An open-label, randomized crossover study to evaluate the acceptability and preference for contraceptive options in female adolescents, 15 to 19 years of age in Cape Town, as a proxy for HIV prevention methods (UChoose).

INTRODUCTION: Young women in Southern Africa have extremely high HIV incidence rates necessitating the availability of female-controlled prevention methods. Understanding adolescent preference for seeking contraception would improve our understanding of acceptability, feasibility and adherence to similar modes of delivery for HIV prevention. METHODS: UChoose was an open-label randomized crossover study over 32 weeks which aimed to evaluate the acceptability and preference for contraceptive options in healthy, HIV-uninfected, female adolescents aged 15 to 19 years, as a proxy for similar HIV prevention methods. Participants were assigned to a contraceptive method for a period of 16 weeks in the form of a bi-monthly injectable contraceptive, monthly vaginal Nuvaring® or daily combined oral contraceptive (COC) and then asked to state their preference. At 16 weeks, participants crossed over to another contraceptive method, to ensure that all participants tried the Nuvaring® (least familiar modality) and additionally, either the injection or COC. Primary outcomes were contraceptive acceptability and preference. At the end of the 32 weeks they were also asked to imagine their preference for an HIV prevention modality. Secondary endpoints included changes in sexual behaviour, contraceptive adherence and preference for biomedical and behavioural HIV prevention methods. RESULTS: Of the 180 participants screened, 130 were enrolled and randomized to the Nuvaring® (n = 45), injection (n = 45) or COC (n = 40). Significantly more Nuvaring® users (24/116; 20.7%) requested to change to another contraceptive option compared to injection (1/73; 1.4% p = 0.0002) and COC users (4/49; 8% p = 0.074). Of those that remained on the Nuvaring® , adherence was significantly higher than to COC (p < 0.0001). Significantly more injection users (77/80; 96.3%) thought this delivery mode was convenient to use compared to Nuvaring® (74/89; 83.1%; p = 0.0409) or COC (38/50; 76.0%; p = 0.0034). Overall, the preferred contraceptive choice was injection, followed by the ring and lastly the pill. CONCLUSIONS: Adherence to daily COC was difficult for adolescents in this cohort and the least favoured potential HIV prevention option. While some preferred vaginal ring use, these data suggest that long-acting injectables would be the preferred prevention method for adolescent girls and young women. This study highlights the need for additional options for HIV prevention in youth.

Surface roughness of different contraceptive vaginal rings: evaluation by scanning electron microscope (SEM).

Objective: The aim of the study was to evaluate whether the compositions of the ethylene vinyl acetate (EVA) membrane of two different contraceptive vaginal rings could influence the surface roughness, which is associated with the possible accumulation of vaginal biomass on the rings during use.Methods: We measured and compared the surface roughness of unused vaginal rings, NuvaRing and Ornibel, using a scanning electron microscope (SEM) and dedicated software that can convert SEM images into 3D models. Average roughness (Ra), average quadratic roughness (Rq) and mean height of the irregularities at 10 points (Rz) were calculated.Results: Different thicknesses of the EVA membranes between the two rings were noted. No significant differences were found between the two rings in the three evaluated values of surface roughness (NuvaRing vs Ornibel, respectively: Ra, 1.53 ± 0.14 vs 1.61 ± 0.14 µm, p = 0.141; Rq, 2.03 ± 0.25 vs 2.07 ± 0.16 µm, p = 0.688; Rz, 11.4 ± 3.1 vs 11.4 ± 2.4 µm, p = 0.987).Conclusion: The different composition of the vaginal rings' EVA membrane is not associated with different surface roughness. Ornibel is equivalent to NuvaRing in terms of surface roughness, despite the different composition of the membrane polymers.

In vitro evaluation of microbial adhesion to a contraceptive vaginal ring with a new polymer composition.

Objective: The aim of the study was to evaluate in vitro the amount of Candida albicans and Lactobacillus acidophilus adhering to the surface of Ornibel, a contraceptive vaginal ring with a new polymer composition, in comparison with NuvaRing. Methods: Ornibel and NuvaRing were tested for adhesion of microorganisms in vitro. The vaginal rings were aseptically sectioned into 1 cm segments. Suspensions of C. albicans (1-2 × 107 colony-forming units [CFU]/ml) and L. acidophilus (1-2 × 108 CFU/ml) were prepared and incubated either in monoculture or as co-culture with the ring segments. After incubation, adherent C. albicans and L. acidophilus were quantified by plate counting. Results: In monoculture, the measured amount of adhesion of C. albicans on the ring surface was significantly lower with Ornibel compared with NuvaRing (p = 6.77 × 10-5), while the adherence of L. acidophilus did not differ between the two rings. Similarly, when co-incubated with C. albicans, the number of adhering L. acidophilus microorganisms was significantly lower with Ornibel compared with NuvaRing (p = .018) . This reduction also resulted in significantly lower levels of adhering L. acidophilus in co-culture compared with L. acidophilus when incubated alone (p = .003). Conclusion: The study demonstrates that the adherence of C. albicans, as well as that of L. acidophilus when co-cultured with C. albicans, is lower with the Ornibel vaginal ring compared with NuvaRing. These in vitro findings warrant future human trials using molecular techniques to assess the vaginal microbiota composition and to establish whether Ornibel can support vaginal health.

Phase II dose-finding study on ovulation inhibition and cycle control associated with the use of contraceptive vaginal rings containing 17ß-estradiol and the progestagens etonogestrel or nomegestrol acetate compared to NuvaRing.

PURPOSE: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%. METHODS: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18-35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17ß-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles. RESULTS: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups. CONCLUSIONS: Contraceptive rings releasing 300 µg E2 and 75-125 µg/day of ENG or 500-900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.

A randomised trial of a contraceptive vaginal ring in women at risk of HIV infection in Rwanda: Safety of intermittent and continuous use.

BACKGROUND: Contraceptive vaginal rings could play a role in expanding the contraceptive method mix and in preparing communities for the introduction of HIV prevention and multipurpose rings. METHODS: We conducted an open label single-centre randomised clinical trial of intermittent versus continuous use of NuvaRing® in Kigali, Rwanda, in 2013-2014. We randomised 120 HIV-negative women 1:1 to intermittent use (three rings with a ring-free week in between rings) or continuous use (four rings without ring-free weeks). Women underwent an interview, counselling, and a speculum examination, and were tested for pregnancy, bacterial vaginosis (BV) by Nugent scoring, yeasts and trichomonads on wet mount, and sexually transmitted infections. FINDINGS: Only one woman withdrew early. Deliberate ring removals were rare, but spontaneous ring expulsions occurred during 14% of ring use periods. There were no incident pregnancies, serious adverse events, serious social harms, or early discontinuations for safety reasons. Systemic side effects were uncommon, and local side effects were not significantly differently distributed between groups except for lower abdominal pain (P = 0.013). The incidence of vaginal yeasts during ring use was high: 22% of intermittent users and 27% of continuous users had incident vaginal yeasts at one or multiple ring removal visits (P = 0.666), and symptomatic vaginal yeast cases were more common in the continuous than intermittent users (P = 0.031). In contrast, mean Nugent scores improved over time in both groups. CONCLUSIONS: Intermittent and continuous NuvaRing® use were safe in Rwandan women and improved Nugent scores over time. However, attention should be paid to ring expulsions and to a potential increased risk of vaginal candidiasis.

The Effects of Sex Differences and Hormonal Contraception on Outcomes after Collegiate Sports-Related Concussion.

There is conflicting evidence regarding whether females are more adversely affected after concussion than males. Further, recent research suggests that hormonal contraceptive (HC) use may affect symptom severity and duration post-concussion. The objective of this study was to examine the effects of sex and HC use on outcomes following concussion among collegiate varsity athletes. We hypothesized that females would have longer length of recovery (LOR), and that peak symptom severity would be associated with longer LOR in both males and females. Among females, we hypothesized that non-HC users would have longer LOR and higher peak symptom severity than HC users. Ninety collegiate student-athletes were included in this study (40 males, 50 females; 24 HC users, 25 non-HC users). Demographic, injury, and recovery information was abstracted via retrospective record review. LOR was defined as days between injury and clearance for full return to play by team physician. Peak symptom severity score (Sport Concussion Assessment Tool [SCAT] 2 or 3) was used in analyses. Study results revealed that males had shorter LOR than females (F[1, 86] = 5.021, p < 0.05, d = 0.49), but had comparable symptom severity scores. Symptom severity was strongly related to LOR for males (r = 0.513, p < 0.01) but not females (r = -0.003, p > 0.05). Among females, non-HC users demonstrated higher symptom severity than HC users (F[1,47] = 5.142, p < 0.05, d = 0.70). No significant differences between female HC users and non-HC users on LOR were observed. This study provides evidence for differential concussion outcomes between male and female collegiate athletes and between HC users and nonusers among females.

Establishment of a Molding Procedure to Facilitate Formulation Development for Co-extrudates.

Co-extrusion offers a number of advantages over conventional manufacturing techniques. However, the setup of a co-extrusion line is cost- and time-intense and formulation development is challenging. This work introduces a novel procedure to test the applicability of a co-extruded reservoir-type system at an early product development stage. We propose vacuum compression molding (VCM), a fast procedure that requires only small material amounts, for the manufacturing of cylindrical reservoir-type system. To this end, the commercially available co-extruded product NuvaRing® and variations thereof were used as test systems. All VCM systems showed a homogeneous skin thickness that adhered well to the core, thereby providing a precise core/skin interface. As drug release is a key criterion for pharmaceutical products, a modified in vitro dissolution method was set up to test the VCM systems. The drug release from the VCM systems was in the same order of magnitude as the corresponding co-extruded strands and followed the same release kinetics. Moreover, the VCM systems were capable of indicating the relative effect of formulation-related modifications on drug release. Overall, this shows that this system is a powerful tool that facilitates formulation tailoring and co-extrusion process setup at the earliest stage.

Residual hormone levels in used contraceptive rings as a measurement of adherence to vaginal ring use.

OBJECTIVE: This study sought to measure residual contraceptive hormone levels in vaginal rings as an adherence marker for monitoring product use in clinical trials. STUDY DESIGN: Residual etonogestrel and ethinyl estradiol levels from used NuvaRings® of 26 self-reported adherent women enrolled in a clinical trial of vaginal ring acceptability were compared to those from 16 women who used NuvaRing® as their contraceptive choice. RESULTS: Twenty-one (81%) clinical trial rings had contraceptive hormone levels within the range of those used as a contraceptive choice. Five returned rings had unused or discordant levels of residual contraceptive hormones. CONCLUSION: Residual vaginal ring drug levels could help assess adherence in clinical trials.

Weight gain, body image and sexual function in young patients treated with contraceptive vaginal ring. A prospective pilot study.

INTRODUCTION: Oral contraceptives could induce mood changes. As far as our knowledge, there are no studies in literature that have examined the role of vaginal contraception in self-perceived body image. AIM: To evaluate the effects of intravaginal contraception on weight gain and perceived body image in relation with the Beck's Depression Inventory questionnaire (BDI) and the McCoy Female Sexuality Questionnaire (MFSQ). METHODS: Twenty-one adult (18-35 years old) eumenorrheic (menstrual cycle of 25-35 days), lean (body mass index - BMI - of 19-25 kg/m2) women who were referred for hormonal contraception were administered the Stunkard Figure Rating Scale (FRS), BDI and MFSQ. Subjects were studied in basal condition and after 6 months of therapy with vaginal contraception (NuvaRing®; Organon-Schering-Plough Italia, Milan, Italy). MAIN OUTCOME MEASURES: BMI, FRS, MFSQ and BDI. RESULTS: After 6 months of therapy with NuvaRing®, both body weight (60.0 ± 8.3; p = 0.050) and BMI (22.1 ± 3.1; p = 0.028) slightly, but statistically, increased. FRS and BDI showed no differences after the vaginal contraception. Hormonal contraception was associated with a significant decrease in the two-factor Italian MFSQ score. CONCLUSIONS: Vaginal ring seems a good alternative to other hormonal contraceptive not significantly altering the female sexuality and not influencing the FRS and BDI.

Pharmacokinetic bioequivalence, safety and acceptability of Ornibel®, a new polymer composition contraceptive vaginal ring (etonogestrel/ethinylestradiol 11.00/3.474 mg) compared with Nuvaring® (etonogestrel/ethinylestradiol 11.7/2.7 mg).

OBJECTIVE: To show the clinical development of Ornibel® (ExeltisHealthcare, Spain) a contraceptive vaginal ring manufactured with a new polymer composition and containing etonogestrel/ethinylestradiol, compared to Nuvaring® (MSD, Spain). SUBJECTS AND METHODS: Randomised, single dose, 2-period, 2-sequence, 2-stage crossover, comparative bioavailability study conducted in 40 healthy female subjects. All subjects received both treatments for 28 days in each of two periods, separated by a 28 days washout. Ornibel® contains etonogestrel/ethinylestradiol 11.00/3.47 mg and Nuvaring® contains etonogestrel/ethinylestradiol 11.7/2.7 mg, both rings delivering 120/15 µg/day. For the calculation of pharmacokinetic parameters, 37 blood samples were collected up to 840 h after each ring insertion to quantify plasma concentrations of etonogestrel and ethinylestradiol using a validated MS/MS-HPLC. Safety was assessed by adverse events recording, clinical laboratory and vital signs and tolerability by vaginal examination. Acceptability was investigated by a 5-point scale questionnaire. RESULTS: Bioequivalence was demonstrated in the first stage as the 94.12% Confidence Intervals of the primary parameters laid within the 80-125% acceptance range for both etonogestrel (Cmax: 96.81-112.20%; AUC0-504h: 98.71-108.61%; AUC0-t: 100.14-109.10%) and ethinylestradiol. (Cmax: 105.91-120.62%; AUC0-504h: 105.47-114.59%; AUC0-t: 108.31-117.61%). During the first day of use a burst effect was observed with Nuvaring®, with significantly higher level of ethinylestradiol (Cmax0-24h ratio: 78.34%, 94.12CI: 73.55-83.45%). Both products were well tolerated and accepted, without significant differences between them. CONCLUSION: Ornibel® is bioequivalent to Nuvaring® in terms of efficacy, safety, tolerability and acceptability. The new polymer composition provides Ornibel® with more stability and gradual hormonal release during the first day of use, particularly for ethinylestradiol.

Efficacy and safety of the contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive in Chinese women: a 1-year randomised trial.

OBJECTIVES: The aim of the study was to assess the efficacy and tolerability of the monthly vaginal ring (NuvaRing; 15 µg ethinylestradiol [EE] and 120 µg etonogestrel per day) compared with a monophasic (21/7) combined oral contraceptive (COC) containing 30 µg EE and 3 mg drospirenone in healthy Chinese women aged 18-40 years. METHODS: This was a phase III, open-label, randomised multicentre trial conducted in China. Participants received NuvaRing or COC for 13 cycles (3 weeks of ring/pill treatment followed by a 1-week ring-free/pill-free period). Contraceptive efficacy was assessed by in-treatment pregnancies and expressed by the Pearl Index (PI; number of pregnancies/100 woman-years of use). Cycle control was assessed by unscheduled (breakthrough) and absence of scheduled (withdrawal) bleeding events. Safety and tolerability were assessed throughout the study. RESULTS: Participants were randomised either to the NuvaRing (n = 732) or to the COC (n = 214); 588 (82.4%) and 182 (78.4%) participants, respectively, completed the study. There were 10 in-treatment pregnancies in the NuvaRing group (PI 1.92; 95% confidence interval [CI] 0.92, 3.53) and five in the COC group (PI 3.12; 95% CI 1.01, 7.29). Breakthrough bleeding/spotting ranged from 18.6% (Cycle 1) to 4.2% (Cycle 11) for NuvaRing and from 21.6% (Cycle 1) to 7.9% (Cycle 11) for COC. Absence of withdrawal bleeding ranged from 8.6% (Cycle 1) to 3.0% (Cycle 11) for NuvaRing and from 14.6% (Cycle 1) to 6.4% (Cycle 5) for COC. For NuvaRing and COC, respectively, 26.6% and 25.0% of participants had treatment-related adverse events, and 7.0% and 9.1% discontinued the study as a result. CONCLUSIONS: Once-monthly NuvaRing is efficacious and safe for use in Chinese women.

Safety and efficacy of the NuvaRing® Applicator in healthy females: a multicenter, open-label, randomized, 2-period crossover study.

INTRODUCTION: We assessed performance and safety of the NuvaRing® Applicator. METHODS: We randomized women (18-45 years) to insert a placebo ring using the applicator or fingers-only and then vice versa. We assessed outcomes post-insertion and then 24-72 h later. RESULTS: Insertion was 100% successful using both methods (applicator, n=163; fingers-only, n=162). A total of 8.6% (applicator) and 4.3% (fingers-only) of subjects reported at least 1 treatment-related adverse event (AE); all were mild. Subjects reported 5 applicator-related AEs (vulvovaginal pain, 4; abdominal cramping, 1). There was no vaginal bleeding within 15 h post-applicator use. Ring expulsions were rare (applicator, 1; fingers-only, 2). CONCLUSION: NuvaRing Applicator is effective and well-tolerated (NCT02275546).

Comparison of combined hormonal vaginal ring with ultralow-dose combined oral contraceptive pills in the management of heavy menstrual bleeding: A pilot study.

The aim of this study was to compare combined hormonal vaginal ring with ultralow-dose combined oral contraceptive (COC) pills in management of heavy menstrual bleeding (HMB). Fifty patients were randomised into Group I: vaginal ring (n = 25) and group II: COC pills (n = 25). Menstrual blood loss (MBL) was assessed at baseline, 1, 3 and 6 months (while on treatment) and at 9 months (3 months after stopping therapy). There was significant reduction in baseline pictorial blood loss assessment chart (PBAC) score from 440 ± 188 (Mean ± SD) to 178 ± 95, 139 ± 117, 112 ± 84 and 120 ± 108 in group I and from 452 ± 206 to 204 ± 152, 179 ± 125, 176 ± 164 and 202 ± 167 in group II at 1, 3, 6 and 9 months, respectively (p = 0.001). Reduction in MBL was 72% and 62% at 6 months and up to 71% and 55% at 9 months in group I and group II, respectively (p = 0.001). Reduction in MBL with ring was greater at higher baseline PBAC score but lesser in patients with fibroid > 2 cm. Combined vaginal hormonal treatment for HMB is as effective as oral hormonal therapy, with minor and transient side effects and persistence of response after cessation of therapy.

Contraceptive Vaginal Rings: Do They Pose an Increased Risk of Venous Thromboembolism in Aesthetic Surgery?

UNLABELLED: Nuvaring (Organon, Kenilworth, NJ) is a vaginal contraception ring inserted by the patient. It was approved by the Food and Drug Administration in 2001 for the prevention of pregnancy. The intent of this paper is to increase the awareness of Nuvaring among plastic surgeons, and to explore the risks associated with its use. We report the cases of two cosmetic surgery patients. These patients developed deep venous thrombosis and pulmonary emboli in the postoperative period while using Nuvaring. The very advantages of the Nuvaring-the ease of use, the avoidance of daily administration, and the insertion and removal of the device by the patient-may lead to the failure of patients to recollect being on a vaginal ring for contraception. LEVEL OF EVIDENCE: 4 Risk.

Evaluating the efficacy and safety of a progestin- and estrogen-releasing ethylene vinyl acetate copolymer contraceptive vaginal ring.

INTRODUCTION: Multiple studies confirm the safety and efficacy of the combined ethinyl estradiol (EE) and etonogestrel contraceptive vaginal ring (NuvaRing®). Advantages of continuous drug delivery through the vagina compared to oral administration include stable levels of contraceptive steroids without the need for daily drug administration. Although the combined contraceptive vaginal ring (CCVR) avoids the problem of missed pills, clinical data do not support greater efficacy. Vaginal administration avoids first-pass hepatic effects; however, EE is a potent inducer of hepatic globulins regardless of the route of administration. Consequently, thromboembolic risk during CCVR use is similar to that with combined oral contraceptives. Some epidemiologic and database studies suggest that the risk of thromboembolism is increased among users of the CCVR compared to levonorgestrel-containing combined pills. AREAS COVERED: This review examined the available literature for level 1 and level 2 evidence of the CCVR and its associated efficacy and safety. Studies are presented in table format with significant findings and conclusions described. EXPERT OPINION: A prospective study with 33,235 woman-years of exposure and with greater ability to control for covariates did not demonstrate an elevation of risk. The safety profile of the CCVR appears to be the same as with other combined hormonal contraceptives.

Cerebral venous sinus thrombosis in the setting of combined vaginal contraception.

We present a case of a 27-year-old women admitted to the hospital with migraine and left upper extremity weakness. Subsequent imaging with computed tomography and magnetic resonance angiography/venography demonstrated an acute-appearing central venous sinus thrombosis. Her only risk factor for venous thromboembolism (VTE) was the use of etonogestrel/ethinyl estradiol vaginal contraceptive ring (NuvaRing). The contraceptive ring was removed and the patient was treated according to the current guidelines. She achieved full neurologic recovery at 6 months' follow-up. Here, we describe this unusual case and review the risk of VTE between combined vaginal contraception and combined oral contraception.

Desogestrel-only contraceptive pill versus sequential contraceptive vaginal ring in the treatment of rectovaginal endometriosis infiltrating the rectum: a prospective open-label comparative study.

OBJECTIVE: To compare the efficacy of two hormonal therapies in treating symptoms caused by bowel endometriosis. DESIGN: Patient preference study. SETTING: University hospital. POPULATION: A total of 143 women with rectovaginal endometriosis infiltrating the rectum. METHODS: This study was performed between January 2008 and June 2011. Patients were treated with a desogestrel-only contraceptive pill or with the sequential combined contraceptive vaginal ring for 12 months. MAIN OUTCOME MEASURES: The primary endpoint of the study was the rate of satisfied patients at 12-month follow up. The changes in symptoms and in the volume of the nodules were secondary endpoints. RESULTS: At 12-month follow up, the rate of satisfied patients was higher in the group treated with the desogestrel-only contraceptive pill than in the group treated with the sequential combined contraceptive vaginal ring (p = 0.004). When only changes in gastrointestinal symptoms were considered, 50% of patients treated with the desogestrel-only contraceptive pill and 31.3% of those treated with the sequential combined contraceptive vaginal ring were satisfied (p = 0.037). The reduction in the volume of the nodules, the percentages of patients who discontinued the therapy after the completion of the study and of those who decided to undergo surgery were similar between the two groups. CONCLUSIONS: Both hormonal therapies are efficacious in treating symptoms caused by rectovaginal endometriosis infiltrating the rectum. Patient satisfaction is higher with the desogestrel-only pill than with a vaginal ring.

Cardiovascular risk associated with the use of an etonogestrel-containing vaginal ring.

OBJECTIVE: To compare the risks of short-term and long-term use of an etonogestrel-containing and ethinylestradiol-containing vaginal ring and combined oral contraceptive pills (OCPs) in a routine clinical study population. METHODS: This was a prospective, controlled, noninterventional cohort study performed in the United States and five European countries with the following two cohorts: new users of the vaginal ring and new users of combined OCPs (starters, switchers, or restarters). The study population included 33,295 users of the vaginal ring or combined OCPs recruited by 1,661 study centers. Follow-up of study participants occurred for 2 to 4 years. Main clinical outcomes of interest were cardiovascular outcomes, particularly venous and arterial thromboembolism. These outcomes were validated by attending physicians and further adjudicated by an independent board. Comprehensive follow-up ensured low loss to follow-up. Statistical analyses were based on Cox regression models. Primary statistical variable was the venous thromboembolic hazard ratio (HR) for the vaginal ring compared with combined OCPs. RESULTS: Study participants were followed-up for 66,489 woman-years. Loss to follow-up was 2.9%. The venous thromboembolism incidence rates for the vaginal ring users and combined OCPs users were 8.3 and 9.2 per 10,000 woman-years, respectively. Cox regression analysis yielded crude and adjusted HRs for the vaginal ring users compared with combined OCPs users of 0.9 and 0.8 for venous thromboembolism (95% confidence intervals [CIs] 0.5-1.6 and 0.5-1.5) and 0.8 and 0.7 (95% CIs 0.2-2.5 and 0.2-2.3) for arterial thromboembolism, respectively. CONCLUSION: Vaginal ring use and combined OCP use were associated with a similar venous and arterial thromboembolic risk during routine clinical use. LEVEL OF EVIDENCE: : II.