Intra-fetal Compared With Intra-amniotic Digoxin Before Dilation and Evacuation: A Randomized Controlled Trial.

OBJECTIVE: To compare the effectiveness of 1.0 mg intra-fetal or intra-amniotic digoxin to achieve fetal asystole before second-trimester surgical pregnancy termination. METHODS: In a randomized trial, women received 1.0 mg transabdominal intra-fetal or intra-amniotic digoxin on the day of laminaria placement before dilation and evacuation between 20 and 24 weeks of gestation. The primary outcome was incidence of fetal asystole, documented immediately before dilation and evacuation. We planned to analyze the primary outcome by original group assignment as well as by as-treated and per-protocol populations. A sample size of 270 was needed to detect an 8% difference in failure rates between groups. Prespecified secondary outcomes included the incidence of adverse events, side effects, and procedural differences. RESULTS: Between January 2012 and January 2013, we screened 381 women and randomized 270 women to receive intra-fetal (n=136) or intra-amniotic (n=134) digoxin. Characteristics were similar across groups; the mean gestational age was 21.6 weeks (standard deviation 1.2). The proportion of fetal asystole was higher in the intra-fetal group (128/135 [94.8%]) than the intra-amniotic group (107/130, 82.3%; relative risk of failure to achieve asystole 3.41, 95% confidence interval 1.52-7.68). Results were similar in the as-treated and per-protocol populations. There were no significant differences in adverse events or side effects and no differences in injection duration, operative time, or estimated blood loss. CONCLUSION: Administration of intra-fetal injection of digoxin led to a higher proportion of participants achieving fetal asystole within 24 hours than intra-amniotic injection. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01047748.

EC4U: results from a pilot project integrating the copper IUC into emergency contraceptive care.

OBJECTIVE: The copper intrauterine contraceptive (IUC) is the most effective method of emergency contraception (EC), yet it is underutilized. The objective was to evaluate a pilot project integrating the copper IUC into EC care. STUDY DESIGN: Single-group evaluation study. Nine geographically diverse reproductive health centers implemented 6-month pilot interventions. All interventions included staff education and inclusion of the IUC in EC patient counseling; some sites developed patient education materials. Health center staff completed manual monthly tracking forms of the number of EC patients receiving oral levonorgestrel, ulipristal acetate or the copper IUC. Sites also tracked and reported the number of patients returning for removal during the 6-month pilot period and for 5 subsequent months. Main study outcomes included the number of IUC for EC insertions, the proportion that were same-day insertions and the proportion of patients receiving each EC type during the pilot period. A secondary outcome was the number of patients who had returned for removal at 5 months postpilot. RESULTS: There were 101 IUC insertions for EC during the pilot period. Seventy-seven percent were same-day insertions; the remainder returned for insertion within 5 days of unprotected intercourse. The percentage of EC patients choosing the IUC varied by site from 1 to 16% (overall=7%). At 5 months postpilot, 20 patients (20%) had returned for removal. CONCLUSIONS: Some women will be interested in the copper IUC for EC, and therefore, all women should be offered this option. Results suggest that the large majority continued to use the IUC for ongoing contraception. IMPLICATIONS: Copper IUCs are a viable option for women in need of EC. All women should be offered the most effective EC option.

Efficacy and safety of medical abortion using mifepristone and buccal misoprostol through 63 days.

OBJECTIVE: The aim of this study was to report on the safety and efficacy of an evidence-based medical abortion regimen utilizing 200 mg of mifepristone orally followed by home use of 800 mcg misoprostol buccally 24-48 h later through 63 days estimated gestational age. STUDY DESIGN: We analyzed outcomes in women presenting for medical abortion between April 1, 2006, and May 31, 2011, using an evidence-based alternative to the United States Food and Drug Administration (FDA)-approved regimen. Cases were identified for this descriptive study from our electronic practice management (EPM) database, and our electronic database on adverse events was queried for information on efficacy and safety. The primary outcome was successful abortion. Logistic regression was used to identify predictors of successful abortion. RESULTS: Among the 13,373 women who completed follow-up, efficacy of the regimen was 97.7%. Efficacy was highest at 29 to 35 days (98.8%) and 36 to 42 days (98.8%) of gestation and lowest at 57 to 63 days (95.5%). The odds of needing aspiration for any reason were greatest at higher gestational ages. Rates of infection requiring hospitalization and rates of transfusion were 0.01 and 0.03%, respectively. CONCLUSIONS: An evidence-based regimen of 200 mg of mifepristone orally followed by home use of 800 mcg of buccal misoprostol 24-48 h later is safe and effective through 63 days estimated gestational age. Further, the need for aspiration for any reason was low, and hospitalization was rare. IMPLICATIONS: This study reinforces the safety and efficacy of the evidence-based regimen for medical abortion (200 mg mifepristone orally followed by home use of 800 mcg of misoprostol buccally 24-48 h later) through 63 days estimated gestational age, and contributes to the existing evidence against restrictions requiring use of the FDA-approved regimen.

The combined etonogestrel/ethinyl estradiol contraceptive vaginal ring.

Many factors influence the effectiveness of contraceptive methods. Oral contraceptives are the second most popular contraceptive method after female sterilization in the US. A total of 25% of women do not use their oral contraceptives correctly; 30% of women do not use them consistently. Several new contraceptive methods with alternate routes of delivery and less frequent dosing are available. The combined etonogestrel/ethinyl estradiol contraceptive vaginal ring is marketed under the name of NuvaRing. This is the only contraceptive ring approved by the FDA. The administration of steroids by the vaginal route may offer many advantages. Because of less frequent dosing, self-administration, and possibly, an improved side effect profile, the ring has the potential to increase successful use.

Nonoxynol-9 induces apoptosis of endometrial explants by both caspase-dependent and -independent apoptotic pathways.

Contraceptive microbicides formulated as vaginal gels offer the possibility of women-controlled contraception and prevention of HIV infection. The effects of these gels on the upper reproductive tract are largely unknown. The purpose of this study was to determine whether nonoxynol-9 (N-9) induces apoptosis in human endometrium using endometrial explant as a model. Apoptosis was determined by gel electrophoresis for the detection of DNA fragmentation and by immunohistochemistry using the M30 CytoDEATH and anti-cleaved caspase-3 (CASP3) antibodies for the detection of caspase activity. The ability of the broad-spectrum caspase inhibitor and CASP3-specific inhibitor to prevent N-9-induced cell death was measured. Expression of apoptosis-related genes such as BCL2, BAX, Fas receptor (FAS), and Fas ligand (FASLG) was quantified using real-time polymerase chain reaction (PCR) analysis. This study demonstrated that N-9 induced DNA fragmentation and caspase activity in endometrial explants in a dose- and time-dependent manner. Caspase inhibitors did not fully prevent the N-9-induced DNA fragmentation. Real-time PCR analysis revealed that FAS and FASLG were largely increased following N-9 treatment. Together, these results suggested that apoptosis triggered by N-9 in endometrial explants is mediated upstream via FAS and FASLG, followed by CASP3 activation leading to final cell death. It appears that other factors besides caspases are also involved in the N-9-induced apoptosis.

The effect of nonoxynol-9 on human endometrium.

Contraceptive microbicides formulated as vaginal gels offer the possibility of women-controlled contraception and prevention of HIV infection. However, the effects of these gels on the upper reproductive tract is largely unknown. The purpose of this study was to determine the effects of nonoxynol-9 (N-9) on human endometrium. Human endometrial biopsies were cultured and incubated with various dosages of N-9 for 6 or 24 h. Endometrial histology was assessed by light microscopy using hematoxylin and eosin. Inflammatory response was determined by analyzing proinflammatory cytokines with enzyme-linked immunosorbent assay. Endometrial mucin was assessed by immunohistochemistry and real-time polymerase chain reaction. Histological changes consistent with focal coagulative necrosis were seen after 6 and 24 h of culture. All cytokines (interleukin 1beta, tumor necrosis factor alpha and interleukin 8) decreased at all concentrations of N-9 after 24 h of incubation. The expression of Mucin1 (MUC-1) was inhibited in a dose-dependent manner at both the protein and messenger RNA levels. These results demonstrate for the first time that N-9 has multiple, potential deleterious effects on the human endometrium characterized by necrosis, alteration of proinflammatory cytokines and inhibition of MUC-1 expression. Taken together, these in vitro findings suggest that N-9 can interrupt the functional barrier provided by the endometrium and, thus, facilitate infection with HIV and other pathogens.

Mifepristone for the prevention of breakthrough bleeding in new starters of depo-medroxyprogesterone acetate.

Depo-medroxyprogesterone acetate (DMPA) is an effective injectable contraceptive with worldwide availability. However, it is associated with a high incidence of breakthrough bleeding (BTB) during the first 6 months of use which often leads to discontinuation. Mifepristone is a progesterone receptor antagonist that has been demonstrated to decrease BTB caused by the levonorgestrel subdermal implant (Norplant). The purpose of this study was to determine if mifepristone would decrease BTB in new starters of DMPA. Twenty regularly cycling women who were new starters of DMPA were randomized to receive 50 mg of mifepristone or placebo every 2 weeks for 24 weeks. Percent days of BTB and number of cycles with bleeding intervals > or =8 and > or =14 days were evaluated using daily bleeding diaries. Ovulation was determined by measuring thrice-weekly urinary metabolites of estrogen and progesterone. Endometrial concentrations of ER and PR were determined by immunohistochemistry. Mifepristone significantly decreased the percent days of BTB and the number of cycles with prolonged bleeding intervals when compared to placebo. No subject ovulated in either group. ER immunostaining increased and PR immunostaining decreased after mifepristone treatment. In conclusion, a 50 mg dose of mifepristone taken every 2 weeks decreases the incidence of BTB in new starters of DMPA. This effect may be due to modulation of endometrial estrogen and progesterone receptors.