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Abstract

Despite the availability of a variety of contraceptive methods, millions of women still have an unmet need for contraceptive choices. Short-acting methods are plagued by issues with adherence, leading to imperfect or inconsistent use and subsequent unintended pregnancy. Long-acting contraceptive methods such as intrauterine devices and contraceptive implants, while providing highly effective and safe contraception, do not meet the needs of all women, often due to cost, access or acceptability issues. Several new methods are in various stages of development and are designed to address the shortcomings of current methods. Providers should be aware of these future options and how they might better meet women's needs.

Keywords

contraception contraceptive implant contraceptive vaginal ring intrauterine device injectable contraception long-acting reversible contraceptive multipurpose prevention technology

Setting

Globally, women and men have greater access to contraception than in any time in history. More than 60% of women worldwide between the ages of 15 and 49 years old who are married or in union use a method of contraception [1]. Even in regions considered less developed (excluding China), more than half of women use a method. Despite these figures, more than 200 million women who would like to avoid pregnancy are not using an effective method of contraception [2]. Even in the USA, more than half of all pregnancies are unintended, a figure that has increased in recent years [3].

Many of the most common causes of unmet need for contraception and unintended pregnancy are shared across populations and could be addressed with future improved methods. While some women do not have access to effective methods due to social, cultural or economic constraints, others are not satisfied with existing options citing side effects or other concerns such as opposition from male partners [2]. Misperceptions about pregnancy risk due to infrequent sex or lack of a regular sexual partner sometime lead women to inconsistently or incorrectly use methods [4]. In fact, in the USA, roughly half of all unintended pregnancies occur among women who report using a contraceptive method the month they became pregnant [5]. Hormonal contraceptive methods used by most women are fraught by low adherence (e.g., daily combined oral contraceptive pills), and/or low continuation rates due to frequent re-injection schedules (e.g., depot medroxyprogesterone acetate [DMPA] or norethisterone enanthate [NET-EN]).

Recognition of the significant implications of unplanned pregnancy for women's’ health and well-being, as well as the economic development of nations, culminated in the 2013 London Summit on Family Planning. The Summit generated a global commitment to bring voluntary family planning services to an additional 120 million women and girls in the world's poorest countries by 2020. To reach this goal, innovative solutions will be required to transcend long-standing barriers such as cost and acceptability. This chapter describes several new mid- to long-acting reversible female contraceptive methods that may help to fill some of the current gaps in the contraceptive method mix by offering improved or more affordable options.

Injectables

Currently, over 40 million women worldwide use injectable contraceptives [6]. In sub-Saharan Africa, more than one-third of modern method contraceptive users rely on injectable contraceptives; this is in stark contrast to the 2% user rate in the USA [7]. However, discontinuation rates remain high, often due to side effects such as menstrual irregularities or difficulty in timely return for reinjection. Efforts to improve on existing injectables include the addition of estrogen, reformulation to improve the pharmacokinetic profile and to extend duration, and the use of alternative progestins.

Monthly combined injectables

A monthly injectable containing 25 mg medroxyprogesterone acetate plus 5 mg estradiol cypionate is marketed as Cyclofem and is used by an estimated 2.5 million women worldwide. The product is designed to induce a more regular bleeding pattern than progestin-only injectable products. Cyclofem is highly effective (one pregnancy per 1200 years of use) with fewer reported menstrual irregularities, less amenorrhea than DMPA and more rapid return to fertility [8]. This product was marketed in the USA between 2000 and 2002 as Lunelle until it was withdrawn because of production issues. The Concept Foundation recently licensed Sun Pharmaceutical Industries Ltd. (Mumbai, India) to manufacture and market Cyclofem to expand its geographical availability, with a focus on Africa and South Asia, and to bring the product back to the USA. A recent US pharmacokinetic study showed the new formulation to produce contraceptive levels of MPA, similar to Lunelle, with suppression of ovulation in most women [9]. The timing of a future US FDA application and approval in the USA for Cyclofem is unclear.

Alternative progestin-only injectables

Injectable discontinuation and late return rates are high, often due to users’ difficulty complying with the defined short re-injection intervals. In 2011, FHI 360, with support from the Bill & Melinda Gates Foundation, launched a new initiative to identify injectable technologies with the potential to be developed into 6-month injectable contraceptives. Current proof-of-concept studies are evaluating multiple approaches, including using microspheres, porous silicon microparticles and biodegradable gels. It is estimated that such a product would not be commercially available for at least a decade. Although longer acting injectable contraceptives represent a welcome addition to the contraceptive armamentarium, concerns have been expressed regarding their longer irreversible contraceptive effect. Other efforts have focused on progestin-only injectables that would produce a superior pharmacokinetic profile and have fewer side effects than DMPA. Early work has led to the synthesis and screening of a large number of esters of levonorgestrel (LNG) and norethindrone (NET); LNG butanoate (LNG-B) was chosen as having the best potential. A 20 mg/ml concentration of injectable LNG-B was used for an initial Phase I study in women in 2011 but did not provide the desired PK profile. Reformulation is ongoing; and the timeline for the next Phase I study is unclear [10].

Implants

Implants are one of the most highly effective long-term methods available, requiring no user action, clinical follow-up or resupply. Currently, two contraceptive implant systems are widely available worldwide: a two-rod system containing 150mg of LNG (Jadelle, Bayer HealthCare, Germany) and a single rod system containing 68 mg of etonogestrel (Implanon/Nexplanon, Merck, NJ, USA). Only the latter is available in the USA, but both are widely available worldwide. Despite availability, use remains relatively low with less than 1% of all women aged 15–49 years using the method [11].

Currently available implants must be removed when pregnancy is desired or when the effective life of the product has been reached. While the structural integrity of implants, which allows for removal, is a key advantage of this method over injectables, the need for removal can present a significant challenge in resource-constrained settings where lack of access to trained clinicians is common.

The development of a contraceptive implant that would not need to be removed (e.g., a biodegradable implant) would fill a distinct gap in the current contraceptive method mix. However, the successful development of a biodegradable contraceptive implant has been elusive. While various approaches have been successful in delivering steroids at constant low, yet highly effective contraceptive levels, several challenges have emerged:

Biodegradable implants that have been evaluated to date have had relatively slow absorption in situ (lasted substantially longer than planned);

Steroid release kinetics have not been constant and implants have led to sub therapeutic levels of progestins for long periods (i.e., long tails);

Partially degraded implants have been difficult to remove.

In the 1970s–1980s, several animal studies and human trials were conducted with a variety of formulations of a 1-year biodegradable implant containing fused pellets of 90% NET and 10% cholesterol (Figure 1). Studies demonstrated excellent safety but variable efficacy.

Figure 1.

Norethindrone and cholesterol fused pellets with trocar.

In the last trial, conducted by Family Health International, no pregnancies occurred within at least 2 years of use [12]. However, complete absorption of the pellets took more than 3 years, longer than desired. Another biodegradable implant, Capronor, was developed by the Research Triangle Institute, and consisted of a single 4 cm caprolactone rod loaded with LNG. Clinical trials were conducted, but the product was abandoned due to long release tails, skin irritation and funding issues [13].

Since then, polymer science and sustained release drug delivery technologies have advanced substantially. Biodegradable materials are now widely used in drug delivery (e.g., oncology and ophthalmology), and in orthopedics as tissue scaffolds. With funding from the US Agency for International Development (USAID) and the Bill & Melinda Gates Foundation, FHI 360 is working with innovators in the field of novel drug delivery systems to develop prototype biodegradable contraceptive implants that will last for 1–2 years, are removable if necessary, and will rapidly be bioabsorbed at the end of the desired effectiveness period. Proof-of-concept testing began in 2014.

Intrauterine devices

Intrauterine devices (IUDs) are the most commonly used form of reversible contraception worldwide, yet are used by few US women [14]. While the benefits of IUDs are many, the method has suffered from persistent negative perceptions and clinical and programmatic requirements that have limited their availability and acceptability in many settings.

Hormonal IUDs

Introduction of the LNG IUD (Mirena, Bayer), containing 52 mg of LNG, has contributed substantially to increased uptake of intrauterine contraception in the US over the last decade (an increase from about 2% to almost 8% of contraceptive users) [15]. However, the cost of Mirena ($850 in the US) remains prohibitive for both resource-limited settings and for some women in the USA. With the goal of producing a lower cost hormonal IUD and increasing worldwide access, Medicines 360 has developed a product (Liletta) similar to Mirena, which was approved by the FDA in early 2015 and indicated for 3 years of use. Results of an ongoing 5-year effectiveness trial are expected in 2017 [16]. Additionally, two Indian manufacturers, Pregna and HLL Lifecare Ltd., have received regulatory approval in India to market their LNG IUDs (Eloira and Emily, respectively). These devices also contain 52 mg of LNG and release approximately 20 μg LNG per day, similar to Mirena.

With the goals of improving ease of insertion and use, particularly for nulliparous women, Bayer Healthcare has developed two smaller, lower-dose (13.5 and 19.5 mg LNG) hormonal IUDs with narrower inserters than Mirena. In a recent Phase III clinical trial, both devices were highly effective with cumulative 3-year failure rate of <1%, and were well-tolerated [17]. In January 2013, the FDA approved the 13.5 mg device as a 3-year product under the brand name Skyla; it is also approved in Europe as Jaydess. The other device has an anticipated duration of up to 5 years, but regulatory filing plans are not publicly available.

Merck has recently completed a Phase II, randomized controlled, trial of three doses of an etonogestrel-releasing IUD to explore safety and acceptability compared with a copper IUD [18]. Results are pending. HRA Pharma is developing an IUD using ulipristal acetate (UPA, CDB 2914), a selective progesterone modulator that is currently approved as an emergency contraceptive in a single oral dose of 30 mg in the EU and the USA, and is also being studied as an oral contraceptive [19,20]. The UPA IUD was shown to suppress endometrial growth in primates; timing of future studies is not publicly available [21].

Variations on copper IUDs

Although millions of women have used copper IUDs across the globe for more than 40 years, side effects lead many women to discontinue this method. Expulsion, especially in nulliparous or young women, and dysmenorrhea and heavy menstrual bleeding that lead to early removal are particular challenges. In some countries, smaller copper IUDs, which could theoretically lead to fewer side effects or expulsions, particularly among nulliparous women, are available. In addition, copper IUDs containing indomethacin (a nonsteroidal anti-inflammatory drug), designed to alleviate dysmenorrhea and menstrual blood loss, are available in China [22,23]. Such products have not been evaluated rigorously but have the potential to improve copper IUD continuation rates.

Another variation on copper IUDs is the frameless IUD (Gynefix), designed to reduce side effects attributed to the rigid frames of T-shaped devices; the device must be anchored in the uterine fundus. In a large, 8-year WHO multicenter randomized trial, a frame-less copper IUD had more insertion failures, expulsions and pregnancies in the first year than a copper IUD, but fewer pregnancies from the second through the eighth year; by 8 years the frameless device had fewer ectopic pregnancies and removals for pain [24]. GyneFix is approved for marketing in the EU (CE Mark) and in China, Indonesia and Kenya. Timing of application to the FDA is unknown.

Apart from the frameless IUD, most current IUDs consist of t-shaped flat plastic frames. OCON Medical, an Israeli company, has developed an IUD consisting of a shape memory alloy, threaded through a series of copper spheres. The IUD wire is straight while in the applicator but curls into 3D ball once inserted (Figure 2). Because the product curls after it is pushed out of the inserter, perforation is believed to be less likely than with standard t-shaped IUDs, and the device could theoretically reduce expulsions and side effects. In the only published study of the product, a single physician inserted this device into 15 women, who were followed for 1 year. The IUD was easy to insert and no perforations, expulsions, complications or pregnancies were reported [25]. Randomized trials comparing the device with the copper T380 IUD began in 2014 [26].

Figure 2.

The intrauterine ball (OCON Medical) and the ParaGard T380A (Ortho-McNeil).

Contraceptive vaginal rings

Vaginal ring technology arose in the 1970s soon after the discovery that controlled drug release from polymeric material was feasible [27,28]. While many vaginal ring products have been evaluated over the last four decades, only one contraceptive ring is currently FDA approved and commercially available: an ethylene vinyl acetate copolymer (EVA) ring releasing 120 μg of etonogestrel and 15 μg of ethinylestradiol (EE) per day (NuvaRing, Merck). NuvaRing is designed for one cycle of use (3 weeks in/1 week out) and replaced monthly. At least three novel vaginal rings for contraception are currently in development or available in limited markets, including a 1-year combined estrogen and progestin ring, a progesterone-only ring designed for breastfeeding women and a 3-month ring containing UPA.

Progesterone vaginal ring

The progestin-only ring, Progering (Laboratorios Andromaco, Santiago, Chile), was one of the first vaginal rings developed and the only progestin-only ring to reach the commercial market. Progering releases 10 mg of the natural steroid progesterone (P4) daily over 3 months and is for use only in breastfeeding women. Developed by Silesia Labs in Chile in collaboration with the Population Council, the ring consists of a silicon matrix containing 2.074 g of progesterone, and is used to extend the contraceptive effectiveness of lactational amenorrhea. In clinical trials, Progering has shown high contraceptive efficacy (over 98%) and a good safety profile [29]. Because of the relative cost and processing requirements of silicone, recent development efforts have focused on the feasibility of a progesterone ring made with a more versatile elastomeric polymer such as ethylene vinyl acetate (EVA) [30]. In addition, while the product is registered in eight Latin American countries and offered commercially in six, available market data indicate limited market penetration [31]. Work is currently underway to determine acceptability of a progesterone ring in different populations where breastfeeding is popular and to expand availability of the progesterone ring in other parts of the world [32,33].

Nestorone vaginal rings

The Population Council has developed a 1-year combined ring releasing 150 μg of the progestin Nestorone (NES) and 15 μg of EE daily (Figure 3). NES is a highly potent progestin that is not active orally but is ideal for vaginal delivery [33]. Though it has an excellent metabolic profile with no androgenic or estrogenic activity and no effect on lipoproteins, in a dose-finding study for a NES-only ring, menstrual irregularities were common, especially at lower doses [34,35]. The combination of NES and a low dose of EE, however, has been found to improve cycle control, prevent breakthrough bleeding and allow for regular withdrawal bleeding [36]. Users keep the ring in place for 3 weeks, remove it for 1 week and reinsert the same ring a week later, reducing the need for regular resupply and offering opportunity for an overall lower product cost [37]. A Phase III clinical trial including more than 2000 women in 27 sites, which assessed safety, efficacy and acceptability of the NES/EE ring, was recently completed with positive results [38]. A New Drug Application (NDA) is expected to be submitted to the FDA in 2016. Limited data from the Phase III study also suggest that the NES/EE ring may be used an emergency contraceptive method, with the potential advantage of being a bridging method for an additional 12 cycles [33]. A 3-month NES ring in combination with the less potent estrogen estradiol (E2) is also being evaluated in a randomized dose-finding study with the goal of developing a ring with lower venous thrombosis risk especially for overweight and obese women [33].

Figure 3.

The 1-year Nestorone/ethinyl estradiol vaginal ring.

Selective progesterone receptor modulator rings

With the goal of developing an estrogen-free vaginal ring with a simplified regimen, in other words, no need for removal for a hormone-free interval and the potential for improved user compliance and contraceptive efficacy, UPA is also being investigated in a ring delivery system [20]. The Population Council and HRA Pharma (Paris, France) recently completed a dose-finding study for a 3-month UPA vaginal ring, in which a ring releasing 2500 μg/day achieved 90% ovulation suppression [40].

Multipurpose prevention technologies

Many women at risk for pregnancy are also at high risk of acquiring sexually transmitted infections (STIs). In 2013 alone, 2.1 million people became infected with HIV/AIDS [41]. Each day more than a million people acquire STIs [42]. Women with certain STIs are at a threefold or greater risk of acquiring HIV [42]. Currently, the only contraceptive methods that have the potential to also reduce risk of STIs are barrier methods (male and female condoms). Other contraceptive methods such as hormonal methods and IUDs do not offer STI protection. Condoms, however, are challenging to use and use is inconsistent. Research is ongoing to develop new and easy-to-use multipurpose prevention technologies (MPTs) – approaches designed to be effective against both pregnancy and STIs, primarily HIV.

First-generation MPT products fall into two categories: ‘on demand’ products that can be used around the time of intercourse and are most appropriate for women who have infrequent sex, and long-acting, sustained release systems including vaginal rings and injectables. Sustained release systems would not require daily action and, as such, overall adherence and effectiveness should be greater than typically seen with coitally related methods.

Four different vaginal rings combining an antiretroviral (ARV) and a progestin are being developed. The International Partnership on Microbicides (IPM) is developing an LNG plus dapivirine silicone ring expected to last 60 days; CONRAD is developing a segmented LNG plus tenofovir 90-day ring (Figure 4); the Population Council is developing an LNG, MIV–150 and zinc acetate ring; and Merck is assessing use of their existing NuvaRing platform to deliver an ARV and etonogestrel [43,44]. Finally, long-acting injectable ARV formulations include rilpivirine (TMC278) and GSK1265744 have entered clinical evaluation [44]. The primary challenge in development of an injectable MPT is matching the durations of action of the two therapeutic agents. Questions remain as to whether combination strategies are appropriate for injectables or whether providing two injections, one a contraceptive and one an ARV, concurrently would be a more logical and rapid path to market.

Figure 4.

The levonorgestrel and dapivirine silicone vaginal ring for the prevention of pregnancy and HIV.

Conclusion & future perspective

After decades of waning support for contraceptive research, the past several years have seen a renewed focus on developing new and improved contraceptive technologies. While this effort has largely been led by the public and philanthropic sectors, as research progresses and additional breakthroughs achieved, the incentive for private sector engagement will increase. Sustained investment will be key for ensuring that the new methods under development today will ultimately reach the women around the world who need them.

Executive summary

More than 200 million women across the world have an unmet need for contraception. New contraceptive technologies are needed to address long-standing barriers to use.

Improvements to existing injectable contraceptives include the addition of estrogen, reformulation to improve the pharmacokinetic profile and extend duration and use of alternative progestins.

New long-acting biodegradable contraceptive implants could reduce the programmatic challenge of removal at the end of effectiveness.

Hormonal intrauterine devices have improved bleeding patterns and greater acceptability than copper intrauterine devices in many settings but are cost-prohibitive; new lower cost options may soon be available.

Changing the shape and size of copper intrauterine devices could improve ease of insertion, reduce side effects and increase acceptability.

New contraceptive vaginal ring products currently in development offer potential for extended use with a single year-long product (nestorone-ethinylestradiol ring) and a ring requiring no hormone-free interval (ulipristal acetate ring).

Long-acting multipurpose prevention technologies in development include several vaginal rings that release both a progestin and an antiretroviral.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Alkema

Kantorova

Menozzi

Biddlecom

. National, regional, and global rates and trends in contraceptive prevalence and unmet need for family planning between 1990 and 2015: a systematic and comprehensive analysis. Lancet 381(9878), 1642–1652 (2013).

Darroch

Singh

. Trends in contraceptive need and use in developing countries in 2003, 2008, and 2012: an analysis of national surveys. Lancet 381(9879), 1756–1762 (2013).

Finer

Zolna

. Shifts in intended and unintended pregnancies in the United States, 2001–2008. Am. J. Public Heath 104(Suppl. 1), S43–S48 (2014).

Frost

Singh

Finer

. Factors associated with contraceptive use and nonuse, United States, 2004. Perspect. Sex. Reprod. Health 39(2), 90–99 (2007).

Finer

Henshaw

. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect. Sex. Reprod. Health 38(2), 90–96 (2006).

United Nations. Department of Economic and Social Affairs Population Division. World Contraceptive Use 2011. United Nations, NY, USA (2011). www.un.org.

Jones

Mosher

Daniels

. Current contraceptive use in the United States, 2006–2010, and changes in patterns of use since 1995. National Health Statistics Reports (2012). www.cdc.gov.

Gallo

Grimes

Lopez

Schulz

D'arcangues

. Combination injectable contraceptives for contraception. Cochrane Database Syst. Rev. (4), CD004568 (2008).

Thurman

Kimble

Hall

Schwartz

Archer

. Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics. Contraception 87(6), 738–743 (2013).

10.

CONRAD. Research grid: contraceptive research. www.conrad.org.

11.

Hubacher

Kimani

Steiner

Solomon

Ndugga

. Contraceptive implants in Kenya: current status and future prospects. Contraception 75(6), 468–473 (2007).

12.

Raymond

Singh

Archer

Saxena

Baker

Cole

. Contraceptive efficacy, pharmacokinetics, and safety of Annuelle biodegradable norethindrone pellet implants. Fertil. Steril. 66(6), 954–961 (1996).

13.

Darney

Klaisle

Monroe

Cook

Phillips

Schindler

. Evaluation of a 1–year levonorgestrel-releasing contraceptive implant: side effects, release rates, and biodegradability. Fertil. Steril. 58(1), 137–143 (1992).

14.

United Nations population division: world contraceptive use 2011. www.un.org.

15.

Hubacher

Finer

Espey

. Renewed interest in intrauterine contraception in the United States: evidence and explanation. Contraception 83(4), 291–294 (2011).

16.

Clinical trials database: NCT00995150. https://clinicaltrials.gov/ct2/show/NCT00995150.

17.

Nelson

Apter

Hauck

Two low-dose levonorgestrel intrauterine contraceptive systems: a randomized controlled trial. Obstet. Gynecol. 122(6), 1205–1213 (2013).

18.

Clinical trials database: NCT00967746. https://clinicaltrials.gov/ct2/show/NCT00967746.

19.

Glasier

Cameron

Fine

Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-%inferiority trial and meta-analysis. Lancet 375(9714), 555–562 (2010).

20.

Jensen

. Vaginal ring delivery of selective progesterone receptor modulators for contraception. Contraception 87(3), 314–318 (2013).

21.

Brenner

Slayden

Nath

Tsong

Sitruk-Ware

. Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques. Contraception 81(4), 336–342 (2010).

22.

Zhang

Chen

[A multi-%center randomized controlled trial of intrauterine device use in Chinese women]. Zhonghua yi xue za zhi 91(45), 3172–3175 (2011).

23.

Wang

Zhao

Wang

. [A random control study of indomethacin-containing MYCu intrauterine contraceptive device for 60 months]. Zhonghua yi xue za zhi 93(7), 496–499 (2013).

24.

Meirik

Rowe

Peregoudov

Piaggio

Petzold

. The frameless copper IUD (GyneFix) and the TCu380A IUD: results of an 8-year multicenter randomized comparative trial. Contraception 80(2), 133–141 (2009).

25.

Baram

Weinstein

Trussell

. The IUB, a newly invented IUD: a brief report. Contraception 89(2), 139–141 (2014).

26.

Clinical trials database: NCT02036177. https://clinicaltrials.gov/ct2/show/NCT02036177.

27.

Malcolm

Fetherston

Mccoy

Boyd

Major

. Vaginal rings for delivery of HIV microbicides. Int. J. Womens Health 4, 595–605 (2012).

28.

Mishell

Jr Lumkin

. Contraceptive effect of varying dosages of progestogen in silastic vaginal rings. Fertil. Steril. 21(2), 99–103 (1970).

29.

Nath

Sitruk-Ware

. Progesterone vaginal ring for contraceptive use during lactation. Contraception 82(5), 428–434 (2010).

30.

Helbling

Ibarra

Luna

. The optimization of an intravaginal ring releasing progesterone using a mathematical model. Pharm. Res. 31(3), 795–808 (2014).

31.

Reproductive health supplies coalition: progesterone vaginal ring. Product Brief (2013). www.rhsupplies.org.

32.

Population Council: New USAID cooperative agreement with the population council facilitates contraceptive development, supports introduction of new methods in low resource settings. www.popcouncil.org.

33.

Brache

Payan

Faundes

. Current status of contraceptive vaginal rings. Contraception 87(3), 264–272 (2013).

34.

Brache

Alvarez-Sanchez

Faundes

Jackanicz

Mishell

Jr Lahteenmaki

. Progestin-only contraceptive rings. Steroids 65(10–11), 687–691 (2000).

35.

Brache

Mishell

Lahteenmaki

Ovarian function during use of vaginal rings delivering three different doses of Nestorone. Contraception 63(5), 257–261 (2001).

36.

Sivin

Mishell

Jr Alvarez

Contraceptive vaginal rings releasing Nestorone and ethinylestradiol: a 1-year dose-finding trial. Contraception 71(2), 122–129 (2005).

37.

Dorflinger

. New developments in contraception for US women. Contraception 87(3), 343–346 (2013).

38.

Population Council: Population Council announces positive results from a Phase 3 trial of one-year contraceptive vaginal ring. www.popcouncil.org.

39.

The future of birth control. http://healthland.time.com.

40.

Huang

Jensen

Brache

A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception. Contraception 90(6), 565–574 (2014).

41.

UNAIDS. 2013 Global fact sheet. www.unaids.org.

42.

World Health Organization: Sexually transmitted infections (STIs) Fact sheet No. 110. http://www.who.int.

43.

Thurman

Clark

Hurlburt

Doncel

. Intravaginal rings as delivery systems for microbicides and multipurpose prevention technologies. Int. J. Womens Health 5, 695–708 (2013).

44.

Friend

Clark

Kiser

Clark

. Multipurpose prevention technologies: products in development. Antiviral Res. 100(Suppl.), S39–S47 (2013).

45.

HIV/AIDS, an intravaginal ring to prevent infection? https://destinationsante.com.

Addressing Gaps in the Contraceptive Method Mix: Methods in Development

Abstract

Keywords

Setting

Injectables

Monthly combined injectables

Alternative progestin-only injectables

Implants

Intrauterine devices

Hormonal IUDs

Variations on copper IUDs

Contraceptive vaginal rings

Progesterone vaginal ring

Nestorone vaginal rings

Selective progesterone receptor modulator rings

Multipurpose prevention technologies

Conclusion & future perspective

Footnotes

References