Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study.

BACKGROUND: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2) doses. STUDY DESIGN: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. RESULTS: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (Cmax) 918 pg/mL; time to maximum concentration (Tmax) 3.5 h. For E2, the Cmax occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment. CONCLUSION: PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. IMPLICATIONS: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.

Risk of Chlamydia trachomatis infection during pregnancy: effectiveness of guidelines-based screening in identifying cases.

Our goal was to define the risk factors for Chlamydia trachomatis (CT) infection among pregnant women at a large urban medical centre. In a retrospective study, clinical records at a US maternity unit from July 2005 through February 2008 were reviewed. The study population included all pregnant women with a singleton newborn of at least 20 weeks gestation and antenatal care information. Logistic regression was used to analyse the association between a positive CT test and demographic, behavioural and prenatal care variables. A total of 2127 women were included in this analysis. The prevalence of CT infection was 4.7%. Cases were more likely to be younger, black and single. Other risk factors included tobacco use and Neisseria gonorrhoeae infection. Our findings suggest that factors other than age may impact upon the diagnosis of CT in pregnant women and that a more comprehensive testing strategy should be considered.

Chlamydia trachomatis infection during pregnancy and the risk of preterm birth: a case-control study.

Our goal was to define the risks of preterm birth associated with Chlamydia trachomatis (CT) and other sexually transmitted infections (STIs) among pregnant women. We accessed clinical records from July 2005 to February 2008. The study population included all pregnant women who gave birth to a singleton newborn of at least 20 weeks' gestation, and who had antenatal care information. We estimated the impact of CT and other STI on the odds of preterm birth using logistic regression. Overall, 2127 women were included in this analysis. The prevalence of CT infection was 4.7%. CT diagnosis was not associated with preterm birth. In conclusion, this study did not find an association between CT and preterm birth. The lack of an association may be explained by early treatment. Future studies evaluating the timing of screening for STIs may help clarify whether pregnant women would benefit more from earlier screening.

Successful use of oral contraceptives.

Typical failure rates for oral contraceptives remain much higher than ideal failure rates. Patients can cite the pill's perceived risks more readily than its benefits, and many women use oral contraceptives inconsistently or discontinue them entirely without a medical reason. Successful use of oral contraceptives mandates that we rethink our roles as providers. Medical barriers, such as mandatory pelvic examinations, impede clients' access to services and require reevaluation. Efforts must also focus on thorough, individualized counseling. Because compliance poses difficulties for many women and noncompliance results in reduced efficacy, counseling must address content points relevant to proper, consistent use. Additionally, as unexpected side effects often cause frustration and method discontinuation, counseling should anticipate their occurrence. Adolescents present additional challenges. However, with careful attention to concerns relevant to teenage women and consideration of obstacles to compliance, oral contraceptives can indeed be used successfully in this group. Regardless of age, all clients should receive information regarding emergency contraception, and instructions for pill use should be individualized to meet the needs of each patient.

The repeatability of serum carotenoid, retinoid, and tocopherol concentrations in specimens of blood collected 15 years apart.

Community-wide programs to collect blood for a research serum bank were carried out in Washington County, Maryland in 1974 and 1989. Of the 8395 persons who participated in both programs, 64 were controls in a nested case-control study of the association of antioxidant micronutrients with subsequent breast cancer, and 30 and 166 were controls in similar studies of lung and prostate cancer. Assay results for five carotenoids, two retinoids, and two tocopherols in samples of blood collected 15 years apart were thus available for comparisons of micronutrient concentrations. The mean Spearman rank order correlation coefficient for all comparisons was 0.44, with two coefficients greater than 0.60 and two less than 0.30. Blood pressure readings at the two blood collections had a mean rank order correlation coefficient of 0.46. Because blood pressure readings in 1974 were shown to be significantly predictive of atherosclerosis 15-18 years later, the present results suggest that ranked concentrations of antioxidant micronutrients from a single sample are sufficiently representative to be used as predictors of subsequent concentrations and are thus suitable for assessment as risk factors for subsequent illnesses.

Controlled trial of the effect of length, incentives, and follow-up techniques on response to a mailed questionnaire.

Mailed questionnaires are an economical method of data collection for epidemiologic studies, but response tends to be lower than for telephone or personal interviews. As part of a follow-up study of volunteers who provided a brief health history and blood sample for a blood specimen bank in 1989, the authors conducted a controlled trial of the effect of length, incentives, and follow-up techniques on response to a mailed questionnaire. Interventions tested included variations on length of the questionnaire, effect of a monetary incentive, and effect of a postcard reminder versus a letter accompanied by a second questionnaire. Response was similar for the short (16-item, 4-page) and long (76-item, 16-page) questionnaire groups. The non-monetary [corrected] incentive did not improve the frequency of response. The second mailing of a questionnaire was significantly better than a postcard reminder in improving responses (23% vs. 10%). It is important to systematically test marketing principles to determine which techniques are effective in increasing response to mailed questionnaires for epidemiologic studies.

The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity.

Lung cancer cases diagnosed during the period 1975 through 1993 and matched controls were identified in the rosters of Washington County, Maryland residents who had donated blood for a serum bank in 1974 or 1989. Plasma from participants in the 1989 project was assayed for ascorbic acid; serum or plasma was assayed for participants in either project for alpha- and beta-carotene, cryptoxanthin, lutein/zeaxanthin, lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Among the total group of 258 cases and 515 controls, serum/plasma concentrations were significantly lower among cases than controls for cryptoxanthin, beta-carotene, and lutein/zeaxanthin with case-control differences of -25.5, -17.1, and -10.1%, respectively. Modest nonsignificant case-control differences in a protective direction were noted for alpha-carotene and ascorbic acid. There were only trivial differences for lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Findings are reported for males and females and for persons who had never smoked cigarettes, former smokers, and current smokers at baseline. These results and those from previous studies suggest that beta-carotene is a marker for some protective factor(s) against lung cancer; that cryptoxanthin, alpha-carotene, and ascorbic acid need to be investigated further as potentially protective factors or associates of a protective factor; and that lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity are unlikely to be associated with lung cancer risk. Until specific preventive factors are identified, the best protection against lung cancer is still the avoidance of airborne carcinogens, especially tobacco smoke; second best is the consumption of a diet rich in fruits and vegetables.

Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVES: Because oxidative damage has been implicated in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus, this study was designed to see if serum concentrations of alpha tocopherol, beta carotene, and retinol, substances believed to be involved in the prevention or repair of oxidative damage, might be lower among persons who develop rheumatoid arthritis or systemic lupus erythematosus than among those who do not. METHODS: For this prospective case-control study, persons with rheumatoid arthritis and systemic lupus erythematosus that developed two to 15 years after donating blood for a serum bank in 1974 were designated as cases. For each case, four controls were selected from the serum bank donors, matched for race, sex, and age. Stored serum samples from cases and controls were assayed for alpha tocopherol, beta carotene, and retinol. RESULTS: Cases of both diseases had lower serum concentrations of alpha tocopherol, beta carotene, and retinol in 1974 than their matched controls. For rheumatoid arthritis, the difference for beta carotene (-29%) was statistically significant. CONCLUSIONS: These findings support those of a previous study that low antioxidant status is a risk factor for rheumatoid arthritis. They suggest a similar association for systemic lupus erythematosus.

Methotrexate and misoprostol for early abortion: a multicenter trial. Acceptability.

A prospective trial was conducted including 300 pregnant women seeking elective abortion to evaluate the efficacy and acceptability of methotrexate and misoprostol for abortion at < or = 56 days gestation. Subjects received methotrexate 50 mg/m2 intramuscularly followed 7 days later by misoprostol 800 micrograms vaginally. The misoprostol dose was repeated the next day if the abortion did not occur. Efficacy is reported elsewhere. Subjects were questioned before the study as to their reasons for choosing a medical abortion and past experience with surgical abortion. After the study was completed, the women were questioned about their medical abortion experience. All questions were asked in an open-ended manner. Main outcome measures included reasons for abortion and study participation, attitudes about the nonsurgical abortion experience, and feelings about preference of nonsurgical or surgical abortion. The most common reason cited as to why women chose to have a nonsurgical abortion was to avoid some aspect of the surgery (48.4%). The percent of women who cited that avoiding surgery was an important reason in their choice of nonsurgical abortion varied by study site and according to whether the woman had a prior surgical abortion. Upon completion of the study, 73.4% of women stated it was a good experience, 19.5% a neutral experience, 7.1% a bad experience, and 1.0% gave no response. When asked what method they would choose if they had to have another abortion, 83.5% would choose this method of medical abortion rather than a surgical abortion. Intramuscular methotrexate and vaginal misoprostol are an acceptable and desirable method of abortion.

PIP: Researchers analyzed data on 61 women at San Francisco General Hospital in California, 51 women at Magee-Women's Hospital in Pittsburgh, Pennsylvania, and 47 women at Women's Health Care Services in Wichita, Kansas, to examine their acceptability of the methotrexate and misoprostol regimen for early abortion (56 or fewer days of gestation). The women had participated in a clinical trial of this regimen. They received intramuscular injection of 50 mg/sq. m methotrexate and then vaginal administration of 800 mcg misoprostol seven days later. If the abortion did not occur within 24 hours, they then received the another dose of misoprostol. 55.8% (159) women had had a prior surgical abortion. The leading reason for opting for a nonsurgical abortion was avoidance of some aspect of surgical abortion (59.6%). In Wichita, women who had not had a prior surgical abortion were more likely to want to avoid surgery than those who had had a prior surgical abortion (64.7% vs. 36.2%; p = 0.0011), suggesting that women in Wichita who had had a prior surgical abortion had a more positive experience with surgical abortion than those in other regions. Overall, avoidance of surgery as an important reason in their choice of nonsurgical abortion varied by study site and by the existence of past surgical abortion experience (p = 0.01). Only 7.1% of the women claimed the nonsurgical abortion was a bad experience. 73.4% considered it a good experience, 19.5% a neutral experience. Among the women considering the experience good, the leading reasons for finding it so were avoidance of surgical procedure (29.8%) and the fact that it was more natural than surgical abortion (18.9%). Among the 20 women considering the experience negative, the leading reasons for finding it so were severe pain or cramping (30%), the fact that it was emotionally hard (25%), and the fact that a surgical procedure was required (25%). 83.5% of the women would choose medical abortion again rather than a surgical abortion, if they had to terminate another pregnancy in the future. These findings suggest that this regimen for drug induced abortion is acceptable and desirable.

Influence of verbal ability on the expression of aggression in physically abused children.

The relationship between verbal ability and aggressive behavior in 53 physically abused children in a residential treatment center was examined. Characteristics differentiating aggressive children from their less aggressive peers were identified. Although general verbal ability was similar in aggressive and nonaggressive abused children, reading and expressive language deficits were more prevalent in the highly aggressive children. Highly aggressive children were significantly more deficient in reading ability and more often required speech-language services. Implications of these findings for treatment and future research are discussed.