Anita L. Nelson

Randomised controlled trial of prophylactic antibiotics before insertion of intrauterine devices

Summary Background The value of antibiotic prophylaxis before insertion of an intrauterine device (IUD) remains uncertain. We undertook a triple-masked, randomised, placebo-controlled trial to find out whether such prophylaxis reduces the rate of IUD removal within 90 days. Methods 11 clinic sites in southern California enrolled women who requested IUD insertion and were at low risk of sexually transmitted infection according to self-reported medical history. We randomly assigned 1985 participants either 500 mg azithromycin or placebo capsules of identical appearance taken about 1 h before insertion of a Copper T 380A IUD. 118 women did not have an IUD inserted. We followed up 1833 of the remaining 1867 (98%) participants for at least 90 days after insertion. Findings The rate of IUD removal for any reason other than partial expulsion was 3·8% (35/918) in the antibiotic group and 3·4% (31/915) in the placebo group (relative risk 1·1 [95% Cl 0·7–1·8]). The two treatment groups sought medical attention with equal frequency (mean 38 visits per 100 women). During the 90 days after IUD insertion, only one woman from each assignment group had salpingitis, as defined by established criteria. Interpretation Prophylaxis with azithromycin did not affect the likelihood that a woman would retain her IUD at 90 days or the frequency of postinsertion medical attention. In appropriately screened women, the risk of upper-genitaltract infection is negligible after IUD insertion, with or without the administration of prophylactic antibiotics.

Two low-dose levonorgestrel intrauterine contraceptive systems: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of two low-dose levonorgestrel intrauterine contraceptive systems. METHODS: Nulliparous and parous women aged 18−35 years with regular menstrual cycles (21−35 days) requesting contraception were randomized to 3 years of treatment with one of two levonorgestrel intrauterine contraceptive systems: 13.5 mg total content or 19.5 mg total content. The primary outcome was the pregnancy rate, calculated as the Pearl Index. RESULTS: Overall, 1,432 and 1,452 women in the 13.5 mg intrauterine contraceptive system and 19.5 mg intrauterine contraceptive system groups, respectively, had a placement attempted and were included in the full analysis set to evaluate efficacy and safety. Mean (standard deviation) age was 27.1 (4.8) years; 39.2% were nulliparous. Over the 3-year study period, 0.33 pregnancies per 100 women-years (95% confidence interval [CI] 0.16–0.60) were observed with the 13.5 mg intrauterine contraceptive system compared with 0.31 per 100 women-years (95% CI 0.15–0.57) with the 19.5 mg intrauterine contraceptive system. Kaplan-Meier estimates for that period were 0.009 and 0.010, respectively. At least partial expulsions occurred in 4.56% and 3.58% and discontinuation rates resulting from a reported adverse event occurred in 21.9% and 19.1%, respectively. Ten of the 20 pregnancies were ectopic. Serious adverse events included six cases of pelvic inflammatory disease and one partial uterine perforation. CONCLUSIONS: Both lower-dose levonorgestrel intrauterine contraceptive systems were highly effective for 3 years of use and generally well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00528112. LEVEL OF EVIDENCE: I

Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections

BACKGROUND Depot medroxyprogesterone acetate (DMPA) is a highly effective progestin-only contraceptive that is widely used by adolescents. We investigated bone mineral density (BMD) changes in female adolescents during and following use of this method. STUDY DESIGN A multicenter, prospective, non-randomized observational study in 98 healthy female adolescents aged 12-18 years who initiated DMPA intramuscular injections for contraception and provided BMD data for up to 240 weeks while receiving DMPA and for up to 300 weeks after DMPA cessation. BMD at the lumbar spine (LS), total hip (TH) and femoral neck (FN) was assessed by dual-energy X-ray absorptiometry. A mixed model analysis of variance was used to examine BMD changes. RESULTS At the time of their final DMPA injection, participants had mean BMD declines from baseline of 2.7% (LS), 4.1% (TH) and 3.9% (FN) (p<.001 at all three sites). Within 60 weeks of discontinuation of DMPA, mean LS BMD had returned to baseline levels, and 240 weeks after DMPA discontinuation, the mean LS BMD was 4.7% above baseline. Mean TH and FN BMD values recovered to baseline values more slowly: 240 weeks and 180 weeks, respectively, after the last DMPA injection. CONCLUSIONS BMD loss in female adolescents receiving DMPA for contraception is substantially or fully reversible in most girls following discontinuation of DMPA, with faster recovery at the LS than at the hip.

Real-world patterns of prescription refills for branded hormonal contraceptives: a reflection of contraceptive discontinuation.

OBJECTIVE: The objective was to describe timely refills of hormonal contraceptive products among a large, geographically diverse population of U.S. women as an estimate of method continuation over time. METHODS: Longitudinal prescription refills from the Verispan database were collected from 99% of retail pharmacies in the United States between October 2003 and August 2005 for specific branded hormonal contraceptives. We calculated refill rates for different contraceptive categories, for individual products, and for different age groups. RESULTS: Refill data were available for nearly 1.7 million women for 240 days and for almost 1 million women for 420 days. After 30 days, only 59.4–75.1% of women refilled their prescriptions for the various products on a timely basis. By 3 months, only 47.7–61.2% of women returned for timely refills. By 12 months, only 16.3–34.5% of women had consistently refilled their prescriptions. Very young women had refill rates for most methods that were at least as good as those of older women. CONCLUSION: These low rates of timely refill rates in actual practice indicate that few women had the potential for correct and consistent contraceptive use. New methods with extended cycles or a new progestin had higher rates than did other 28-day products. These high discontinuation rates suggest that barriers to successful utilization of contraceptives exist, and they highlight the need to routinely provide condoms and emergency contraception to women initiating hormonal contraception. LEVEL OF EVIDENCE: II

Comparison of once-daily and twice-daily dosing of 0.75% metronidazole gel in the treatment of bacterial vaginosis.

BACKGROUND AND OBJECTIVES Bacterial vaginosis is the most common cause of vaginal symptoms in women and has potential complications. Efforts to improve treatment of this disease process are warranted. GOAL OF THIS STUDY The goal of this study was to compare the safety and efficacy of once-daily intravaginal administration of 0.75% metronidazole gel for 5 days to the established twice-daily regimen in the treatment of bacterial vaginosis. STUDY DESIGN Nonpregnant women with bacterial vaginosis diagnosed by accepted clinical criteria at 14 geographically diverse general gynecology clinics were enrolled in this prospective, randomized, investigator-blind, parallel study. They were treated with either once-daily or twice-daily 0.75% metronidazole gel 5 g intravaginally for 5 days and were reevaluated at 7 to 12 days and 28 to 35 days after completing treatment. Efficacy was determined by clinical criteria. Adverse drug reactions were monitored. RESULTS Of the 514 evaluable women enrolled, bacterial vaginosis was cured at the first return visit among evaluable patients in 153 of 199 (77%) of those who received the once-daily and in 157 of 196 (80%) of those who received the twice-daily administration. Bacterial vaginosis was cured among evaluable patients at the final visit in 104 of 180 (58%) of those who received once-daily and 109 of 178 (61%) of those who received the twice-daily regimen. Intent-to-treat analysis showed cure at 1 month in 118 of 207 (57%) of those treated once daily and 129 of 209 (62%) of those treated twice daily. Side effects were mild, and none caused treatment discontinuation. CONCLUSIONS Once-daily dosing of 0.75% metronidazole gel 5 g for 5 days yields efficacy, safety, and tolerance equivalent to the currently used twice-daily dosing in the treatment of bacterial vaginosis, adding another competitive choice to the available therapeutic options for this condition.

Breakage and acceptability of a polyurethane condom: a randomized, controlled study.

CONTEXT Although the first commercial polyurethane condom was approved for use several years ago, no U.S. clinical trial has compared its performance to that of the latex condom. METHODS In a masked crossover study, 360 couples were randomized to use three polyurethane condoms and three latex condoms. After each use, couples recorded condom breaks, condom slips and other aspects of performance. At completion of the study, couples compared the sensitivity, ease of use, fit and lubrication of the two types of condoms. RESULTS The clinical breakage rate of the polyurethane condom was 7.2%, compared with 1.1% for the latex condom (relative risk of 6.6, 95% confidence interval of 3.5-12.3). The complete slippage rate (combining incidents during intercourse and withdrawal) of the polyurethane condom was 3.6%, compared with 0.6% for the latex condom (relative risk of 6.0, 95% confidence interval of 2.6-14.2). Most male users preferred the sensitivity provided by the polyurethane condom to that of the latex condom. CONCLUSIONS The clinical breakage rate of the polyurethane condom is significantly higher than that of the latex condom. However, nearly half of the users preferred the polyurethane condom, which provides an option for couples who have rejected conventional condoms or who cannot use latex products.

Use of prostate-specific antigen (PSA) to measure semen exposure resulting from male condom failures: implications for contraceptive efficacy and the prevention of sexually transmitted disease

Accurate measurement of semen exposure resulting from condom failures can refine public health messages and improve predictions of condom efficacy in preventing pregnancy and HIV transmission. Eight hundred and thirty couples enrolled in a condom efficacy study were asked to collect a baseline sample of ejaculate from the inside of the first study condom they used and to collect a postcoital vaginal sample whenever a study condom broke or slipped off during intercourse. All samples were quantitatively tested for prostate-specific antigen (PSA), a substance found only in human semen, using rocket immunoelectrophoresis, and inspected microscopically for presence of sperm. Sixty-eight baseline ejaculate samples collected from the inside of the first study condom by couples who subsequently experienced a condom failure averaged 13.4 microg PSA per swab and 79% of the samples averaged one or more sperm per high power field (hpf). Seventy-nine postcoital vaginal samples obtained after a condom break averaged 5.7 microg PSA per swab and only 38% averaged one or more sperm per hpf. The PSA results indicated a 50% reduction in semen exposure compared to baseline levels (p = 0.0001). Seventeen samples obtained after a condom slip-off averaged 2.5 microg PSA per swab and none of the samples averaged one or more sperm per hpf. The PSA results indicated an 80% reduction in semen exposure compared to baseline levels (p = 0.0001). Our results suggest that even condoms that fail reduce the risk of pregnancy and the transmission of sexually transmitted disease compared to unprotected intercourse. We also used PSA results to adjust a model designed to predict consistent-use pregnancy rates from condom breakage and slippage data.

Evaluation of prostate-specific antigen as a quantifiable indicator of condom failure in clinical trials

The ability of condoms to retain all elements of semen during intercourse has been assessed by postcoital visual inspection and in vitro permeability studies. Yet, these observations may not be sufficiently precise or realistic. This pilot study evaluated prostate-specific antigen (PSA) as a semen marker of inapparent failure of the condom barrier under conditions of actual use. Twelve couples collected samples from the vagina and surfaces of the condom using sterile cotton swabs. We obtained precoital and postcoital samples for 24 acts of unprotected intercourse, 54 acts of intercourse using intact condoms, and 40 acts of intercourse using condoms that had been deliberately punctured. We used electrophoresis to determine the amount of PSA present in the samples. PSA was detected in 100% (24/24) of vaginal samples collected immediately after unprotected intercourse and in none of the vaginal samples collected more than 24 h after intercourse (0/90). PSA was also present in 98% (83/85) of the samples collected from the inside of the condom that had failed during intercourse. Excluding uses where the condom failed during intercourse, PSA was detected in 2% (1/47) of the postcoital vaginal samples collected after use of intact condoms and in 41% (14/34) of the samples collected after use of condoms with known 1-mm punctures. We conclude that PSA shows great promise as a semen biomarker in clinical trials of barrier methods. We recommend that future studies further investigate the ability of this biomarker to identify condom failures and quantify the extent of semen exposure associated with various types of condom failures.

Breast Cancer Chemoprevention Tamoxifen: Current Issues and Future Prospective

Intervention clinical trials are under way to address whether tamoxifen can prevent breast cancer development. This effort is based on laboratory evidence that tamoxifen interferes with the initiation and promotion of mammary cancer, clinical evidence of decreased breast cancer incidence in the opposite breast of women participating in tamoxifen adjuvant breast cancer trials, and a favorable toxicity profile of tamoxifen providing reasonable assurance of drug safety when used in a population without cancer. The apparently favorable effects of tamoxifen on lipid metabolism and bone mineral density provide additional impetus to this evaluation. Potentially life threatening toxicity of thromboembolism and development of a second cancer remain concerns. With respect to implications of such clinical trials, even upon successful study completion, difficult issues will remain; these issues include the potential for interaction between tamoxifen and dietary fat reduction (also proposed as potential breast cancer prevention), the cost and cost‐effectiveness of wide scale (or selective) implementation of positive results, and the generalizability of study results to socioeconomically disadvantaged and racial and ethnic minority populations that historically have been under‐represented in medical clinical trials. These important issues should be addressed concurrently as large‐scale prevention trials go forward to optimize the practical utility of efficacy data obtained.

Global fee prohibits postpartum provision of the most effective reversible contraceptives.

Early postpartum access to highly effective reversible contraceptives (intrauterine contraceptives (IUCs) and the implant) and sterilization is key to helping women prevent unintended pregnancy.[1] Yet most current hospital reimbursement policies deny postpartum women access to IUCs and implants prior to hospital discharge. For women whose deliveries are covered by private insurance or Medicaid, hospitals receive a global fee based on the diagnosis-related group (DRG) for all delivery-related care. Postpartum sterilization is carved out by insurance companies and Medicaid as a procedure that may be billed separately from the global fee, which in turn means that hospitals are not financially driven to deny such procedures. In contrast, in most states, postpartum IUCs and implants are not carved out for separate reimbursement and the costs of the devices must be deducted from the DRG payment. Since the wholesale acquisition costs for IUCs and implants range from