Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings.

BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

Effect of a single dose of a combination injectable contraceptive for treatment of bothersome uterine bleeding in contraceptive implant(s) users: A randomized double-blind placebo-controlled trial.

OBJECTIVES: This study aimed to determine the proportion of participants whose uterine bleeding/spotting was interrupted for at least 7 days during the month after they received a combined hormonal injection. We also evaluated bleeding at 21 days and 12 weeks after the injection. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled trial in 46 contraceptive implant users who presented with bothersome uterine bleeding/spotting. A single dose of a combination injectable contraceptive or placebo was administered intramuscularly at enrollment. RESULTS: The proportions of participants whose uterine bleeding/spotting was interrupted for at least 7 days the month after they received a combined hormonal injection were higher in the combination injectable contraception group than in the placebo group (87% vs 48%, p = 0.005). Participants who reported that they were bleeding free at 21 days after treatment were 52% and 35% in the combination injectable contraception group and placebo group, respectively (p = 0.24). At 12 weeks posttreatment, 17% of participants in the combination injectable contraception group and 4% in the placebo group reported cessation of bleeding with no recurrence (p = 0.34). The median days until the first bleeding interruption was shorter in the combination injectable contraception group compared with the placebo group (1 [interquartile range, 1-2] vs 8 [interquartile range, 1-28], p = 0.007). CONCLUSIONS: The combination injectable contraception interrupted bothersome uterine bleeding/spotting in contraceptive implant(s) users compared with placebo. However, this effect was limited only within the month when the treatment was administered. IMPLICATIONS: Bothersome uterine bleeding/spotting is a common side effect leading to contraceptive implant(s) discontinuation. In implant users experiencing these symptoms with no estrogen contraindications, a combined injectable contraception appears to rapidly improve bleeding for the duration of injectable exposure (1 month).

Retrograde coiled spring jejunal intussusception in an infant due to Foley catheter gastrostomy: a case report.

BACKGROUND: For infants who need long-term enteral feeding but are unable to maintain sufficient oral intake, feeding gastrostomy tube placement is required. The use of a Foley catheter as a replacement catheter in a Stamm gastrostomy is indicated in the absence of dedicated gastrostomy feeding tubes; however, this approach has been associated with many morbidities. In this report, an unusual case of an infant who underwent a major operation due to coiled spring jejunal intussusception caused by Foley catheter migration is described. CASE PRESENTATION: A 6-month-old neurologically impaired premature female patient was admitted to the emergency unit with respiratory distress, nonbilious vomiting and an ineffective gastrostomy feeding tube. Her history revealed that, at the age of 2 months, she had undergone Stamm gastrostomy for enteral feeding with a Pezzer catheter. However, at the age of 5 months, the Pezzer catheter became dislodged and was replaced with a Foley catheter. The patient subsequently underwent emergent exploratory laparotomy due to intestinal obstruction. During the operation, retrograde coiled spring jejunal intussusceptions with multiple areas of local necrosis and perforations were observed. Resection of the affected jejunal segment and end-to-end anastomosis were performed. The postoperative period was long and very demanding due to the presence of several comorbidities. To our knowledge, this is the first operative demonstration of coiled spring intussusception. CONCLUSION: This case report aims to increase clinical awareness of the possibility of coiled spring intussusception following the use of Foley catheter in a gastrostomy and the difficulties encountered in the surgical course of a premature infant.

Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States.

INTRODUCTION: Vaginal rings are a promising approach to provide a woman-centred, long-acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV-1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three-month rings with different DPV dosages, compared with the monthly DPV ring. METHODS: From December 2017 to October 2018, MTN-036/IPM-047 enrolled 49 HIV-negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three-month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow-up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs in the extended duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations/outages) with no differences between the monthly versus three-month rings. Most participants found the ring acceptable (median = 8 on 10-point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms (p = 0.01 and p = 0.15 respectively). CONCLUSIONS: The extended duration DPV rings were well-tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three-month DPV rings for HIV prevention.

Twelve-month Continuation of the Etonogestrel Implant in Adolescents With Polycystic Ovary Syndrome.

STUDY OBJECTIVE: To identify why adolescents with polycystic ovary syndrome (PCOS) chose the etonogestrel (ENG) contraceptive implant, to determine the 12-month continuation rate, and to characterize factors related to discontinuation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective chart review of adolescents seen at a tertiary care children's hospital between July 1, 2008, and August 30, 2019, with PCOS diagnosis confirmed per National Institutes of Health criteria and ≥12-month ENG follow-up. INTERVENTIONS AND MAIN OUTCOME MEASURES: Demographic characteristics, reasons for ENG insertion and removal, and information on other hormonal/contraceptive therapies were collected. Patients were categorized as ENG continuers (use ≥12 months) or discontinuers (removal at <12 months), and groups were compared. RESULTS: A total of 96 patients met inclusion criteria (age 17.7 ± 2.2 years, body mass index 34.8 ± 8 kg/m2). Reasons for ENG were documented in 74% (51% contraception, 32% ease of use, 15% other, 13% estrogen avoidance). In all, 27% had never been sexually active, and 67% had had prior sexual activity. Treatments prior to ENG placement included 74% combined hormonal contraception, 20% medroxyprogesterone acetate withdrawal, and 17% depot medroxyprogesterone. A total of 77% continued ENG at 12 months. The main reasons for discontinuation were bleeding (41%), concern about weight gain (23%), and mood changes (18%). No preimplantation characteristics were independently predictive of continuation, although 100% of patients with type 2 diabetes (n = 11) continued. Patients who sought additional care, including telephone calls (41% vs 12%, P = .006) and clinic visits (64% vs 20%, P < .001) were more likely to discontinue. CONCLUSIONS: The ENG implant was well tolerated in adolescents with PCOS and similar to published 12-month continuation rates.

Hormonal Contraceptives and Dermatology.

Hormones play a significant role in normal skin physiology and many dermatologic conditions. As contraceptives and hormonal therapies continue to advance and increase in popularity, it is important for dermatologists to understand their mechanisms and dermatologic effects given the intricate interplay between hormones and the skin. This article reviews the dermatologic effects, both adverse and beneficial, of combined oral contraceptives (COCs), hormonal intrauterine devices (IUDs), implants, injections, and vaginal rings. Overall, the literature suggests that progesterone-only methods, such as implants and hormonal IUDs, tend to trigger or worsen many conditions, including acne, hirsutism, alopecia, and even rosacea. Therefore, it is worthwhile to obtain detailed medication and contraceptive histories on patients with these conditions. There is sufficient evidence that hormonal contraceptives, particularly COCs and vaginal rings, may effectively treat acne and hirsutism. While there are less data to support the role of hormonal contraceptives in other dermatologic disorders, they demonstrate potential in improving androgenetic alopecia and hidradenitis suppurativa.

Safety, efficacy and quality of life of the novel vaginal contraceptive ring containing etonogestrel/ethinylestradiol 11.0/3.474 mg after 3 years of "real life" experience.

Combined contraceptive vaginal rings (CVR) are increasingly appreciated due to several beneficial properties like avoidance of the hepatic first-pass effect, a comparatively low dosage of hormones and comfortable use. A further development of the widely used CVR releasing 0.12 mg etonogestrel (ETO) and 0.015 mg ethinylestradiol (EE) per 24 hours has been marketed since 2017. The 11.00/3.474 mg ETO/EE CVR Ornibel® is bioequivalent to the former product but differs in its polymer composition leading to improved stability. Here, results from recent studies on the novel CVR Ornibel® are reviewed including clinical trials on bleeding profile, acceptability, sexual function and other quality of life (QoL) parameters as well as in vitro studies on microbial adhesion to the CVR and the influence of ring rupture on hormone release. Findings are complemented with new data on contraceptive efficacy and safety of the new CVR that were assessed during 3 years of real-life experience.

Analysis and new contraception frontiers with combined vaginal rings.

Combined vaginal rings (ethinylestradiol (EE)/desogestrel), indicated for contraception, are highly effective, comparable to other combined hormonal contraceptives, such as pills. In addition to this benefit, vaginal rings are easy to use, with a probable lower risk of forgetting, due to their non-daily, monthly schedule. Besides, for users with poor gastric tolerance to oral formulations, they represent a method with safety and comparable extraconceptive benefits. The latest generation rings have a novel polymeric structure, do not need special storage methods and do not generate accelerated initial release of EE, reducing the early increased systemic exposure to the synthetic steroids they contain. This review describes main aspects related to its use, efficacy, and safety for contraceptive purposes.

Brief Report: Phase IIa Safety Study of a Vaginal Ring Containing Dapivirine in Adolescent Young Women.

BACKGROUND: Young women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence. METHODS: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews. RESULTS: Ninety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits. CONCLUSION: The dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents.

Eritema nodoso asociado al uso de anillo vaginal anticonceptivo / Erythema nodosum associated with the use of contraceptive vaginal ring

El eritema nodoso (EN) es la forma de paniculitis más común. Este trastorno representa una reacción de hipersensibilidad frente a diferentes antígenos, así como múltiples enfermedades sistémicas y fármacos, aunque en la mayoría de casos se desconoce la causa. Nuevos fármacos se añaden a la lista de involucrados en la etiopatogenia del eritema nodoso conforme van pasando los años, siendo uno de ellos los anticonceptivos hormonales orales combinados. El objetivo de este trabajo es proponer una relación entre los estrógenos de cualquier método anticonceptivo como puede ser el anillo vaginal combinado y la aparición del eritema nodoso.

Erythema nodosum (EN) is the most common form of panniculitis. This disorder represents a hypersensitivity reaction in front of different antigens, as well as multiple systemic diseases and drugs, although in most cases the cause is unknown. New drugs are added to the list of those involved in the etiopathogenesis of erythema nodosum as the years go by, one of them being combined oral hormonal contraceptives. The objective of this study is to propose a relationship between estrogens from any contraceptive method such as the combined vaginal ring and the appearance of erythema nodosum.

Referral Center Experience With Nonpalpable Contraceptive Implant Removals.

OBJECTIVE: To describe our experience with office removal of nonpalpable contraceptive implants at our referral center. METHODS: We performed a retrospective cohort study by reviewing the charts of patients referred to our family planning specialty center for nonpalpable or complex contraceptive implant removal from January 2015 through December 2018. We localized nonpalpable implants using high-frequency ultrasonography and skin mapping in radiology, followed by attempted removal in the office using local anesthesia and a modified vasectomy clamp. We abstracted information on demographics, implant location, and outcomes. RESULTS: Of 61 referrals, 55 patients attended their scheduled appointments. Seven patients had palpable implants; six elected removal. The other 48 patients had ultrasound localization, which identified 47 (98%) of the implants; the remaining patient had successful localization with computed tomography imaging. Nonpalpable implants were suprafascial (n=22), subfascial (n=25) and intrafascial (n=1); four of these patients opted to delay removal. Of 50 attempted office removals, all palpable (n=6), all nonpalpable suprafascial (n=21 [100%, 95% CI 83-100%]), and 19 out of 23 (83%, 95% CI 67-98%) subfascial implants were successful. Three of the four patients with failed subfascial implant office removal had successful operating room removal with a collaborative orthopedic surgeon; the other patient sought removal elsewhere. Transient postprocedure neuropathic complaints were noted in 7 out of 23 (30%, 95% CI 12-49%) subfascial and 1 out of 21 (5%, 95% CI 0-13%) suprafascial removals (P=.048). Nonpalpable implants were more likely to be subfascial in nonobese patients (24/34, 71%) as compared with obese (1/13, 8%) patients (P<.001). Seven (28%) of the 25 subfascially located implants had been inserted during a removal-reinsertion procedure through the same incision. CONCLUSION: Most nonpalpable contraceptive implants can be removed in the office by an experienced subspecialty health care provider after ultrasound localization. Some patients may experience transient postprocedure neuropathic pain. Nonpalpable implants in thinner women are more likely to be in a subfascial location.

A New Year-Long Combination Hormonal Contraceptive.

The U.S. Food and Drug Administration approved a new combination hormonal contraceptive in August 2018. Sold under the brand name Annovera, it is a combination of segesterone acetate and ethinyl estradiol, and it is the first multiuse vaginal contraceptive system that prevents ovulation for up to 13 menstrual cycles in a year. Although there are several combination hormonal contraceptives on the market, this is the first single system that can be repeatedly used for an entire year and does not require placement by a health care provider. This innovation gives women control over when to stop using the contraceptive, should they so desire. Annovera is stored at room temperature when not in use, allowing women living in uncontrolled-temperature climates to use one contraceptive method for an entire year.

Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation.

OBJECTIVES: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. STUDY DESIGN: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive days and removed it for 7 days of each 28-day cycle. Four studies used the final manufactured CVS, including a 1-year pharmacokinetic study, two 1-year phase 3 trials and a second-year treatment extension study. We assessed safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. RESULTS: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m2] received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of use. Women using the final CVS most commonly reported adverse events of headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%) and abdominal pain (n=225, 10%). Few (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29 kg/m2 (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions in 4259 (19.5%) cycles and complete expulsions in 1509 (7%) cycles, most frequently in the initial cycle [499/2050 (24.3%) and 190/2050 (9.3%), respectively]. Safety-focused studies revealed no safety concerns. CONCLUSION: The 1-year SA/EE CVS has an acceptable safety profile. Additional studies are warranted in obese women at higher risk of VTE. IMPLICATIONS: This 1-year contraceptive vaginal system represents a new long-term, user-controlled and procedure-free option with a safety profile similar to other combination hormonal contraceptives. The same precautions currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.

Contraception.

Contraception counseling and provision are vital components of comprehensive health care. Unplanned pregnancy can be devastating to any woman but is particularly dangerous for those with chronic illness. Internal medicine providers are in a unique position to provide contraception, as they often intersect with women at the moment of a new medical diagnosis or throughout care for a chronic problem. A shared decision-making approach can engage patients and ensure that they choose a contraceptive method that aligns with their reproductive plans and medical needs.

Contraceptive rings promote vaginal lactobacilli in a high bacterial vaginosis prevalence population: A randomised, open-label longitudinal study in Rwandan women.

BACKGROUND: Hormonal contraception has been associated with a reduced risk of vaginal dysbiosis, which in turn has been associated with reduced prevalence of sexually transmitted infections (STIs), including HIV. Vaginal rings are used or developed as delivery systems for contraceptive hormones and antimicrobial drugs for STI and HIV prevention or treatment. We hypothesized that a contraceptive vaginal ring (CVR) containing oestrogen enhances a lactobacilli-dominated vaginal microbial community despite biomass accumulation on the CVR's surface. METHODS: We enrolled 120 women for 12 weeks in an open-label NuvaRing® study at Rinda Ubuzima, Kigali, Rwanda. Vaginal and ring microbiota were assessed at baseline and each ring removal visit by Gram stain Nugent scoring (vaginal only), quantitative PCR for Lactobacillus species, Gardnerella vaginalis and Atopobium vaginae, and fluorescent in situ hybridization to visualize cell-adherent bacteria. Ring biomass was measured by crystal violet staining. RESULTS: Bacterial vaginosis (BV) prevalence was 48% at baseline. The mean Nugent score decreased significantly with ring use. The presence and mean log10 concentrations of Lactobacillus species in vaginal secretions increased significantly whereas those of G. vaginalis and presence of A. vaginae decreased significantly. Biomass accumulated on the CVRs with a species composition mirroring the vaginal microbiota. This ring biomass composition and optical density after crystal violet staining did not change significantly over time. CONCLUSIONS: NuvaRing® promoted lactobacilli-dominated vaginal microbial communities in a population with high baseline BV prevalence despite the fact that biomass accumulated on the rings.

Surgical Management After Hysteroscopic Sterilization: Minimally Invasive Approach Incorporating Intraoperative Fluoroscopy for Symptomatic Patients with >2 Essure® Devices.

OBJECTIVE: To describe a non-hysterectomy surgical technique for symptomatic patients with >2 Essure® (Bayer Healthcare, Whippany, New Jersey) devices. DESIGN: Patients (n=4) presented with sharp pelvic pain, irregular vaginal bleeding, dyspareunia, weight gain, hair loss, fatigue, and/or diffuse skin rash, all of which were absent before undergoing hysteroscopic sterilization (HS). Hysterosalpingogram obtained before surgical excision of contraceptive tubal implants confirmed more than two Essure® devices in all patients. Except for HS-associated complaints, all patients were in otherwise good general health and none had any history of prior pelvic pathology. Hysteroscopy was followed by 5mm triple-port laparoscopic cornual dissection, modified partial bilateral salpingectomy, and foreign body removal under fluoroscopy and/or radiographic guidance. RESULTS: In this group, mean±SD patient age was 41±8yrs and interval between HS and device removal was 6.4±2.7yrs. At the conclusion of each case (mean±SD operative time=179±11min), imaging studies were reviewed by an attending radiologist and verified no retained metal in the abdomen. Conversion to laparotomy, hysterectomy, or blood transfusion was unnecessary for any patients, and all were discharged home within three hours. Their postoperative course continues to be satisfactory. CONCLUSION: Patients with more than two Essure® devices comprise an unusual group with a complex pelvic foreign body presentation. This is the first report on surgical management for such patients, underscoring the importance of localizing these contraceptive devices with careful imaging before, during, and after surgery. Moreover, hysterectomy is not absolutely mandatory in this setting and intraoperative fluoroscopy/radiography can facilitate complete, safe removal of all implants on an out-patient basis. Creation of ICD-10 modifiers for various post-HS complaints would allow for improved surveillance of the Essure® phenomenon.

Safety of a silicone elastomer vaginal ring as potential microbicide delivery method in African women: A Phase 1 randomized trial.

BACKGROUND: Women in sub-Saharan Africa are in urgent need of female-initiated human immunodeficiency virus (HIV) preventative methods. Vaginal rings are one dosage form in development for delivery of HIV microbicides. However, African women have limited experience with vaginal rings. OBJECTIVES: This Phase I, randomized, crossover trial assessed and compared the safety, acceptability and adherence of a silicone elastomer placebo vaginal ring, intended as a microbicide delivery method, inserted for a 12-week period in healthy, HIV-negative, sexually active women in South Africa and Tanzania. METHODS: 170 women, aged 18 to 35 years were enrolled with 88 women randomized to Group A, using a placebo vaginal ring for 12 weeks followed by a 12-week safety observation period. 82 women were randomized to Group B and observed for safety first, followed by a placebo vaginal ring for 12 weeks. Safety was assessed by clinical laboratory assessments, pelvic/colposcopy examinations and adverse events. Possible carry-over effect was addressed by ensuring no signs or symptoms of genital irritation at crossover. RESULTS: No safety concerns were identified for any safety variables assessed during the trial. No serious adverse events were reported considered related to the placebo vaginal ring. Vaginal candidiasis was the most common adverse event occurring in 11% of participants during each trial period. Vaginal discharge (2%), vaginal odour (2%), and bacterial vaginitis (2%) were assessed as possibly or probably related to the vaginal ring. Thirty-four percent of participants had sexually transmitted infections (STIs) at screening, compared to 12% of participants who tested positive for STIs at crossover and the final trial visit. Three participants (2%) tested HIV positive during the trial. CONCLUSIONS: The silicone elastomer vaginal ring had no safety concerns, demonstrating a profile favorable for further development for topical release of antiretroviral-based microbicides.

A phase I randomized postcoital testing and safety study of the Caya diaphragm used with 3% Nonoxynol-9 gel, ContraGel or no gel.

OBJECTIVES: The Caya® Diaphragm is a newly approved single-size, nonlatex diaphragm. Contragel® is a personal lubricant containing lactic acid approved in Europe and other countries for use with vaginal barrier devices. This study assessed the effectiveness in preventing sperm from penetrating midcycle cervical mucus of Caya with Contragel, Caya with 3% nonoxynol-9 (N-9) and Caya alone. STUDY DESIGN: Phase I multicenter, single-blind, randomized, crossover, nonsignificant risk study at two sites: Eastern Virginia Medical School, Norfolk, VA, USA, and Profamilia, Santo Domingo, Dominican Republic. Healthy, sexually active women 18-45years old, not at risk for pregnancy due to tubal occlusion, were eligible. Each participant was seen in nine visits, completing a baseline cycle (without product use) followed by three test cycles (sequence determined by randomization), each consisting of a cervical mucus check visit and a postcoital test visit. To proceed to test cycles, the baseline postcoital test had to show adequate cervical mucus and >5 progressively motile sperm per high power field (PMS/HPF). RESULTS: All women had an average of <5 PMS/HPF during the test cycle of each study arm, the primary endpoint. Caya with ContraGel and Caya with N-9 reduced the average number of PMS/HPF from 22.5 to 0. Caya alone reduced the average number of PMS/HPF from 22.5 to 0.4. There were two possibly product-related mild adverse events. CONCLUSION: This study supports that Caya with ContraGel is safe and functions as well as Caya with N-9 in preventing PMS from reaching midcycle cervical mucus. IMPLICATIONS: A single-size diaphragm used with a personal lubricant gel containing lactic acid appears to be safe and to function as well as the same diaphragm used with N-9 in preventing PMS from reaching midcycle cervical mucus.

Immediate versus delayed postpartum insertion of contraceptive implant for contraception.

BACKGROUND: The spacing of pregnancies has a positive impact on maternal and newborn health. The progestin contraceptive implant, which is a long-acting, reversible method of contraception, has a well-established low failure rate that is compatible with tubal sterilization. The standard provision of contraceptive methods on the first postpartum visit may put some women at risk of unintended pregnancy, either due to loss to follow-up or having sexual intercourse prior to receiving contraception. Therefore, the immediate administration of contraception prior to discharge from the hospital that has high efficacy may improve contraceptive prevalence and prevent unintended pregnancy. OBJECTIVES: To compare the initiation rate, effectiveness, and side effects of immediate versus delayed postpartum insertion of implant for contraception. SEARCH METHODS: We searched for eligible studies up to 28 October 2016 in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and POPLINE. We examined review articles and contacted investigators. We also checked registers of ongoing clinical trials, citation lists of included studies, key textbooks, grey literature, and previous systematic reviews for potentially relevant studies. SELECTION CRITERIA: We sought randomised controlled trials (RCTs) that compared immediate postpartum versus delayed insertion of contraceptive implant for contraception. DATA COLLECTION AND ANALYSIS: Two review authors (JS, YW) independently screened titles and abstracts of the search results, and assessed the full-text articles of potentially relevant studies for inclusion. They extracted data from the included studies, assessed risk of bias, compared results, and resolved disagreements by consulting a third review author (PL or SK). We contacted investigators for additional data, where possible. We computed the Mantel-Haenszel risk ratio (RR) with 95% confidence interval (CI) for binary outcomes and the mean difference (MD) with 95% CI for continuous variables. MAIN RESULTS: Three studies that included 410 participants met the inclusion criteria of the review. We did not identify any ongoing trials. Two included studies were at low risk of selection, attrition, and reporting biases, but were at high risk of performance and detection biases due to the inability to blind participants to the intervention. One included study was at high risk of attrition bias. The overall quality of the evidence for each comparison ranged from very low to moderate; the main limitations were risk of bias and imprecision.Initiation rate of contraceptive implants at the first postpartum check-up visit was significantly higher in the immediate insertion group than in the delayed insertion group (RR 1.41, 95% CI 1.28 to 1.55; three studies, 410 participants; moderate quality evidence).There appeared to be little or no difference between the groups in the continuation rate of contraceptive implant used at six months after insertion (RR 1.02, 95% CI 0.93 to 1.11; two studies, 125 participants; low quality evidence) or at 12 months after insertion (RR 1.04; 95% CI 0.81 to 1.34; one study, 64 participants;very low quality evidence)Women who received an immediate postpartum contraceptive implant insertion had a higher mean number of days of abnormal vaginal bleeding within six weeks postpartum (MD 5.80 days, 95% CI 3.79 to 7.81; one study, 215 participants; low quality evidence) and a higher rate of other side effects in the first six weeks after birth (RR 2.06, 95% CI 1.38 to 3.06; one study, 215 participants; low quality evidence) than those who received a delayed postpartum insertion. There appeared to be little or no difference between the groups in heavy, irregular vaginal bleeding or associated severe cramping within 12 months (RR 1.01, 95% CI 0.72 to 1.44, one study, 64 participants;very low quality evidence).It was unclear whether there was any difference between the groups in scores for participant satisfaction on a 0-10 scale (MD -0.40, 95% CI -1.26 to 0.46, low quality evidence), or in rates of unintended pregnancy (RR 1.82, 95% CI 0.38 to 8.71, 1 RCT, 64 women, very low quality evidence) at 12 months, or in rate of breastfeeding rate at six months (RR 2.01, 95% CI 0.72 ro 5.63, 1 RCT, 64 women, very low quality evidence) rate did not differ significantly between the groups. AUTHORS' CONCLUSIONS: Evidence from this review indicates that the rate of initiation of contraceptive implant at the first postpartum check-up visit was higher with immediate postpartum insertion than with delayed insertion. There appeared to be little or no difference between the groups in the continuation rate of contraceptive implant use at 6 months. It was unclear whether there was any difference between the groups in continuation of contraceptive use at 12 months or in the unintended pregnancy rate at 12 months.