Bleeding changes after levonorgestrel 52-mg intrauterine system insertion for contraception in women with self-reported heavy menstrual bleeding.

BackgroundThe levonorgestrel 52-mg intrauterine system has proven efficacy for heavy menstrual bleeding treatment in clinical trials, but few data exist to demonstrate how rapidly the effects occur and the effects in women with self-reported heavy bleeding, as seen commonly in clinical practice.ObjectiveEvaluate changes in bleeding patterns in women with self-reported heavy menstrual bleeding before levonorgestrel 52-mg intrauterine system insertion.Study designA total of 1714 women aged 16-45 years old received a levonorgestrel 52-mg intrauterine system in a multicenter trial evaluating contraceptive efficacy and safety for up to 10 years. At screening, participants described their baseline menstrual bleeding patterns for the previous 3 months. Participants completed daily diaries with subjective evaluation of bleeding information for the first 2 years. For this analysis, we included women with at least 1 complete 28-day cycle of intrauterine system use and excluded women using a hormonal or copper intrauterine contraception in the month prior to study enrollment. We evaluated changes in menstrual bleeding and discontinuation for bleeding complaints per 28-day cycle over 26 cycles (2 years) in women who self-reported their baseline pattern as heavy. We also compared rates of amenorrhea, defined as no bleeding or spotting, within the entire study population in women with subjective heavy menstrual bleeding at baseline compared with those who did not complain of heavy menstrual bleeding.ResultsOf the 1513 women in this analysis, 150 (9.9%) reported baseline heavy menstrual bleeding. The majority of women reported no longer experiencing heavy menstrual bleeding by the end of cycle 1 (112/150, 74.7%) with even greater rates by cycle 2 (124/148, 83.8%). At the end of cycles 6, 13, and 26, 129 of 140 (92.1%; 95% confidence interval, 87.7%-96.6%), 114 of 123 (92.7%; 95% confidence interval, 88.1%-97.3%), and 100 of 103 (97.1%; 95% confidence interval, 93.8%-100%) women reported no heavy menstrual bleeding, respectively. After cycles 13 and 26, 63 of 123 (51.2%; 95% confidence interval, 42.4%-60.1%) and 66 of 103 (64.1%; 95% confidence interval, 54.8%-73.3%), respectively, reported their bleeding as amenorrhea or spotting only. A lower proportion of women with baseline self-reported heavy menstrual bleeding reported amenorrhea as compared with women in the overall study cohort without heavy menstrual bleeding at the end of 6 cycles (319 [25.5%] vs 21 [15.0%], P=.005) and 13 cycles (382 [34.4%] vs 26 [21.1%], P=.003); differences were not significant after 19 cycles (367 [37.2%] vs 36 [31.0%], P=.022) and 26 cycles (383 [43.5%] vs 38 [36.9%], P=.21). Only 4 (2.7%) women with baseline heavy menstrual bleeding discontinued for bleeding complaints (2 for heavy menstrual bleeding and 2 for irregular bleeding), all within the first year.ConclusionMost women who self-report heavy menstrual bleeding experience significant improvement quickly after levonorgestrel 52-mg intrauterine system insertion. Discontinuation for bleeding complaints among women with baseline heavy menstrual bleeding is very low

Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system

AbstractObjectiveTo assess 3-year data on the efficacy and safety of a new 52-mg levonorgestrel intrauterine contraceptive (LNG20) designed for up to 7 years use.Study DesignNulliparous and parous women aged 16–45 years at enrollment with regular menstrual cycles and requesting contraception were enrolled in an open-label, partially randomized trial to evaluate LNG20. The primary outcome was pregnancy rate for women aged 16–35 years calculated as the Pearl Index. Women aged 36–45 years received LNG20 for safety evaluation only. All participants had in-person or phone follow-up approximately every 3 months during the study.ResultsA total of 1600 women aged 16–35 years and 151 women aged 36–45 years agreed to LNG20 placement, including 1011 (57.7%) nulliparous and 438 (25.1%) obese women. Successful placement occurred in 1714 (97.9%) women. Six pregnancies occurred, four of which were ectopic. The Pearl Index for LNG20 was 0.15 (95% CI 0.02–0.55) through Year 1, 0.26 (95% CI 0.10–0.57) through Year 2, and 0.22 (95% CI 0.08–0.49) through Year 3. The cumulative life-table pregnancy rate was 0.55 (95% CI 0.24–1.23) through 3 years. Expulsion was reported in 62 (3.5%) participants, most (50 [80.6%]) during the first year of use. Of women who discontinued LNG20 and desired pregnancy, 86.8% conceived spontaneously within 12 months. Pelvic infection was diagnosed in 10 (0.6%) women. Only 26 (1.5%) LNG20 users discontinued due to bleeding complaints.ConclusionThe LNG20 intrauterine system is highly effective and safe over 3 years of use in nulliparous and parous women.Implications statementA new 52-mg levonorgestrel-releasing intrauterine system is effective and safe for nulliparous and parous women for at least 3 years

Ekpyrotic collapse with multiple fields

A scale invariant spectrum of isocurvature perturbations is generated during collapse in the scaling solution in models where two or more fields have steep negative exponential potentials. The scale invariance of the spectrum is realised by a tachyonic instability in the isocurvature field. We show that this instability is due to the fact that the scaling solution is a saddle point in the phase space. The late time attractor is identified with a single field dominated ekpyrotic collapse in which a steep blue spectrum for isocurvature perturbations is found. Although quantum fluctuations do not necessarily to disrupt the classical solution, an additional preceding stage is required to establish classical homogeneity.Comment: 13 pages, 1 figur

Dose-finding study of a 90-day contraceptive vaginal ring releasing estradiol and segesterone acetate.

ObjectiveTo evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism.Study designWe conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40 pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information.ResultsSixty-five participants enrolled in E2 75 (n = 22), 100 (n = 21), and 200 (n = 22) mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100 mcg/day groups were <40 pg/mL. In the 200 mcg/day group, median E2 concentrations peaked on days 4-5 of CVR use at 194 pg/mL (range 114-312 pg/mL) and remained >40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28-62 pg/mL) on days 88-90 (n = 11). Among the E2 200 mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0-16) and three (range 0-19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days.ConclusionsEstradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use.ImplicationsA 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation

Curvature perturbations from ekpyrotic collapse with multiple fields

A scale-invariant spectrum of isocurvature perturbations is generated during collapse in the ekpyrotic scaling solution in models where multiple fields have steep negative exponential potentials. The scale invariance of the spectrum is realized by a tachyonic instability in the isocurvature field. This instability drives the scaling solution to the late time attractor that is the old ekpyrotic collapse dominated by a single field. We show that the transition from the scaling solution to the single field dominated ekpyrotic collapse automatically converts the initial isocurvature perturbations about the scaling solution to comoving curvature perturbations about the late-time attractor. The final amplitude of the comoving curvature perturbation is determined by the Hubble scale at the transition.Comment: 15 pages, 3 figures, a reference added, to be published in CQG, a remark on the comoving density perturbation correcte

Validity of self-reported history of Chlamydia trachomatis infection

BACKGROUND: Chlamydia trachomatis infection is common and largely asymptomatic in women. If untreated, it can lead to sequelae such as pelvic inflammatory disease and infertility. It is unknown whether a patient's self-reported history of Chlamydia trachomatis infection is a valid marker of past infection. OBJECTIVE: Our objective was to evaluate the validity of women's self-reported history of Chlamydia trachomatis infection compared with Chlamydia trachomatis serology, a marker for previous infection. STUDY DESIGN: We analyzed data from the Fertility After Contraception Termination study. We compared participants' survey responses with the question, "Have you ever been told by a health care provider that you had Chlamydia?" to serological test results indicating the presence or absence of antibodies to Chlamydia trachomatis as assessed by a microimmunofluorescence assay. Prevalence of past infection, sensitivity, specificity, predictive values, and likelihood ratios were calculated. The Cohen's kappa statistic was computed to assess agreement between self-report and serology. RESULTS: Among 409 participants, 108 (26%) reported having a history of Chlamydia trachomatis infection, whereas 146 (36%) had positive serological test results. Relative to positive microimmunofluorescence assay, the sensitivity and specificity of self-reported history of Chlamydia trachomatis infection were 52.1% (95% confidence interval, 43.6-60.4%) and 87.8% (95% confidence interval, 83.3-91.5%), respectively. The positive predictive value of the self-report was 70.4% (95% confidence interval, 60.8-78.8%), and the negative predictive value was 76.7% (95% confidence interval, 71.6-81.4%). The likelihood ratio was found to be 4.28. Agreement between self-report and serology was found to be moderate (kappa = 0.42, P < .001). CONCLUSION: Self-reported history of Chlamydia trachomatis infection commonly yields false-negative and false-positive results. When definitive status of past Chlamydia trachomatis infection is needed, serology should be obtained

The New Deal: jeopardised by the geography of unemployment?

The New Deal is the Labour government's flagship programme to "end the tragic waste of youth and long-term unemployment" by getting people off welfare benefits and into work. This paper argues that the principal weakness of the New Deal is that it seeks to influence the character of labour supply (i.e. the motivation and skills of the unemployed) while neglecting the state of labour demand, which varies greatly between places. The uneven geography of unemployment in the UK is likely to have a crucial bearing on the programme's impact and effectiveness, but this has been largely ignored in its development. The paper outlines some of the practical consequences of this imbalance and suggests how it could be rectified for the programme to be more effective

Intrauterine device use, sexually transmitted infections, and fertility: a prospective cohort study

Background In the 1970s, numerous medical reports, media coverage, and litigation around the Dalkon Shield intrauterine device led to a perception that all intrauterine devices cause upper genital tract infection and infertility. Objective This study aimed to assess the association between intrauterine device use and time to conception. Study Design The Fertility After Contraceptive Termination Study is a multicenter, prospective cohort study of women stopping their contraceptive method to attempt conception. We recruited participants between 2011 and 2017. Participants were a convenience sample of women recruited from academic centers in Philadelphia, PA; Los Angeles, CA; St. Louis, MO; Indianapolis, IN; Aurora, CO; and Salt Lake City, UT. Women were eligible if they stopped their contraceptive method within the past 120 days before enrollment, were between 18 and 35 years of age, had no history of infertility or sterilization, and had at least 6 months of follow-up. Baseline data included demographic and reproductive characteristics, past contraceptive use, nucleic acid amplification testing for sexually transmitted infections, and serology for past infection with Chlamydia trachomatis, Trichomonas vaginalis, and Mycoplasma genitalium. The primary exposure was intrauterine device use (ever); the primary outcome was time to conception. All participants were observed longitudinally for up to 24 months. We used piecewise exponential proportional hazards models with multiple imputation to provide hazard ratios and their respective 95% confidence intervals. Results Of the 461 participants, mean age was 28.2 years, 178 (38.7%) were Black, 157 (34.1%) were considered as low socioeconomic status, and 275 (59.7%) had a history of intrauterine device use. Without adjusting for any covariates, the median time to conception was shorter for participants who had a history of intrauterine device use (5.1 months) than participants who never used an intrauterine device (7.5 months). After controlling for potential confounders, the association of past intrauterine device use with time to conception was not statistically significant (adjusted hazard ratio, 1.25; 95% confidence interval, 0.99–1.58). In our multivariable model, age, nulligravidity, Black race, low socioeconomic status, and past Mycoplasma genitalium infection were associated with longer times to conception (hazard ratio, 0.76; 95% confidence interval, 0.58–0.99). Conception by 12 months was lower in participants with past Mycoplasma genitalium infection (68% vs 80% without past infection; P=.019). Conclusion We found no impairment of fertility with ever use of an intrauterine device. Serologic evidence of past Mycoplasma genitalium infection was associated with longer times to conception and higher rates of infertility. Mycoplasma genitalium infection is a potential modifiable cause of infertility

Multiple Inflation, Cosmic String Networks and the String Landscape

Motivated by the string landscape we examine scenarios for which inflation is a two-step process, with a comparatively short inflationary epoch near the string scale and a longer period at a much lower energy (like the TeV scale). We quantify the number of $e$-foldings of inflation which are required to yield successful inflation within this picture. The constraints are very sensitive to the equation of state during the epoch between the two inflationary periods, as the extra-horizon modes can come back inside the horizon and become reprocessed. We find that the number of $e$-foldings during the first inflationary epoch can be as small as 12, but only if the inter-inflationary period is dominated by a network of cosmic strings (such as might be produced if the initial inflationary period is due to the brane-antibrane mechanism). In this case a further 20 $e$-foldings of inflation would be required at lower energies to solve the late universe's flatness and horizon problems.Comment: 27 pages, 6 figures; v2: refences adde

Distinguishing Causal Seeds from Inflation

Causal seed models, such as cosmological defects, generically predict a distinctly different structure to the CMB power spectrum than inflation, due to the behavior of the perturbations outside the horizon. We provide a general analysis of their causal generation from isocurvature initial conditions by analyzing the role of stress perturbations and conservation laws in the causal evolution. Causal stress perturbations tend to generate an isocurvature pattern of peak heights in the CMB spectrum and shift the first compression, i.e.~main peak, to smaller angular scales than in the inflationary case, unless the pressure and anisotropic stress fluctuations balance in such a way as to reverse the sense of gravitational interactions while also maintaining constant gravitational potentials. Aside from this case, these causal seed models can be cleanly distinguished from inflation by CMB experiments currently underway.Comment: 22pgs, revtex, 5 figs.; revision clarifies discussion of astro-ph/9604172, includes new supporting sections on assumptions and anisotropic stresses, and discusses astro-ph/9607109; main conclusions unchanged; supporting material at http://www.sns.ias.edu/~wh