Metabolic and cardiovascular effects of TX-001HR in menopausal women with vasomotor symptoms.

Objective: This study aimed to evaluate the effects of TX-001HR (17ß-estradiol [E2] and progesterone [P4] in a single oral capsule) on cardiometabolic markers and outcomes. Methods: Four E2/P4 doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) were compared with placebo in menopausal women with vasomotor symptoms (VMS) and a uterus in the phase 3 REPLENISH (ClinicalTrials.gov, NCT01942668) trial. Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months as well as cardiovascular events are summarized. Results: A total of 1835 participants took ≥1 capsule of daily E2/P4; 1684 received E2/P4 and 151 received placebo. No clinically significant changes in lipid parameters, coagulation factors, or glucose were observed between treatment groups. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1-4%, 6-11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). One episode of deep venous thrombosis and three cases of cardiovascular disease were observed, similar to expected rates of these events in the general population. Conclusions: In the REPLENISH trial, postmenopausal women with VMS treated with E2/P4 had no clinically meaningful effects on lipids, glucose, or coagulation parameters compared with placebo.

Vasomotor symptoms and the risk of incident venous thrombosis in postmenopausal women.

Essentials Vasomotor symptoms have been proposed as markers of changing cardiovascular risk. In this cohort study, we evaluated these symptoms as markers of venous thrombosis (VT) risk. We found no evidence that vasomotor symptom presence or severity were associated with VT risk. Among these postmenopausal women, vasomotor symptoms are not a useful marker of VT risk. SUMMARY: Background Vasomotor symptoms may be markers of changes in cardiovascular risk, but it is unknown whether these symptoms are associated with the risk of venous thrombosis (VT). Objective To evaluate the association of vasomotor symptom presence and severity with incident VT risk among postmenopausal women, independent of potential explanatory variables. Methods This cohort study included participants of the Women's Health Initiative (WHI) Hormone Therapy Trials (n = 24 508) and Observational Study (n = 87 783), analyzed separately. At baseline, women reported whether hot flashes or night sweats were present and, if so, their severity. Using Cox proportional hazards models, we estimated the VT risk associated with vasomotor symptom presence and severity, adjusted for potential explanatory variables: age, body mass index, smoking status, race/ethnicity, and time-varying current hormone therapy use. Results At baseline, WHI Hormone Therapy Trial participants were aged 64 years and WHI Observational Study participants were aged 63 years, on average. In the WHI Hormone Therapy Trials over a median of 8.2 years of follow-up, 522 women experienced a VT event. In the WHI Observational Study, over 7.9 years of follow-up, 1103 women experienced a VT event. In adjusted analyses, we found no evidence of an association between vasomotor symptom presence (hazard ratio [HR]adj  0.91, 95% confidence interval [CI] 0.75-1.1 in the WHI Hormone Therapy Trials; HRadj  1.1, 95% CI 0.99-1.3 in the WHI Observational Study) or severity (HRadj for severe versus mild 0.99, 95% CI 0.53-1.9 in the WHI Hormone Therapy Trials; HRadj  1.3, 95% CI 0.89-2.0) in the WHI Observational Study) and the risk of incident VT. Conclusions Although vasomotor symptoms have been associated with the risk of other cardiovascular events in published studies, our findings do not suggest that vasomotor symptoms constitute a marker of VT risk.

Balancing the efficacy and safety of misoprostol: a meta-analysis comparing 25 versus 50 micrograms of intravaginal misoprostol for the induction of labour.

BACKGROUND: The optimal dose of misoprostol for the induction of labour remains uncertain. OBJECTIVES: To compare the efficacy and safety of 25 versus 50 micrograms of intravaginal misoprostol tablets for the induction of labour and cervical ripening. SEARCH STRATEGY: We performed electronic and manual searches to identify relevant randomised trials. SELECTION CRITERIA: The efficacy outcomes assessed were rates of vaginal delivery within 24 hours, delivery within one dose, and oxytocin augmentation, and interval to delivery. The safety outcomes assessed were incidences of tachysystole, hyperstimulation, caesarean delivery, cesarean delivery for non-reassuring fetal heart rate (FHR), operative vaginal delivery, abnormal 5-minute Apgar score, abnormal cord gas values, admission to a neonatal intensive care unit (NICU), and meconium passage. DATA COLLECTION AND ANALYSIS: Thirteen studies (1945 women) were included. Relative risk (RR) and 95% confidence intervals (CI) were calculated using fixed-effects and random-effects models. MAIN RESULTS: We found that 25 micrograms was less efficacious, with lower rates of delivery after one dose (RR 0.59; 95% CI 0.39-0.88) and vaginal delivery within 24 hours (RR 0.88; 95% CI 0.79-0.96), and with increased rates of oxytocin augmentation (RR 1.54, 95% CI 1.36-1.75). We noted an improved safety profile with 25 micrograms, however, with decreased rates of tachysystole (RR 0.46; 95% CI 0.35-0.61), hyperstimulation (RR 0.5; 95% CI 0.31-0.78), caesarean deliveries for non-reassuring FHR (RR 0.67; 95% CI 0.52-0.87), NICU admissions (RR 0.63; 95% CI 0.4-0.98), and meconium passage (RR 0.65; 95% CI 0.45-0.96). CONCLUSIONS: Although 50 micrograms of intravaginal misoprostol may be more efficacious, safety concerns make the 25-microgram dose preferable.

Management of pain associated with the insertion of intrauterine contraceptives.

BACKGROUND: Most intrauterine contraception (IUC) placements do not require pain relief. However, small proportions of nulliparous (∼17%) and parous (∼11%) women experience substantial pain that needs to be proactively managed. This review critically evaluates the evidence for pain management strategies, formulates evidence-based recommendations and identifies data gaps and areas for further research. METHODS: A PubMed literature search was undertaken. Relevant articles on management of pain associated with IUC insertion, published in English between 1980 and November 2012, were identified using the following search terms: 'intrauterine contraception', 'insertion' and 'pain'. RCTs were included; further relevant articles were also identified and included as appropriate. RESULTS: Seventeen studies were identified and included: 12 RCTs and one non-randomized study of pre-insertion oral analgesia, cervical priming and local anaesthesia; one systematic review and one RCT on post-insertion analgesia and two non-randomized studies on non-pharmacological interventions. There was no conclusive evidence that any prophylactic pharmacological intervention reduces pain associated with IUC insertion. However, most of the regimens studied were adopted from hysteroscopy or abortion and effectiveness in specific subsets of women has not been studied adequately. A systematic review found non-steroidal anti-inflammatory agents (NSAID) to be effective in reactively treating post-insertion pain, but no benefit was found with prophylactic use. CONCLUSIONS: No prophylactic pharmacological intervention has been adequately evaluated to support routine use for pain reduction during or after IUC insertion. Women's anxiety about the procedure may contribute to higher levels of perceived pain, which highlights the importance of counselling, and creating a trustworthy, unhurried and professional atmosphere in which the experience of the provider also has a major role; a situation frequently referred to as 'verbal anaesthesia'.

Contraceptive efficacy and safety of DMPA-SC.

DMPA-SC 104 mg/0.65 mL is a new, low-dose subcutaneous (SC) formulation of Depo-Provera contraceptive injection (150 mg/mL medroxyprogesterone acetate injectable suspension) that provides efficacy, safety and immediacy of onset equivalent to Depo-Provera intramuscular (IM) injection. Two large, open-label, Phase 3 studies assessed the 1-year contraceptive efficacy, safety and patient satisfaction with DMPA-SC administered every 3 months (12-13 weeks). Zero pregnancies were reported in both studies, which included a total of 16,023 woman-cycles of exposure to DMPA-SC and substantial numbers of overweight or obese women. DMPA-SC was well-tolerated and adverse events were similar to those reported previously with Depo-Provera IM. Thus, DMPA-SC offers women a new, highly effective and convenient long-acting contraceptive option.

Human chorionic gonadotropin in cervicovaginal secretions as a predictor of preterm delivery.

OBJECTIVES: To determine whether human chorionic gonadotropin (hCG) detected in cervicovaginal secretions of patients with symptoms suggestive of preterm labor is a predictor of preterm birth. METHODS: Women presenting to labor and delivery with symptoms of preterm labor were invited to participate. After collecting secretions with a cotton-tipped applicator from the posterior fornix and endocervical canal, we placed the swab in a test tube containing 1 ml of normal saline. From this solution, we performed qualitative and quantitative hCG measurements. Qualitative and quantitative hCG results from women who delivered at term were compared with those delivering prior to 37 weeks' gestation. RESULTS: Samples were obtained and analyzed from 86 women at a mean (+/- standard deviation) gestational age of 30.7+/-2.9 weeks. Of the 86 subjects enrolled, 28 (32.6%) delivered preterm. A positive rapid qualitative assay from cervicovaginal secretions between 24 and 34 weeks' gestation was associated with a significant increase in the incidence of preterm delivery (relative risk 2.62, 95% confidence interval (CI) 1.38, 4.98). The likelihood ratios for a positive and negative test were 2.19 (95% CI 1.35, 3.56) and 0.51 (95% CI 0.30, 0.85) respectively. Using a cut-off of 19 mIU/ml, similar diagnostic accuracy for predicting preterm birth was obtained with the quantitative test 1.93 (95% CI 1.14, 3.26) and 0.62 (95% CI 0.40, 0.98). CONCLUSIONS: Qualitative and quantitative hCG measurements from cervicovaginal secretions may be useful predictors of preterm birth in symptomatic patients. The qualitative hCG test can be used at the bedside with results obtained in minutes.

Misoprostol use during the third stage of labor.

OBJECTIVES: To systematically review the efficacy of misoprostol compared with placebo or other uterotonics in preventing maternal morbidity associated with the third stage of labor. METHODS: We identified, retrieved, evaluated, abstracted data, and assessed the quality of all published studies (from January 1996 to May 2002) which assessed misoprostol's efficacy in minimizing uterine blood loss during the third stage of labor. Seventeen studies included 28170 subjects; of these, approximately one-half received misoprostol with the remainder receiving either a placebo or another uterotonic agent. An estimate of the odds ratio (OR) and risk difference for dichotomous outcomes was calculated using a random- and fixed-effects model. Continuous outcomes were pooled using a variance-weighted average of within-study difference in means. RESULTS: In assessing studies comparing misoprostol with placebo, those who received oral misoprostol had a decreased risk of needing additional uterotonics (OR 0.64, 95% confidence interval 0.46, 0.90). Compared with placebo, use of misoprostol was associated with an increased risk for shivering and pyrexia. In contrast, in studies comparing misoprostol with oxytocin, oxytocin was associated with significantly lower rates of postpartum hemorrhage, maternal shivering and pyrexia. In studies comparing misoprostol with Syntometrine, misoprostol was associated with higher rates of the need for additional uterotonic agent as well as shivering. CONCLUSIONS: Misoprostol was inferior to oxytocin and other uterotonics with regard to any of the third stage of labor outcomes assessed. However, when compared to placebo, misoprostol had a decreased risk of needing additional uterotonics. Thus, in less-developed countries where administration of parenteral uterotonic drugs may be problematic, misoprostol represents a reasonable agent for the management of the third stage of labor. Additional randomized clinical trials examining objective outcome measures (i.e. need for blood transfusion or 10% hemoglobin change) may further define benefits and risks of misoprostol use during the third stage of labor.

Current options for injectable contraception in the United States.

Two injectable forms of hormonal contraception, depot medroxyprogesterone acetate (DMPA, Depo-Provera) and medroxyprogesterone acetate/estradiol cypionate (MPA/E(2)C, Lunelle), are now available to American women. Both formulations have demonstrated high degrees of efficacy, safety, and ease of use in international and U.S. trials. Data on DMPA have shown a number of noncontraceptive and therapeutic benefits, the most prominent of which is an 80% reduction in the risk of endometrial cancer. Although such benefits are less documented for MPA/E(2)C, they are expected to be similar to those seen with DMPA and oral contraceptives. Minor side effects of both formulations include menstrual irregularities in the early months of treatment and amenorrhea with DMPA. Patient counseling about the potential for these side effects, as well as possible risks, is important to long-term successful use of these contraceptive methods.

Adjunctive intravaginal metronidazole for the prevention of postcesarean endometritis: a randomized controlled trial.

OBJECTIVE: To estimate the efficacy of preoperative administration of intravaginal metronidazole for the prevention of postcesarean endometritis. METHODS: This double-masked, placebo-controlled randomized trial included patients of at least 24 weeks' gestation undergoing cesarean deliveries for various indications. Patients were randomized to receive either 5 g of metronidazole gel intravaginally or matching placebo before the initiation of the cesarean. All patients underwent surgical cleansing of the abdomen, and most received prophylactic antibiotics after cord clamping. Patients with chorioamnionitis and/or suspected allergy to metronidazole were excluded. For a two-sided alpha of 0.05 and beta of 0.20 (80% power), 120 subjects were required in each group. The main outcome variable was the incidence of postcesarean endometritis. Secondary outcome variables included presence of febrile morbidity, wound infection, days on antibiotics, and length of postpartum hospitalization. Neonatal outcomes included birth weight, Apgar scores less than 7 at 5 minutes, umbilical arterial pH less than 7.16, admission and length of stay in the neonatal intensive care unit, and length of hospital stay. RESULTS: Of 112 patients receiving metronidazole, eight (7%) developed postcesarean endometritis, compared with 19 of 112 (17%) of those receiving placebo gel (relative risk 0.42, 95% confidence interval 0.19, 0.92). No significant differences were noted between treatment groups with respect to the other outcome variables. CONCLUSION: The preoperative administration of 5 g of intravaginal metronidazole gel appears to reduce the incidence of postcesarean endometritis.

Lunelle monthly injectable contraceptive. An effective, safe, and convenient new birth control option.

Lunelle, an injectable estrogen/progestin contraceptive, is administered on a monthly basis and is now available as the first monthly injectable in the United States. International and US clinical trials have established its safety and confirmed its contraceptive efficacy. Fertility returns rapidly after discontinuation of injections. Studies have noted a high level of patient satisfaction with Lunelle, suggesting that monthly injectable contraception will become a first-line contraceptive option in the United States.

Oral contraceptive use in perimenopause.

Perimenopause represents a transition period lasting about 5 years before the permanent cessation of spontaneous menses. During this transition, the emphasis of clinical care changes. Although women still need effective contraception during perimenopause, issues including loss of bone mineral density, menstrual cycle changes, and vasomotor instability also need to be addressed. Hormone replacement therapy is not the first-line treatment for women with symptomatic perimenopause because hormone replacement therapy neither suppresses ovulation nor provides contraception; also, it will not prevent and in fact may aggravate unpredictable perimenopausal bleeding. Oral contraceptives offer many benefits for healthy, nonsmoking, perimenopausal women. Oral contraceptive use by women in their 40s has been found to decrease the risk of postmenopausal hip fractures and regularize menses in women with dysfunctional uterine bleeding, reducing the need for surgical intervention for benign menstrual conditions. Use of oral contraceptives also can reduce long-term risk of endometrial and ovarian cancers. There is also good evidence that oral contraceptives relieve vasomotor symptoms in perimenopausal women. Oral contraceptives can be viewed as a strategy not only to improve perimenopausal symptoms, provide effective contraception, and reduce some long-term health risks, but also to enhance the quality of life for perimenopausal women.

The hormone continuum: accrual of women's health benefits.

The hormone continuum is a treatment strategy that advocates maintaining hormone continuity, from the reproductive years into menopause and beyond. This entails the use first of oral contraceptives (OCs), which confer well-known health benefits--especially reductions in ovarian and endometrial cancers--besides effective contraception, and later, hormone replacement therapy (HRT), which provides relief of perimenopausal and menopausal symptoms and protects older women from (a) decreasing bone mineral density; (b) cardiovascular disease, according to several studies; and (c) Alzheimer's disease, as suggested by a number of studies. In perimenopause, use of OCs declines by about one-half, and then by a further four-fifths up to menopause. This is unfortunate, because in these later reproductive years women are subject to unintended pregnancy, which in 65% of cases is terminated by abortion. Furthermore, women are thereby deprived also of alleviation of dysmenorrhea and even vasomotor symptoms that often characterize the perimenopause. After menopause is well established, a "seamless" transition to HRT can be made, often with the same progestin that was contained in the OC. This paper discusses risks as well as benefits of hormone therapy, especially of HRT, with an emphasis on patient counseling and individualizing of therapy.

Route of breech delivery and maternal and neonatal outcomes.

OBJECTIVE: To compare maternal and neonatal outcomes in elective cesarean vs. attempted vaginal delivery for breech presentation at or near term. METHODS: We reviewed the maternal and neonatal charts of all singleton breech deliveries of at least 35 weeks' gestation or 2000 g delivered between 1986 and 1997 at our institution. Patients delivered by elective cesarean were compared to those attempting a vaginal delivery. The neonatal outcomes analyzed were: corrected mortality; Apgar scores less than 7 at 5 min; abnormal umbilical cord blood gases; birth trauma; and admissions to the intensive care nursery. Maternal morbidity was also assessed and compared. RESULTS: Of 848 women meeting criteria for evaluation, 576 were delivered by elective cesarean while 272 attempted a vaginal delivery. Of 272 women undergoing a trial of labor, 203 (74.6%) were delivered vaginally, while 69 (25.4%) failed an attempt at vaginal delivery and underwent a cesarean. When comparing patients delivered by elective cesarean with those attempting a vaginal delivery, no significant differences were noted in neonatal outcomes. However, maternal morbidity was higher among women delivered by cesarean, regardless of the indications for the procedure. Similar neonatal and maternal results were noted when nulliparous patients were analyzed separately. CONCLUSIONS: Cesarean delivery of selected near-term infants presenting as breech is associated with increased maternal morbidity without corresponding improvement in neonatal outcomes.

Prophylactic amnioinfusion for intrapartum oligohydramnios: a meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the effectiveness of intrapartum prophylactic amnioinfusion in pregnancies complicated by oligohydramnios. DATA SOURCES: Randomized controlled trials of prophylactic amnioinfusion in women with oligohydramnios were identified using computerized databases, index reviews, and references cited in original studies and review articles. METHODS OF STUDY SELECTION: We evaluated, abstracted data from, and analyzed randomized studies of prophylactic intrapartum amnioinfusion in women with oligohydramnios. In every study the group allocation was based exclusively on presence of oligohydramnios. Only published studies with clearly documented outcome data were included. The quality of each trial was evaluated for methodology, inclusion and exclusion criteria, adequacy of randomization, amnioinfusion protocols, definition of outcomes, and statistical analyses. The trials were evaluated concerning cesarean deliveries for fetal heart rate (FHR) abnormalities, overall cesarean rates, acidemia at birth, intrapartum fetal heart rate abnormalities, Apgar scores under 7 at 5 minutes, and postpartum endometritis. TABULATION, INTEGRATION, AND RESULTS: Thirty-five studies were identified, of which 14 met the inclusion criteria for this systematic review. They included 1533 patients, 793 in the amnioinfusion group, and 740 controls. Odds ratios (OR) with their 95% confidence intervals (CI) for each outcome were calculated. We calculated an estimate of the OR and risk difference for dichotomous outcomes using random and fixed-effects models. A test of homogeneity was done across studies. Women with oligohydramnios who received intrapartum amnioinfusion had lower incidence of cesarean for FHR abnormalities (OR 0.23; 95% CI 0.15, 0.35). Intrapartum amnioinfusion also was associated with lower overall rates of cesarean deliveries (OR 0.52; 95% CI 0.40, 0. 68), acidemia at birth (OR 0.40; 95% CI 0.30, 0.55), FHR abnormalities during labor (OR 0.24; 95% CI 0.17, 0.34), and Apgar scores under 7 at 5 minutes (OR 0.52; 95% CI 0.29, 0.91). Postpartum endometritis rates were similar among the study groups. CONCLUSION: In the presence of oligohydramnios, prophylactic intrapartum amnioinfusion significantly improves neonatal outcome and lessens the rate of cesarean delivery, without increasing the rate of postpartum endometritis.

Injectable contraception. New and existing options.

DMPA and MPA/E2C contraception offer women safe, effective, convenient, and reversible birth control choices. The use of DMPA, a 3-month injectable, is characteristically associated with amenorrhea. Lactating women and women in whom contraceptive doses of estrogen are contraindicated can use this progestin-only birth control method. Return of fertility can be delayed in women discontinuing DMPA to become pregnant. In some cases, the use of DMPA also confers important noncontraceptive and therapeutic benefits. A monthly estrogen/progestin injectable contraceptive, MPA/E2C should appeal to women who are concerned about daily pill taking, who prefer regular cycles to amenorrhea, and who find monthly injections acceptable and accessible. As is true for oral contraceptives, MPA/E2C represents an appropriate choice for women who prefer a rapidly reversible contraceptive. Currently, the proposed contraindications for MPA/E2C parallel those for combined oral contraceptives. As MPA/E2C contraception becomes available for American women, clinicians will learn how to best include this new method among the array of contraceptive choices. By individualizing contraceptive selection, counseling, and management approaches based on the relevant behavioral and medical considerations reviewed herein, clinicians can maximize their patients' success with injectable contraceptives. The more innovative that clinicians, family planning agencies, and insurers are in facilitating access to care (including reinjections), the more women will be able to avail themselves of safe, effective, and reversible methods of contraception. In addition to the physician's office or health clinic, other sites at which women might receive contraceptive injections include employee health clinics, college health clinics, or perhaps the pharmacy where the prescription is filled. Self-administration may become an appropriate option for some users of injectable contraception.

Efficacy, cycle control, and safety of two triphasic oral contraceptives: Cyclessa (desogestrel/ethinyl estradiol) and ortho-Novum 7/7/7 (norethindrone/ethinyl estradiol): a randomized clinical trial.

The contraceptive efficacy, cycle control, and safety of a new low-dose, triphasic desogestrel/ethinyl estradiol oral contraceptive (CTR 77, Cyclessa(TM)) was compared to that of a marketed, triphasic norethindrone/ethinyl estradiol oral contraceptive (Ortho-Novum(R) 7/7/7). Two identical multicenter, open-label, randomized, parallel group, comparative Phase III 6-cycle trials were designed to each enroll 4200 healthy women. The combined comparative data for Cyclessa versus Ortho-Novum 7/7/7 for both studies are reported here. Cyclessa and Ortho-Novum 7/7/7 had comparable contraceptive efficacy. Despite a lower ethinyl estradiol dose (25 microg/day vs. 35 microg/day), the Cyclessa group had significantly improved cycle control in comparison to the Ortho-Novum 7/7/7 group for presence of a withdrawal bleed (p = 0.001), lack of early withdrawal bleed (p = 0.01), and breakthrough bleeding/spotting (p = 0.001). For each of the months of the study, the incidence of breakthrough bleeding/spotting was lower in the Cyclessa group than the Ortho-Novum 7/7/7 group (breakthrough bleeding, p = 0.006; breakthrough spotting, p = 0.001). The incidence of other adverse events was similar among treatment groups, an observation that supports the safety of both formulations. There was significantly less weight gain (p = 0.0002) and less increase in the body mass index (BMI) (p = 0.0002) in the Cyclessa group. The contraceptive efficacy and safety of Cyclessa is comparable to Ortho-Novum 7/7/7. Cyclessa provides significantly improved cycle control with no weight gain.