A randomized crossover study to evaluate local tolerability following subcutaneous administration of a new depot medroxyprogesterone acetate contraceptive formulation.

Objectives: This study aimed to evaluate and compare local tolerability of investigational drug TV-46046 and reference drug Depo-subQ Provera 104, both containing medroxyprogesterone acetate (MPA) as an active ingredient. Study design: We conducted a randomized, crossover, single-center study. Twenty-seven healthy women aged 25 to 47 years at low risk of pregnancy received a subcutaneous injection of each of the four study drugs (120 mg/0.3 mL of TV-46046, 60 mg/0.3 mL of diluted TV-46046, 0.3 mL of TV-46046 placebo, and 104 mg/0.65 mL of Depo-subQ 104) in different quadrants of the abdomen. We assessed local tolerability by occurrence of injection site reactions (ISRs), as well as injection site pain and overall safety for at least 9 months postinjections. Results: Of a total of 108 study injections, three injections were partial due to needle blockage. We observed a total of 30 ISRs following 105 full-dose injections, including hypopigmentation (n = 24), bruising (n = 4), and atrophy/dimple (n = 2). Eleven cases of hypopigmentation occurred following 25 full-dose injections of undiluted TV-46046 (44.0%), six following 27 full-dose injections of diluted TV-46046 (22.2%), and seven following 26 full-dose injections of Depo-subQ 104 (26.9%). Hypopigmentations occurred on average 8 months postinjection. Injection pain was minimal and dissipated quickly after all four injections. Conclusions: Subcutaneous administration of MPA in a suspension formulation is associated with the delayed onset of hypopigmentation at the site of injection. Although not statistically significant, the rate of ISRs was over 60% higher for undiluted TV-46046 compared to Depo-subQ 104. This difference bears careful monitoring in future studies of TV-46046. Implications: From a safety standpoint, investigational drug TV-46046 is appropriate for further clinical testing as a 6-month contraceptive injectable. The previously underreported hypopigmentation associated with subcutaneous administration of MPA warrants further investigation and acceptability assessment among users of existing Depo-subQ 104 as well as careful monitoring of local tolerability of TV-46046 in future clinical trials. Trial registration: Registered at clinicaltrials.gov no: NCT02817464.

Return to ovulation after Sayana Press is injected every 4 months for one year: Empirical and pharmacokinetic/pharmacodynamic modeling results.

Objective: To characterize return to ovulation after injecting Sayana Press (104 mg/0.65 mL medroxyprogesterone acetate [MPA] in the Uniject device) every 4 months for 1 year of treatment. Study design: We followed a subset of women for return to ovulation in a trial that demonstrated Sayana Press remains highly effective when the subcutaneous reinjection interval is extended from 3 to 4 months. We measured serum progesterone in weeks 38 to 42 and 46 to 50 after a final (third) injection and used a concentration ≥4.7 ng/mL as a surrogate for ovulation. We also performed pharmacokinetic and pharmacodynamic modeling to predict differences in MPA accumulation and return to ovulation had - contrary to fact - injections been given every 3 months. Results: Ten of 19 women (53%; 95% confidence interval: 29-76) ovulated within 50 weeks of their last injection. We predicted that typical 12-month trough MPA concentrations are 34% lower (0.46 vs 0.69 ng/mL) and the median time from last dose to ovulation is 1.1 months shorter (13.1 vs 14.2 months) when injections are given every four months for 1 year. Conclusion: Extending the Sayana Press reinjection interval from 3 to 4 months leads to less drug accumulation, without a noticeable loss in efficacy. Although the Sayana Press patient leaflet specifies that over 80% of women desiring pregnancy will conceive within a year of stopping the method (independent of treatment duration), our empirical and modeling results indicate women should anticipate waiting a year or more for fertility to return after repeat dosing, with a somewhat shorter delay were the reinjection interval extended to four months. Implications: Providers should counsel women regarding the distinct possibility that return to fertility will take a year or longer following repeat use of Sayana Press. Extending the dosing interval from 3 to 4 months would result in approximately a 1-month shorter delay, without any appreciable reduction in contraceptive efficacy.

Ovulation suppression following subcutaneous administration of depot medroxyprogesterone acetate.

Objectives: To characterize the relationship between serum medroxyprogesterone acetate (MPA) concentrations and ovulation suppression, and to estimate the risk of ovulation for investigational subcutaneous regimens of Depo-Provera CI (Depo-Provera) and Depo-subQ Provera 104 (Depo-subQ). Study Design: We performed a secondary analysis of 2 studies that assessed the pharmacokinetics and pharmacodynamics of MPA when Depo-Provera is administered subcutaneously rather than by the labeled intramuscular route. Each woman received a single 45 mg to 300 mg subcutaneous injection of Depo-Provera, a single 104 mg subcutaneous injection of Depo-subQ, or 2 injections of Depo-subQ at 3-month intervals. We used an elevation of serum progesterone ≥4.7 ng/mL as a surrogate for ovulation and non-parametric statistical methods to assess pharmacokinetic and pharmacodynamic relationships. Results: This analysis included 101 women with body mass index (BMI) 18 to 34 kg/m2. Return of ovulation occurred at a median MPA concentration of 0.07 ng/mL (95% CI: 0.06-0.08) and the 90th percentile was 0.10 ng/mL (95% CI: 0.09-0.14). Neither age, race, nor BMI significantly influenced this relationship. The estimated probabilities of ovulation within 4 months of a 104 mg subcutaneous injection and within 7 months of a 150 mg subcutaneous injection (6 plus a 1-month grace) were each below 2.2%. Conclusions: The typical MPA concentration associated with loss of ovulation suppression is substantially less than the commonly cited threshold of 0.2 ng/mL. Based on our results, MPA levels would rarely be low enough to permit ovulation if the Depo-subQ reinjection interval were extended to four months or if 150 mg Depo-Provera were injected subcutaneously every 6 months. Implications: Extending the three-month Depo-subQ reinjection interval by one month would result in a 25% reduction in yearly MPA exposure, with little risk of pregnancy. Off-label subcutaneous administration of 150 mg Depo-Provera every 6 months would be a highly effective repurposing of an excellent product, with a similar reduction in cumulative exposure.

Contraceptive effectiveness, pharmacokinetics, and safety of Sayana® Press when injected every four months: a multicenter phase 3 trial.

BACKGROUND: Sayana Press® is a 3-monthly contraceptive injection approved by regulatory agencies in more than 40 countries worldwide. Existing effectiveness and pharmacokinetics (PK) data suggest that high contraceptive efficacy may be maintained if the reinjection interval of Sayana Press is extended from 3 to 4 months. METHODS: We conducted a phase 3 trial at three sites in the Dominican Republic, Brazil, and Chile from September 2017 through April 2020. We enrolled 750 women at risk of pregnancy who agreed to use Sayana Press off-label every 4 months (3 treatment cycles) for 12 months. The effectiveness cohort included 710 participants randomized equally to receive injections in the abdomen or thigh. Forty additional participants received injections in the back of the upper arm for comparative PK analyses. The primary outcome was pregnancy, defined by a positive urine pregnancy test confirmed by ultrasound and/or serum human chorionic gonadotropin. Secondary outcomes included PK, safety, and acceptability. Laboratory and trial Sponsor staff were blind to injection site. This study is registered with ClinicalTrials.gov, number NCT03154125. FINDINGS: There were no pregnancies during follow-up; the Pearl Index during 629.3 woman-years (WY) of follow-up in the primary effectiveness analysis was 0.00 (95% CI 0.00, 0.59). Pharmacokinetic profiles differed by injection site, with higher geometric mean (GM) medroxyprogesterone acetate concentrations for the abdomen than the thigh and arm. At month 8, significantly higher GM concentrations were observed in the abdomen and the thigh as compared to the arm, as well as at month 12 in the abdomen as compared to the arm. Injection site reactions were reported by 10.7% of participants. INTERPRETATION: Both pregnancy and PK results confirm that Sayana Press is a highly effective contraceptive method when administered every 4 months. These findings may inform modification of the dosing schedule, or duration of the grace period for reinjection, or both, to reduce overall drug exposure while maintaining contraceptive efficacy. FUNDING: This work is made possible by the generous support of the American people through the U.S. Agency for International Development (USAID), provided to FHI 360 through Cooperative Agreement AID-OAA-A-15-00,045, and a grant from the Gates Foundation. The contents are the responsibility of FHI 360 and do not necessarily reflect the views of USAID, the United States Government, or the Gates Foundation, nor does any mention of trade names, commercial products, or organizations imply endorsement by FHI 360, USAID, the United States Government, or the Gates Foundation.

Suppression of ovulation and pharmacokinetics following subcutaneous administration of various doses of Depo-Provera®: a randomized trial.

OBJECTIVES: To identify the lowest dose of Depo-Provera that, when administered off-label subcutaneously, suppressed ovulation and had a pharmacokinetic profile consistent with a 4-month contraceptive effect. STUDY DESIGN: We conducted a randomized, multicenter, parallel-group study to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of medroxyprogesterone acetate (MPA) after subcutaneous injection of three different doses of Depo-Provera. We randomized sixty women between 18 and 40 years of age at low risk of pregnancy with confirmed ovulation and body mass index of 18 to 35 kg/m2 to receive a single injection of 45, 75 or 105 mg of Depo-Provera, or a single injection of Depo-subQ provera 104 as a reference drug (15 women per group) and followed them for 7.5 months. We evaluated suppression of ovulation as the primary outcome, and MPA concentrations, pharmacokinetic parameters, safety, and local tolerability as secondary outcomes. RESULTS: Five women ovulated within four months of treatment initiation (three in the 45 mg group and two in the 75 mg group). MPA levels associated with ovulation were in general low, largely ≤ 0.2 ng/mL (the presumed contraceptive threshold). No women in either the 105 mg group or the Depo-subQ provera 104 group ovulated within four months. The PK parameters including Cmax, C119, and AUC0-119 for these 2 groups were similar but not equivalent. CONCLUSION: A dose of 105 mg of Depo-Provera injected subcutaneously was the lowest tested dose that consistently suppressed ovulation and maintained serum MPA levels consistent with contraceptive effect for at least 4 months. The PK and PD results for the 105 mg dose were similar to Depo-subQ provera 104 over this period.

Clinical trial to evaluate pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after subcutaneous administration of Depo-Provera.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after a single subcutaneous injection in the abdomen of 150 or 300 mg Depo-Provera and compare results to two injections of Depo-SubQ Provera 104 given 3 months apart. DESIGN: Partially randomized, multicenter, parallel-group study. SETTING: Research unit. PATIENT(S): Forty-two women of reproductive age with confirmed ovulatory cycle and body mass index of 18-35 kg/m2. INTERVENTION(S): Women received a single subcutaneous injection of 150 mg (n = 24) or 300 mg (n = 9) of Depo-Provera or two injections of Depo-SubQ Provera 104 (n = 9). MAIN OUTCOME MEASURE(S): Suppression of ovulation as measured by progesterone, serum medroxyprogesterone acetate concentrations, and estimated pharmacokinetics parameters. RESULT(S): No ovulations were observed during 7 months after a single injection of 150 or 300 mg Depo-Provera. The 150 mg group had a similar Cmax as observed over two injection cycles of Depo-SubQ Provera 104 and a similar 6-month trough concentration as the 3-month trough of Depo-SubQ Provera 104. CONCLUSION(S): Our pharmacodynamics and pharmacokinetics data provide proof of concept that Depo-Provera (150 mg) may be an effective contraceptive method when injected subcutaneously every 6 months, with up to a 4-week grace period for reinjections. CLINICAL TRIAL REGISTRATION NUMBER: NCT02456584.

Injectable contraception: updates and innovation.

PURPOSE OF REVIEW: Injectable contraception is a highly effective form of birth control that is globally popular. Recent research has focused on ways to make injectables such as depot medroxyprogesterone acetate (DMPA) more accessible and to improve the side-effect profile of injectables. This review will focus on new directions and approaches to the use of injectable contraception. RECENT FINDINGS: Research in the area of injectable contraception has focused on improving access for women through home or self-injection, and also task-shifting and community-based distribution in low-resource areas. Specific to DMPA, studies have focused on lowering the overall dose of medication while maintaining efficacy, and improving drug-delivery systems. More research into the association between DMPA and HIV is needed, and also the effects of administration of DMPA at the time of medication abortion. SUMMARY: Injectable contraceptives are an important part of the global method mix of highly effective birth control. Improving the accessibility and side effect profile of commodities such as DMPA will make injectables even more valuable for women seeking effective contraception.

Ectopic pregnancy with use of progestin-only injectables and contraceptive implants: a systematic review.

BACKGROUND: Use of contraception lowers a woman's risk of experiencing an ectopic pregnancy. In the case of method failure, however, progestin-only contraceptives may be more likely to result in ectopic pregnancies than some other methods such as combined hormonal and barrier contraceptives. OBJECTIVE: To describe ectopic pregnancy risk associated with use of implants and progestin-only injectable contraceptives through a systematic review of published studies. DATA SOURCES: We searched electronic databases for articles in any language published through May 2015 describing studies of progestin-only injectables and implants. We also searched bibliographies and review articles for additional studies. STUDY SELECTION AND EXTRACTION: Studies that reported any pregnancies were included in the review. Independent data extraction was performed by two authors based on predefined data fields, and where possible, we calculated the proportion of pregnancies that were ectopic and the ectopic pregnancy incidence rate per 1000 woman-years. RESULTS: Fifty-three studies of implants and 28 studies of injectables were identified; 79% reported pregnancy location. The proportion of ectopic pregnancy ranged from 0 to 100% with an incidence of 0-2.9 per 1000 woman-years in studies of marketed levonorgestrel implants. Studies of etonogestrel implants and the injectables, depot-medroxyprogesterone acetate and norethisterone enanthate, reported few ectopic pregnancies. CONCLUSION: Progestin-only contraceptive implants and injectables protect against ectopic pregnancy by being highly effective in preventing pregnancy overall; however, the absolute risk of ectopic pregnancy varies by type of progestin. Risk of ectopic pregnancy should not be a deterrent for use or provision of these methods.

Towards the development of a longer-acting injectable contraceptive: past research and current trends.

OBJECTIVES: A longer-acting injectable contraceptive that lasts for 6 months would be a valuable addition to the contraceptive method mix and ideal for women who are interested in spacing births and/or uncertain about their future reproductive plans. Here we review past applications of drug delivery technologies to injectable contraceptives as well as recent advancements in sustained drug delivery technologies that hold promise for the development of a new longer-acting injectable contraceptive product. STUDY DESIGN: A global landscape analysis was conducted, promising sustained drug delivery technologies, and research opportunities and partnerships were established with experts in the fields of contraception and drug delivery to identify new approaches in developing a longer-acting injectable contraceptive product. RESULTS: The landscape analysis confirmed that a number of existing polymer systems, such as poly-lactic-co-glycolic acid and poly(epsilon-caprolactone), remain promising candidates for application to a longer-acting injectable product. Novel polymers and materials also hold promise for achieving longer release profiles and/or having other advantages over existing polymer systems, but products using these materials could potentially have longer roads to regulatory approval. Additionally, recent advancements in the manufacturing process of microspheres may benefit the development of a longer-acting injectable contraceptive. CONCLUSION: The design of any new injectable product must take into account the limitations of current injectable contraceptives and address concerns that women may have for a longer-acting product. FHI 360 is supporting several research collaborations for proof of concept of various drug delivery approaches for achieving longer-acting product that fits an established target product profile.

Repeated use of pre- and postcoital hormonal contraception for prevention of pregnancy.

BACKGROUND: Repeated use of postcoital hormonal contraception is not currently recommended due to the higher risk of side effects and lower contraceptive effectiveness compared to other modern methods of contraception. However, emerging evidence indicates renewed interest in a regular coitally-dependent method of oral contraception. We evaluated the existing data on safety and effectiveness of pericoital use of levonorgestrel and other hormonal drugs to prevent pregnancy. OBJECTIVES: To determine the effectiveness and safety of repeated use of pre- and postcoital hormonal contraception for pregnancy prevention. SEARCH METHODS: We searched until 1 September 2014 for trials that tested repeated pre- and postcoital use of hormonal drugs for pregnancy prevention. Databases included CENTRAL, MEDLINE, and POPLINE. We searched for current trials via ClinicalTrials.gov and ICTRP. For the initial review, we also searched EMBASE, CINAHL, and LILACS, and wrote to researchers to identify other trials. SELECTION CRITERIA: We considered published and unpublished studies of repeated postcoital or immediately precoital use of hormonal drugs for contraception with pregnancy as an outcome. DATA COLLECTION AND ANALYSIS: Two authors independently confirmed eligibility and extracted data from the included studies. We calculated confidence intervals (CI) around individual study Pearl indices using a Poisson distribution. We presented individual study estimates and pooled estimates and their 95% CI, where appropriate. MAIN RESULTS: We found 22 trials that evaluated pericoital use of LNG and other hormonal drugs on a regular basis to prevent pregnancy. The studies included a total of 12,400 participants, and were conducted in Europe, Asia, and the Americas. The drugs and doses evaluated included levonorgestrel (LNG) 0.75 mg (11 studies), LNG in doses other than 0.75 mg (4 trials), and hormones other than LNG (7 trials). Outcomes included pregnancy rates, discontinuation, side effects, and acceptability.Pericoital levonorgestrel was reasonably efficacious and safe. The pooled Pearl Index for the 0.75 mg dose of LNG was 5.4 per 100 woman-years (95% CI 4.1 to 7.0). The pooled Pearl Index for all doses of LNG was 5.0 per 100 woman-years (95% CI 4.4 to 5.6). Other hormonal drugs appeared promising but most of them were not studied extensively. Menstrual irregularities were the most common side effects reported. However, the studies provided no consistent evidence of a relationship between bleeding abnormalities and either frequency of pill intake or total dose of the drug. Non-menstrual side effects were reportedly mild and not tabulated in most studies. Most women liked the pericoital method in spite of frequent menstrual irregularities. AUTHORS' CONCLUSIONS: The studies of pericoital LNG regimens provided promising results but many had serious methodological issues. Most reports were decades old and provided limited information. However, we considered the evidence to be moderate quality because of the large number of participants from diverse populations, the low pregnancy rates, and the consistent results across studies. Rigorous research is still needed to confirm the efficacy and safety of pericoital use of LNG as a primary means of contraception among women with infrequent intercourse. If the method is shown to be efficacious, safe and acceptable, the results may warrant revision of the current World Health Organization recommendations and marketing strategies.

A single-arm study to evaluate the efficacy, safety and acceptability of pericoital oral contraception with levonorgestrel.

BACKGROUND: An oral dose of 0.75 mg levonorgestrel (LNG) taken shortly after sex was marketed as a routine, nonemergency contraceptive method until the 1990s. Because a hormonal method used only at the time of intercourse may be desirable for women who have infrequent sex, we conducted a study to reevaluate the potential of pericoital LNG as a primary means of contraception. METHODS: We enrolled women aged 18-45 years in Brazil and the USA who expected to have sex 1-4 days per month for 6.5 months. Participants were instructed to take one tablet 0.75 mg LNG within 24 h before or after sex, with no more than one dose in any 24-h period. The primary efficacy measure was the Pearl Index among women aged 18-35 years. RESULTS: The study was stopped after 72 of the planned 300 participants were enrolled due to slow recruitment and related feasibility considerations. In the primary analysis, three pregnancies occurred during 13.4 woman-years of follow-up, resulting in a Pearl Index of 22.4 (95% confidence interval, 4.6-65.4). No serious adverse events were reported, and vaginal bleeding patterns were generally acceptable. CONCLUSIONS: Our estimated Pearl Index was noticeably higher than expected from previous research of LNG for pericoital contraception. Although the regimen was safe and generally acceptable, the study was challenged by slow enrollment and curtailed person-years of follow-up, resulting in poor precision for the estimated treatment effect. Future research may inform whether our results are symptomatic of the regimen, study design or characteristics of the populations from which we recruited. IMPLICATIONS: Our study failed to confirm prior data suggesting that 0.75 mg LNG for pericoital contraception could be more effective than typical use of barrier methods among women having infrequent sex. Characterizing populations most likely to adhere to, and benefit from, pericoital regimens is essential to future research on these methods.

Pharmacokinetics of subcutaneous depot medroxyprogesterone acetate injected in the upper arm.

BACKGROUND: The abdomen and thigh are recommended injection sites in the label for Depo-SubQ Provera 104™. We evaluated the pharmacokinetic profile of medroxyprogesterone acetate (MPA) following injection of Depo-SubQ Provera 104 in the upper arm, a preferred injection site in developing countries. STUDY DESIGN: Twenty-six women in Norfolk, VA, received a single injection of Depo-SubQ Provera 104 in the upper arm in this prospective noncomparative study. We measured MPA serum concentrations prior to injection (day 1) and 11 times postinjection (days 2, 4, 8, 14, 30, 44, 60, 74, 91, 104 and 120). RESULTS: Serum MPA levels peaked at 0.953 ng/mL 2-14 days (interquartile range; median=8) after dosing. Mean AUC0-91 was 45.1 ng·day/mL. Mean MPA levels at days 91, 104 and 120 were 0.427, 0.367 and 0.327 ng/mL, respectively. A total of 15 individual measurements of MPA were below 0.2 ng/mL. All women but one had MPA levels above 0.1 ng/mL on day 91. CONCLUSIONS: Injection of Depo-SubQ Provera 104™ in the upper arm provided sufficient MPA levels for contraceptive protection for 3 months (13 weeks). The uptake and metabolism of MPA when injected in the upper arm may be different from the abdomen and thigh.

Spermicide used alone for contraception.

BACKGROUND: Spermicides have been used as contraceptives for thousands of years. Despite this long use, only recently have studies examined the comparative efficacy and acceptability of these vaginal medications. Spermicides contain an active ingredient (most commonly nonoxynol-9) and a formulation used to disperse the product, such as foam or vaginal suppository. OBJECTIVES: This review examined all known randomized controlled trials of a spermicide used alone for contraception. SEARCH METHODS: In August 2013, we searched the following computerized databases for randomized controlled trials of spermicides for contraception: CENTRAL, MEDLINE, POPLINE, LILACS, EMBASE, ClinicalTrials.gov, and ICTRP. For the initial review, we examined the reference lists of trials found as well as those of review articles and textbook chapters. SELECTION CRITERIA: We included any trial of a commercial product used alone for contraception. Each included trial must have provided sufficient information to determine pregnancy rates. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information from the trials identified. We did not conduct a meta-analysis, since most trials had large losses to follow up. We entered the data into tables and presented the results descriptively. MAIN RESULTS: We located reports from 14 trials for the initial review, but have not identified any new trials since then. In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. AUTHORS' CONCLUSIONS: The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.

Spermicide used alone for contraception.

BACKGROUND: Spermicides have been used as contraceptives for thousands of years. Despite this long use, only recently have studies examined the comparative efficacy and acceptability of these vaginal medications. Spermicides contain an active ingredient (most commonly nonoxynol-9) and a formulation used to disperse the product, such as foam or vaginal suppository. OBJECTIVES: This review examined all known randomized controlled trials of a spermicide used alone for contraception. SEARCH METHODS: In August 2013, we searched the following computerized databases for randomized controlled trials of spermicides for contraception: CENTRAL, MEDLINE, POPLINE, LILACS, EMBASE, ClinicalTrials.gov, and ICTRP. For the initial review, we examined the reference lists of trials found as well as those of review articles and textbook chapters. SELECTION CRITERIA: We included any trial of a commercial product used alone for contraception. Each included trial must have provided sufficient information to determine pregnancy rates. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information from the trials identified. We did not conduct a meta-analysis, since most trials had large losses to follow up. We entered the data into tables and presented the results descriptively. MAIN RESULTS: We located reports from 14 trials for the initial review, but have not identified any new trials since then. In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. AUTHORS' CONCLUSIONS: The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.

Strategies to improve adherence and acceptability of hormonal methods of contraception.

BACKGROUND: Worldwide, hormonal contraceptives are among the most popular reversible contraceptives. Despite their high theoretical effectiveness, typical use results in much lower effectiveness. In large part, this disparity reflects difficulties in adherence to the contraceptive regimen and low rates for long-term continuation. OBJECTIVES: The intent was to determine the effectiveness of ancillary counseling techniques to improve adherence to, and continuation of, hormonal methods of contraception. SEARCH METHODS: Through August 2013, we searched computerized databases for randomized controlled trials (RCTs) comparing client-provider interventions with standard family planning counseling. Sources included CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov and ICTRP. Earlier searches also included LILACS, PsycINFO, Dissertation Abstracts, African Index Medicus, and IMEMR. SELECTION CRITERIA: We included RCTs of an intensive counseling technique or other client-provider intervention compared to routine family planning counseling. Interventions included group motivation; structured, peer, or multi-component counseling; and intensive reminders of appointments or next dosing. Outcome measures were discontinuation, reasons for discontinuation, number of missed pills or on-time injections, and pregnancy. DATA COLLECTION AND ANALYSIS: One author evaluated the titles and abstracts from the searches to determine eligibility. Two authors extracted data from the included studies. We calculated the Mantel-Haenszel odds ratio (OR) for dichotomous outcomes. For continuous variables, the mean difference (MD) was computed; RevMan uses the inverse variance approach. For all analyses, 95% confidence intervals (CI) were also computed. Since the studies identified differed in both interventions and outcome measures, we did not conduct a meta-analysis. MAIN RESULTS: Nine RCTs met our inclusion criteria. Five involved direct counseling; of those, two also provided multiple contacts by telephone. Four other trials provided intensive reminders, two of which also provided health education information. Three trials showed some benefit of the experimental intervention. In a counseling intervention, women who received repeated structured information about the injectable depot medroxyprogesterone acetate (DMPA) were less likely to discontinue the method by 12 months (OR 0.27; 95% CI 0.16 to 0.44) than women who had routine counseling. The intervention group was also less likely to discontinue due to menstrual disturbances (OR 0.20; 95% CI 0.11 to 0.37). Another trial showed a group with special counseling plus phone calls was more likely than the special-counseling group to report consistent use of oral contraceptives (OC) at 3 months (OR 1.41; 95% CI 1.06 to 1.87), though not at 12 months. The group with only special counseling did not differ significantly from those with standard care for any outcome. The third trial compared daily text-message reminders about OCs plus health information versus standard care. Women in the text-message group were more likely than the standard-care group to continue OC use by six months (OR 1.54; 95% CI 1.14 to 2.10). The text-message group was also more likely to avoid an interruption in OC use longer than seven days (OR 1.53; 95% CI 1.13 to 2.07). AUTHORS' CONCLUSIONS: Only three trials showed some benefit of strategies to improve adherence and continuation. However, several had small sample sizes and six had high losses to follow up. The overall quality of evidence was considered moderate. The intervention type and intensity varied greatly across the studies. A combination of intensive counseling and multiple contacts and reminders may be needed to improve adherence and acceptability of contraceptive use. High-quality RCTs with adequate power and well-designed interventions could help identify ways to improve adherence to, and continuation of, hormonal contraceptive methods.

Steroid hormones for contraception in men.

BACKGROUND: Male hormonal contraception has been an elusive goal. Administration of sex steroids to men can shut off sperm production through effects on the pituitary and hypothalamus. However, this approach also decreases production of testosterone, so 'add-back' therapy is needed. OBJECTIVES: To summarize all randomized controlled trials (RCTs) of male hormonal contraception. SEARCH METHODS: In January and February 2012, we searched the computerized databases CENTRAL, MEDLINE, POPLINE, and LILACS. We also searched for recent trials in ClinicalTrials.gov and ICTRP. Previous searches included EMBASE. We wrote to authors of identified trials to seek additional unpublished or published trials. SELECTION CRITERIA: We included all RCTs that compared a steroid hormone with another contraceptive. We excluded non-steroidal male contraceptives, such as gossypol. We included both placebo and active-regimen control groups. DATA COLLECTION AND ANALYSIS: The primary outcome measure was the absence of spermatozoa on semen examination, often called azoospermia. Data were insufficient to examine pregnancy rates and side effects. MAIN RESULTS: We found 33 trials that met our inclusion criteria. The proportion of men who reportedly achieved azoospermia or had no detectable sperm varied widely. A few important differences emerged. 1) Levonorgestrel implants (160 µg daily) combined with injectable testosterone enanthate (TE) were more effective than levonorgestrel 125 µg daily combined with testosterone patches. 2) Levonorgestrel 500 µg daily improved the effectiveness of TE 100 mg injected weekly. 3) Levonorgestrel 250 µg daily improved the effectiveness of testosterone undecanoate (TU) 1000 mg injection plus TU 500 mg injected at 6 and 12 weeks. 4) Desogestrel 150 µg was less effective than desogestrel 300 µg (with testosterone pellets). 5) TU 500 mg was less likely to produce azoospermia than TU 1000 mg (with levonorgestrel implants). 6) Norethisterone enanthate 200 mg with TU 1000 mg led to more azoospermia when given every 8 weeks versus 12 weeks. 7) Four implants of 7-alpha-methyl-19-nortestosterone (MENT) were more effective than two MENT implants. We did not conduct any meta-analysis due to intervention differences.Several trials showed promising efficacy in percentages with azoospermia. Three examined desogestrel and testosterone preparations or etonogestrel and testosterone, and two examined levonorgestrel and testosterone. AUTHORS' CONCLUSIONS: No male hormonal contraceptive is ready for clinical use. Most trials were small exploratory studies. Their power to detect important differences was limited and their results imprecise. In addition, assessment of azoospermia can vary by sensitivity of the method used. Future trials need more attention to the methodological requirements for RCTs. More trials with adequate power would also be helpful.

Pelvic surgery and hospitalization among Chilean women after nonsurgical sterilization with quinacrine pellets between 1977 and 1989.

BACKGROUND: Concern about quinacrine lingers because of its carcinogenic effects in rats. We describe results of long-term follow-up of women who underwent quinacrine pellet sterilization in Chile between 1977 and 1989 (N=1492). METHODS: We interviewed the women or relatives in five rounds of data collection between 1991-1993 and 2006-2007, and reviewed hospital records. Median follow-up was 18.5 years; total person-time was 23,894 woman-years. This analysis focuses on pelvic and abdominal surgeries and conditions. We used survival analysis to estimate the 15-year cumulative probability of hysterectomy, other pelvic surgical procedures and relevant adverse events. RESULTS: Uterine fibroids were by far the most common gynecologic condition, reported by 11% of the cohort. Surgical procedures were recorded for 15% of the cohort; hysterectomy was the most frequent procedure (10%), followed by salpingectomy (2%). The 15-year probability of any pelvic or abdominal procedure was 14.7 per 100 women (95% confidence interval 12.4-16.9). The probability of hysterectomy was 9.3 per 100 women (95% confidence interval 7.4-11.1). Number of quinacrine insertions had little impact on the probabilities. CONCLUSION: During long-term follow-up of women who received quinacrine pellets for nonsurgical sterilization, the incidence of noncancer adverse outcomes was not unusually high, and no alarming patterns emerged.

Predictors of pregnancy in microbicide trials.

BACKGROUND: High pregnancy rates undermine the conduct and interpretation of HIV prevention trials. We performed this analysis to identify baseline participant characteristics associated with increased risk of pregnancy in recent vaginal microbicide trials. STUDY DESIGN: We analyzed the data from four recently completed Phase III trials of candidate microbicides for prevention of HIV infection. Cox proportional hazard models, stratified by site nested within study, were used to determine the baseline factors that predict pregnancy. Six thousand seven hundred forty-eight women contributed data for this analysis. RESULTS: Pregnancies were detected in a total of 1826 (27.1%) women. The hazard of pregnancy was higher for women who had a history of pregnancy, were living with a man or reported more sexual acts not protected by condoms in the week prior to enrollment. The risk of pregnancy was lower in older participants; in women with more years of education; in women who reported more sexual partners at baseline interview; in women who reported using intrauterine contraception, implants, sterilization or injectables and in women who reported use of a condom during their last act of vaginal intercourse. CONCLUSIONS: Our data suggest that current use or acceptance of intrauterine contraception, implants, sterilization or injectables is the most effective approach to reduce pregnancy rates and might be a useful eligibility criterion in future HIV prevention trials.

Strategies to improve adherence and acceptability of hormonal methods of contraception.

BACKGROUND: Worldwide, hormonal contraceptives are among the most popular reversible contraceptives in current use. Despite their high theoretical effectiveness, typical use results in much lower effectiveness. In large part, this disparity reflects difficulties in adherence to the contraceptive regimen and low rates for long-term continuation. OBJECTIVES: To determine the effectiveness of ancillary techniques to improve adherence to, and continuation rates of, hormonal methods of contraception. SEARCH STRATEGY: We searched computerized databases for randomized controlled trials (RCTs) comparing client-provider interventions with standard family planning counseling. Sources included CENTRAL, MEDLINE, EMBASE, POPLINE, LILACS, PsycINFO, ClinicalTrials.gov and ICTRP. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of an intensive counseling technique or client-provider intervention versus routine family planning counseling. Interventions included group motivation; structured, peer, or multi-component counseling; and intensive reminders of appointments or next dosing. Outcome measures were discontinuation, reasons for discontinuation, number of missed pills and on-time injections, and pregnancy. DATA COLLECTION AND ANALYSIS: The primary author evaluated all titles and abstracts from the searches to determine eligibility. Two authors independently extracted data from the included studies. With RevMan, we calculated the odds ratio for all dichotomous outcomes and the mean difference for continuous data. The studies were so different that we did not conduct a meta-analysis. MAIN RESULTS: We found eight RCTs; only one showed a statistically significant benefit of the experimental intervention. In that trial, women who received repeated, structured information about the injectable contraceptive depo-medroxyprogesterone acetate (DMPA) were less likely to have discontinued the method by 12 months (OR 0.27; 95% CI 0.16 to 0.44) than were women who had routine counseling. The intervention group was also less likely to discontinue due to menstrual disturbances (OR 0.20; 95% CI 0.11 to 0.37). In another study, the intervention group was less likely to discontinue due to dissatisfaction with the contraceptive method (OR 0.61; 95% CI 0.38 to 0.98), but overall continuation was not affected. AUTHORS' CONCLUSIONS: Most studies to date have shown no benefit of strategies to improve adherence and continuation. These trials have important limitations, however. Three had small sample sizes, four had high losses to follow up, and the intervention and its intensity varied across the studies. High-quality research is a priority, since adherence and continuation are fundamentally important to the successful use of hormonal contraceptives.