relatives who are health care providers, by pharmacists [13], or by self-administration [14]. In this issue of Contraception, Beasley and her colleagues report findings from their trial of self-administration versus office-based administration of SC DMPA, the only randomized such trial reported to date [15]. Consistent with earlier reports, the findings from this trial confirm that many US DMPA users are interested in self-administration. Furthermore, because this study assessed medroxyprogesterone pharmacokinetics, the investigators were able to demonstrate that efficacy in women who self-injected SC DMPA should be as high as that seen with injections given in an office setting. One caveat is relevant when considering DMPA self-administration: because generic IM DMPA is inexpensive compared with branded SC DMPA, cost considerations limit access to SC DMPA in many US women. Finally, the findings of this trial point out the promise that subcutaneous formulations of DMPA (e.g., Sayana Press, the focus of multiple articles in this issue of Contraception) hold for expanding use of injectable contraception in low resource regions.
3. Concerns about weight gain Concerns among women and clinicians regarding weight gain represent a major barrier to choice of injectable contraception among US women. Randomized trials have not reported that DMPA causes significant weight gain [16–18]. However, factors other than contraceptive choice appear related to weight changes among women using hormonal contraception. For instance, in CHOICE, women who chose DMPA were more likely to be black than women who chose other methods [8]. While weight changes were variable among women choosing different progestin-only methods, black race predicted weight gain regardless of contraceptive choice [19].
4. Nervousness-based medicine [20] In 2004, the FDA added a Black Box warning regarding skeletal health to package labeling, citing the decline in bone mineral density (BMD) that occurs in current DMPA users [21]. Use of DMPA dropped following the FDA’s action, and between 2005 and 2007 the downward trend in teen births reversed, with the incidence increasing 5% [4]. The 2008 NSFG observed that the prevalence of DMPA use among US reproductive age women declined from 3% in 2002 to 2% for the years 2006–2008 [22]. Although the lower serum estrogen levels associated with current use of DMPA decrease BMD, full recovery occurs one to four years after discontinuation in adolescents [23,24]
and within 3 years after discontinuation in adults [25,26]. The BMD trends associated with use of DMPA appear analogous to similar trends associated with another common hypoestrogenic state — breastfeeding. Although the BMD declines in nursing mothers are similar to those with use of DMPA, nursing is not known to increase the risk of subsequent osteoporotic fractures [27]. Likewise, use of DMPA has not been found to increase risk of postmenopausal osteoporosis [28–30]. Few studies have addressed the association between bone mineral density and fracture risk in young women; however, bone density should not be considered a surrogate end point for fracture in this age group [31]. Basing clinical recommendations on invalid surrogate end points can harm patients [32,33]. FDA recommendations should be based on studies of fractures, not on misleading surrogate end points.
5. DMPA does not increase the risk of fracture Two published case–control studies, one using a national Danish National Patient Registry [34] and one based on the United Kingdom Family Practice Research database [35], found a weak association (odds ratios b 2.0) between DMPA use and fractures in reproductive age women. These weak associations are well below the discriminatory ability of case–control studies and are more likely due to bias than to causation [36]. Furthermore, a cohort analysis using the same British database clarified that the elevated fracture risk observed in women using DMPA occurred prior to initiation of injectable contraception and therefore could not be caused by use of DMPA [37]. If the effect precedes the putative cause, any claim of causality evaporates [38–40]. Importantly, the FDA's black box warning is inconsistent with the assessment of major medical and public health organizations around the world. The World Health Organization [41], the American College of Obstetricians and Gynecologists [42], the Society for Adolescent Medicine [43], and the Society of Obstetricians and Gynaecologists of Canada [44] have indicated that skeletal health concerns should not restrict use (including duration of use) of DMPA. In its Medical Eligibility Criteria for contraceptive use, the CDC has indicated that use of DMPA is Category 1 (no restriction of use) in women 18–45 years of age and category 2 (the advantages of the method generally outweigh the theoretical or proven risks) in younger women [45]. The FDA Black Box warning is not based on empirical evidence. Moreover, it has hurt public health and led to irrational prescribing (e.g., bisphosphonates for teenagers) [46]. Hence, two of us filed a citizen petition with the FDA in early 2013. The petition, accompanied by all the relevant published studies, simply requested removal of the Black Box warning. As required by law, the FDA responded within 180 days, but stated only that the petition raised issues needing further study. The letter failed to identify even one such issue.
Editorial / Contraception 89 (2014) 331–334
6. Safety in perspective To our knowledge, no woman anywhere in the world has ever died as a result of use of this contraceptive. This observation is unique in the history of modern contraceptives. In contrast, scores die from over-the-counter aspirin or acetaminophen each year in the US alone [47]. Regrettably, the Black Box warning has stigmatized this safe and effective method. 7. Noncontraceptive benefits DMPA offers women important noncontraceptive benefits. The menstrual suppression caused by DMPA makes it useful for women with heavy menstrual bleeding or menstrual hygiene problems [48,49]. With efficacy comparable to that of leuprolide, DMPA (the SC formulation) is approved for the treatment of pain associated with endometriosis [17,18]. Use of DMPA is also associated with fewer painful crises in women with sickle cell disease [50,51]. As with oral contraceptives, use of DMPA reduces future risk of endometrial and ovarian cancer [52,53]. 8. Looking ahead Although DMPA represents a second-tier contraceptive when compared with IUDs and the implant [54], some women seeking effective contraception do not have access to these latter methods or choose not to use them. The safety, effectiveness experienced by women who return for repeat injections, convenience (along with the potential for selfadministration of SC DMPA), and noncontraceptive benefits underscore injectable contraception’s importance for women in the US and worldwide [1]. A more rational assessment on the part of the FDA would facilitate wider use of this important method. Andrew M. Kaunitz Jeffrey F. Peipert David A. Grimes Department of Obstetrics and Gynecology University of Florida College of Medicine-Jacksonville Jacksonville, FL, USA Department of Obstetrics and Gynecology Washington University in St. Louis School of Medicine St. Louis, MO, USA Department of Obstetrics and Gynecology UNC School of Medicine, Chapel Hill, NC, USA E-mail address: [email protected] References [1] Darroch JE, Singh S. Trends in contraceptive need and use in developing countries in 2003, 2008, and 2012: an analysis of national surveys. Lancet 2013;381:1756-62.
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[2] Kaunitz AM. Injectable contraception. Clin Obstet Gynecol 1989;32: 356-68. [3] Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ. Use of contraception and use of family planning services in the United States. Adv Data 1982–2002;2004:1-36. [4] Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2007. Natl Vital Stat Rep 2010;58:1-85. [5] Abma JC, Martinez GM, Mosher WD, Dawson BS. Teenagers in the United States: sexual activity, contraceptive use, and childbearing. Vital Health Stat 23 2002;2004:1-48. [6] Trussell J. Contraceptive failure in the United States. Contraception 2011;83:397-404. [7] Jain J, Jakimiuk AJ, Bode FR, Ross D, Kaunitz AM. Contraceptive efficacy and safety of DMPA-SC. Contraception 2004;70:269-75. [8] Winner B, Peipert JF, Zhao Q, et al. Effectiveness of long-acting reversible contraception. N Engl J Med 2012;366:1998-2007. [9] Grimes DA. Forgettable contraception. Contraception 2009;80:497-9. [10] O'Neil-Callahan M, Peipert JF, Zhao Q, Madden T, Secura G. Twentyfour-month continuation of reversible contraception. Obstet Gynecol 2013;122:1083-91. [11] Centers for Disease Control and Prevention. U.S. Selected Practice Recommendations for Contraceptive Use, 2013. MMWR Early Release 2013;62:1-60. [12] Steiner MJ, Kwok C, Stanback J, et al. Injectable contraception: what should the longest interval be for reinjections? Contraception 2008;77: 410-4. [13] Picardo C, Ferreri S. Pharmacist-administered subcutaneous depot medroxyprogesterone acetate: a pilot randomized controlled trial. Contraception 2010;82:160-7. [14] Prabhakaran S. Self-administration of injectable contraceptives. Contraception 2008;77:315-7. [15] Beasley A, O'Connell White K, Cremers S, Westhoff C. Randomized clinical trial of self versus clinical administration of subcutaneous depot medroxyprogesterone acetate. Contraception 2014;89(5):352-6. [16] Pelkman CL, Chow M, Heinbach RA, Rolls BJ. Short-term effects of a progestational contraceptive drug on food intake, resting energy expenditure, and body weight in young women. Am J Clin Nutr 2001; 73:19-26. [17] Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod 2006;21:248-56. [18] Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist A. Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosisassociated pain. Fertil Steril 2006;85:314-25. [19] Vickery Z, Madden T, Zhao Q, Secura GM, Allsworth JE, Peipert JF. Weight change at 12 months in users of three progestin-only contraceptive methods. Contraception 2013;88:503-8. [20] Isaacs D, Fitzgerald D. Seven alternatives to evidence based medicine. BMJ 1999;319:1618. [21] Kaunitz AM, Grimes DA. Removing the black box warning for depot medroxyprogesterone acetate. Contraception 2011;84:212-3. [22] Mosher WD, Jones J. Use of contraception in the United States: 1982–2008. Vital Health Stat 23 2010:1-44. [23] Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med 2005;159:139-44. [24] Harel Z, Johnson CC, Gold MA, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections. Contraception 2010; 81:281-91. [25] Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Injectable hormone contraception and bone density: results from a prospective study. Epidemiology 2002;13:581-7. [26] Kaunitz AM, Miller PD, Rice VM, Ross D, McClung MR. Bone mineral density in women aged 25–35 years receiving depot
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[27]
[28]
[29]
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[31]
[32] [33]
[34]
[35]
[36] [37]
[38] [39] [40] [41]
Editorial / Contraception 89 (2014) 331–334 medroxyprogesterone acetate: recovery following discontinuation. Contraception 2006;74:90-9. Schnatz PF, Barker KG, Marakovits KA, O'Sullivan DM. Effects of age at first pregnancy and breast-feeding on the development of postmenopausal osteoporosis. Menopause 2010;17:1161-6. Cundy T, Cornish J, Roberts H, Reid IR. Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception. Am J Obstet Gynecol 2002;186:978-83. Orr-Walker BJ, Evans MC, Ames RW, Clearwater JM, Cundy T, Reid IR. The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal postmenopausal women. Clin Endocrinol (Oxf) 1998;49:615-8. Viola AS, Castro S, Marchi NM, Bahamondes MV, Viola CF, Bahamondes L. Long-term assessment of forearm bone mineral density in postmenopausal former users of depot medroxyprogesterone acetate. Contraception 2011;84:122-7. Riggs BL, Hodgson SF, O'Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990;322:802-9. Grimes DA, Schulz KF. Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol 2005;105:1114-8. Grimes DA, Schulz KF, Raymond EG. Surrogate end points in women's health research: science, protoscience, and pseudoscience. Fertil Steril 2010;93:1731-4. Vestergaard P, Rejnmark L, Mosekilde L. The effects of depot medroxyprogesterone acetate and intrauterine device use on fracture risk in Danish women. Contraception 2008;78:459-64. Meier C, Brauchli YB, Jick SS, Kraenzlin ME, Meier CR. Use of depot medroxyprogesterone acetate and fracture risk. J Clin Endocrinol Metab 2010;95:4909-16. Grimes DA, Schulz KF. False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstet Gynecol 2012;120:920-7. Lanza LL, McQuay LJ, Rothman KJ, et al. Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture. Obstet Gynecol 2013;121:593-600. Hill AB. The environment and disease association or causation. Proc Royal Soc Med 1965;58:295-300. Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet 2002;359:248-52. Susser M. What is a cause and how do we know one? A grammar for pragmatic epidemiology. Am J Epidemiol 1991;133:635-48. World Health Organization. WHO statement on hormonal contraception and bone health. http://wwwwhoint/reproductive-health/family_planning/ bone_healthhtml, accessed March 27, 2006.
[42] American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG Committee Opinion No. 415: Depot medroxyprogesterone acetate and bone effects. Obstet Gynecol 2008; 112:727-30. [43] Cromer BA, Scholes D, Berenson A, et al. Depot medroxyprogesterone acetate and bone mineral density in adolescents–the Black Box Warning: a Position Paper of the Society for Adolescent Medicine. J Adolesc Health 2006;39:296-301. [44] Black A. Ad Hoc DMPA Committee of the Society of Obstetricians and Gynaecologists of Canada. Canadian contraception consensus– update on Depot Medroxyprogesterone Acetate (dmpa). J Obstet Gynaecol Can 2006;28:305-13. [45] Centers for Disease Control and Prevention. US Medical Eligibility Criteria for Contraceptive Use, 2010. MMWR Recomm Rep 2010;59:1-86. [46] Paschall S, Kaunitz AM. Depo-Provera and skeletal health: a survey of Florida obstetrics and gynecologist physicians. Contraception 2008; 78:370-6. [47] Rogers JJ, Heard K. Does age matter? Comparing case fatality rates for selected poisonings reported to U.S. poison centers. Clin Toxicol (Phila) 2007;45:705-8. [48] Kucuk T, Ertan K. Continuous oral or intramuscular medroxyprogesterone acetate versus the levonorgestrel releasing intrauterine system in the treatment of perimenopausal menorrhagia: a randomized, prospective, controlled clinical trial in female smokers. Clin Exp Obstet Gynecol 2008;35:57-60. [49] Elkins TE, Gafford LS, Wilks CS, Muram D, Golden G. A model clinic approach to the reproductive health concerns of the mentally handicapped. Obstet Gynecol 1986;68:185-8. [50] De Ceulaer K, Gruber C, Hayes R, Serjeant GR. Medroxyprogesterone acetate and homozygous sickle-cell disease. Lancet 1982;2: 229-31. [51] Manchikanti A, Grimes DA, Lopez LM, Schulz KF. Steroid hormones for contraception in women with sickle cell disease. Cochrane Database Syst Rev 2007;1:CD006261. [52] Menil J. Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 1991;49:186-90. [53] Wilailak S, Vipupinyo C, Suraseranivong V, et al. Depot medroxyprogesterone acetate and epithelial ovarian cancer: a multicentre case–control study. BJOG 2012;119:672-7. [54] Steiner MJ, Trussell J, Mehta N, Condon S, Subramaniam S, Bourne D. Communicating contraceptive effectiveness: A randomized controlled trial to inform a World Health Organization family planning handbook. Am J Obstet Gynecol 2006;195:85-91.
Editorial
Injectable contraception: issues and opportunities☆,☆☆,★ Beginning in the 1960s, depot medroxyprogesterone acetate (DMPA) injectable contraception has been widely used in family planning programs abroad, especially in Africa and Southeast Asia [1]. Approved in the US for the treatment of endometrial cancer in the mid-1960s, it was also used offlabel for contraception [2]. In 1992, DMPA received Food and Drug Administration (FDA) approval for contraception and began to have a noticeable impact in preventing unintended pregnancies in the US, particularly among teens. By 2002, some 2 million US women used injectable contraception [3]. Whereas US teen births increased 23% from 1986, peaking in 1991, rates then declined 35% by 2005 [4]. The authors of the 2002 National Survey of Family Growth (NSFG) reported that “Teens were more likely in 2002 to use contraception at first sex and at most recent sex than in 1995 and were more likely to have used highly effective methods such as injectable contraception” [5]. 1. Effective contraception Among users who return for repeat injections, DMPA represents an effective contraceptive. The ‘perfect’ use firstyear failure rate for DMPA, reflecting the weighted average of the results from seven trials of intramuscular 150 mg IM formulation (available in the US as generic) and two trials of the 104 mg SC formulation, the first-year failure rate aggregated from clinical trials (‘perfect’ use) has been reported as two per 1,000 women [6]. In large Phase 3 trials of the 104 mg SC formulation, no pregnancies were reported [7], raising the possibility that the SC formulation (available in the US only as a branded formulation) may be even more effective than IM DMPA [6]. In the St. Louisbased Contraceptive Choice Project (CHOICE), in which women were offered at no cost their choice of contraceptive method, the three-year cumulative failure rate in women ☆
Disclosures: Dr. Kaunitz reports no disclosures regarding Pfizer, manufacturer of Depo-Provera and Depo SubQ-Provera. Dr. Kaunitz consults with Teva (which manufactures generic depot medroxyprogesterone acetate) regarding oral and intrauterine contraception. He also consults with Bayer, Merck and Watson/Actavis. ☆☆ Dr. Peipert serves as a consultant for Teva (which manufactures generic depot medroxyprogesterone acetate), Bayer, Merck, and Watson/ Activis, and receives research funding from Bayer and Merck. ★ Dr. Grimes reports no disclosures regarding injectable contraception. 0010-7824/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2014.03.014
who chose DMPA and returned consistently for injections was 0.7 percent, a failure rate comparable to that of women who chose intrauterine devices (IUDs) or the implant [8]. The typical use failure rate for DMPA is substantially higher [6], reflecting women who do not return for their injections as scheduled. More than a method’s inherent efficacy, compliance and continuation determine contraceptive effectiveness [9]. As with shorter-acting hormonal contraceptives (pills, patches, ring), suboptimal continuation rates impair effectiveness. In Trussell’s 2011 review, based on data from the 2002 NSFG, 56% of women using DMPA indicated they were continuing injections at one year [6]. This percentage is almost identical to data from the Contraceptive CHOICE project in St. Louis. In CHOICE, the 2-year continuation rate for DMPA use was 38%, compared with 43%, 78% and 69% for oral contraceptive, IUD and implant users, respectively. Twenty-eight percent of CHOICE DMPA users were still using the method at three years (unpublished data). Given the superior continuation rates of IUDs and implants, we agree with the CHOICE investigators' conclusion: “Given their effectiveness and high continuation rates, IUDs and implants should be first-line contraceptive options, and shorter-acting methods such as OCPs, patch, ring, and DMPA should be second tier” [10].
2. Improving convenience Improving convenience for users can increase continuation of injectable contraception, thereby reducing unintended pregnancies. Of note, the grace period for repeat injections is longer than previously thought. The Centers for Disease Control and Prevention (CDC) 2013 Selected Practice Recommendations for Contraceptive Use (SPR) [11] indicates that while routine repeat DMPA injections should be administered every 3 months or 13 weeks, injections can be provided before this time when needed, and repeat injections can be given up to 2 weeks late (15 weeks from the last injection) without requiring additional contraceptive protection [12]. The SPR goes on to state that women more than 2 weeks late (N 15 weeks from the last injection) can have the injection if it is reasonably certain she is not pregnant, and that such women should either abstain from
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sexual intercourse or use back-up contraception for the next 7 days [11]. Other approaches to facilitating repeat DMPA injections include administration by friends/relatives who are health care providers, by pharmacists [13], or by self-administration [14]. In this issue of Contraception, Beasley and her colleagues report findings from their trial of self-administration versus office-based administration of SC DMPA, the only randomized such trial reported to date [15]. Consistent with earlier reports, the findings from this trial confirm that many US DMPA users are interested in self-administration. Furthermore, because this study assessed medroxyprogesterone pharmacokinetics, the investigators were able to demonstrate that efficacy in women who self-injected SC DMPA should be as high as that seen with injections given in an office setting. One caveat is relevant when considering DMPA self-administration: because generic IM DMPA is inexpensive compared with branded SC DMPA, cost considerations limit access to SC DMPA in many US women. Finally, the findings of this trial point out the promise that subcutaneous formulations of DMPA (e.g., Sayana Press, the focus of multiple articles in this issue of Contraception) hold for expanding use of injectable contraception in low resource regions.
3. Concerns about weight gain Concerns among women and clinicians regarding weight gain represent a major barrier to choice of injectable contraception among US women. Randomized trials have not reported that DMPA causes significant weight gain [16–18]. However, factors other than contraceptive choice appear related to weight changes among women using hormonal contraception. For instance, in CHOICE, women who chose DMPA were more likely to be black than women who chose other methods [8]. While weight changes were variable among women choosing different progestin-only methods, black race predicted weight gain regardless of contraceptive choice [19].
4. Nervousness-based medicine [20] In 2004, the FDA added a Black Box warning regarding skeletal health to package labeling, citing the decline in bone mineral density (BMD) that occurs in current DMPA users [21]. Use of DMPA dropped following the FDA’s action, and between 2005 and 2007 the downward trend in teen births reversed, with the incidence increasing 5% [4]. The 2008 NSFG observed that the prevalence of DMPA use among US reproductive age women declined from 3% in 2002 to 2% for the years 2006–2008 [22]. Although the lower serum estrogen levels associated with current use of DMPA decrease BMD, full recovery occurs one to four years after discontinuation in adolescents [23,24]
and within 3 years after discontinuation in adults [25,26]. The BMD trends associated with use of DMPA appear analogous to similar trends associated with another common hypoestrogenic state — breastfeeding. Although the BMD declines in nursing mothers are similar to those with use of DMPA, nursing is not known to increase the risk of subsequent osteoporotic fractures [27]. Likewise, use of DMPA has not been found to increase risk of postmenopausal osteoporosis [28–30]. Few studies have addressed the association between bone mineral density and fracture risk in young women; however, bone density should not be considered a surrogate end point for fracture in this age group [31]. Basing clinical recommendations on invalid surrogate end points can harm patients [32,33]. FDA recommendations should be based on studies of fractures, not on misleading surrogate end points.
5. DMPA does not increase the risk of fracture Two published case–control studies, one using a national Danish National Patient Registry [34] and one based on the United Kingdom Family Practice Research database [35], found a weak association (odds ratios b 2.0) between DMPA use and fractures in reproductive age women. These weak associations are well below the discriminatory ability of case–control studies and are more likely due to bias than to causation [36]. Furthermore, a cohort analysis using the same British database clarified that the elevated fracture risk observed in women using DMPA occurred prior to initiation of injectable contraception and therefore could not be caused by use of DMPA [37]. If the effect precedes the putative cause, any claim of causality evaporates [38–40]. Importantly, the FDA's black box warning is inconsistent with the assessment of major medical and public health organizations around the world. The World Health Organization [41], the American College of Obstetricians and Gynecologists [42], the Society for Adolescent Medicine [43], and the Society of Obstetricians and Gynaecologists of Canada [44] have indicated that skeletal health concerns should not restrict use (including duration of use) of DMPA. In its Medical Eligibility Criteria for contraceptive use, the CDC has indicated that use of DMPA is Category 1 (no restriction of use) in women 18–45 years of age and category 2 (the advantages of the method generally outweigh the theoretical or proven risks) in younger women [45]. The FDA Black Box warning is not based on empirical evidence. Moreover, it has hurt public health and led to irrational prescribing (e.g., bisphosphonates for teenagers) [46]. Hence, two of us filed a citizen petition with the FDA in early 2013. The petition, accompanied by all the relevant published studies, simply requested removal of the Black Box warning. As required by law, the FDA responded within 180 days, but stated only that the petition raised issues needing further study. The letter failed to identify even one such issue.
Editorial / Contraception 89 (2014) 331–334
6. Safety in perspective To our knowledge, no woman anywhere in the world has ever died as a result of use of this contraceptive. This observation is unique in the history of modern contraceptives. In contrast, scores die from over-the-counter aspirin or acetaminophen each year in the US alone [47]. Regrettably, the Black Box warning has stigmatized this safe and effective method. 7. Noncontraceptive benefits DMPA offers women important noncontraceptive benefits. The menstrual suppression caused by DMPA makes it useful for women with heavy menstrual bleeding or menstrual hygiene problems [48,49]. With efficacy comparable to that of leuprolide, DMPA (the SC formulation) is approved for the treatment of pain associated with endometriosis [17,18]. Use of DMPA is also associated with fewer painful crises in women with sickle cell disease [50,51]. As with oral contraceptives, use of DMPA reduces future risk of endometrial and ovarian cancer [52,53]. 8. Looking ahead Although DMPA represents a second-tier contraceptive when compared with IUDs and the implant [54], some women seeking effective contraception do not have access to these latter methods or choose not to use them. The safety, effectiveness experienced by women who return for repeat injections, convenience (along with the potential for selfadministration of SC DMPA), and noncontraceptive benefits underscore injectable contraception’s importance for women in the US and worldwide [1]. A more rational assessment on the part of the FDA would facilitate wider use of this important method. Andrew M. Kaunitz Jeffrey F. Peipert David A. Grimes Department of Obstetrics and Gynecology University of Florida College of Medicine-Jacksonville Jacksonville, FL, USA Department of Obstetrics and Gynecology Washington University in St. Louis School of Medicine St. Louis, MO, USA Department of Obstetrics and Gynecology UNC School of Medicine, Chapel Hill, NC, USA E-mail address: [email protected] References [1] Darroch JE, Singh S. Trends in contraceptive need and use in developing countries in 2003, 2008, and 2012: an analysis of national surveys. Lancet 2013;381:1756-62.
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