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.

Reduction in infection-related mortality since modifications in the regimen of medical abortion.

BACKGROUND: From 2001 to March 2006 Planned Parenthood health centers throughout the United States provided medical abortion by a regimen of oral mifepristone followed 24-48 h later by vaginal misoprostol. In response to concerns about serious infections, in early 2006 Planned Parenthood changed the route of misoprostol administration to buccal and required either routine antibiotic coverage or universal screening and treatment for chlamydia; in July 2007, Planned Parenthood began requiring routine antibiotic coverage for all medical abortions. METHODS: We performed a retrospective analysis of Planned Parenthood cases assessing the rates of mortality caused by infection following medical abortion during a time period when misoprostol was administered vaginally (2001 through March 2006), as compared with the rate from April 2006 to the end of 2012 after a change to buccal administration of misoprostol and after initiation of new infection-reduction strategies. RESULTS: The mortality rate dropped significantly in the 81-month period after the joint change to (1) buccal misoprostol replacing vaginal misoprostol and (2) either sexually transmitted infection (STI) screening or routine preventative antibiotic coverage (15 month period) or universal routine preventative antibiotic coverage as part of the medical abortion (66-month period), from 1.37/100,000 to 0.00/100,000, P=.013 (difference=1.37/100,000, 95% CI 0.47-4.03 per 100,000). CONCLUSION: The infection-caused mortality rate following medical abortion declined by 100% following a change from vaginal to buccal administration of misoprostol combined with screen-and-treat or, far more commonly, routine antibiotic coverage. SIGNIFICANCE: Deaths from infection following medical abortion declined to zero after a change in the regimen.

Significant adverse events and outcomes after medical abortion.

OBJECTIVE: To analyze rates of significant adverse events and outcomes in women having a medical abortion at Planned Parenthood health centers in 2009 and 2010 and to identify changes in the rates of adverse events and outcomes between the 2 years. METHODS: In this database review we analyzed data from Planned Parenthood affiliates that provided medical abortion in 2009 and 2010 almost exclusively using an evidence-based buccal misoprostol regimen. We evaluated the incidence of six clinically significant adverse events (hospital admission, blood transfusion, emergency department treatment, intravenous antibiotics administration, infection, and death) and two significant outcomes (ongoing pregnancy and ectopic pregnancy diagnosed after medical abortion treatment was initiated). We calculated an overall rate as well as rates for each event and identified changes between the 2 years. RESULTS: Among 233,805 medical abortions provided in 2009 and 2010, significant adverse events or outcomes were reported in 1,530 cases (0.65%). There was no statistically significant difference in overall rates between years. The most common significant outcome was ongoing intrauterine pregnancy (0.50%); significant adverse events occurred in 0.16% of cases. One patient death occurred as a result of an undiagnosed ectopic pregnancy. Only rates for emergency department treatment and blood transfusion differed by year and were slightly higher in 2010. CONCLUSION: Review of this large data set reinforces the safety of the evidence-based medical abortion regimen. LEVEL OF EVIDENCE: III.

Eliminating the routine postoperative surgical abortion visit.

BACKGROUND: The objective of this study was to determine whether replacing the "routine" postoperative visit after surgical abortion with an "as indicated" visit is associated with an increase in the rates of either failed abortion (continuing pregnancy) or repeat abortion. METHODS: We compared the rate of continuing pregnancy in 50,702 first-trimester surgical abortion patients who were offered routine postoperative visits in one time period (1/1/00-4/30/07) to the rate in 20,315 first-trimester surgical abortion patients from a later time period (5/1/07-12/31/09) in which routine postoperative visits had been discontinued. We also compared the rate of repeat abortion within 1 year of the initial procedure for both first- and second-trimester surgical abortion patients for the same time periods. RESULTS: The rate of continuing pregnancy remained stable before and after routine visits were discontinued (39.4 per 100,000 first-trimester surgical abortions for each group).The rate of repeat abortion within 1 year after the initial procedure was lower after routine visits were discontinued (8.2%) than before routine visits were discontinued (8.7%), p=.007. CONCLUSION: We conclude that elimination of the routine postoperative visit after a surgical abortion and the substitution of an "as indicated" postoperative visit are not associated with an increase in either continuing pregnancies or repeat abortion.

Infection and extramural delivery with use of digoxin as a feticidal agent.

BACKGROUND: Many abortion providers use digoxin to induce fetal demise prior to dilation and evacuation (D&E). Our primary objective was to examine the frequency of infection and extramural delivery following digoxin use. STUDY DESIGN: We conducted a retrospective single-cohort study. Inclusion criteria were all women between 18 and 24 weeks of estimated gestational age who received digoxin in preparation for D&E at our outpatient facility. We queried two electronic databases to collect data on the frequency of extramural delivery and the rate of perioperative infection. RESULTS: From January 1, 2000, to December 31, 2008, 4906 abortions were performed between 18 and 24 weeks of estimated gestation with digoxin injection administered as feticidal agent 1 day prior to D&E. Extramural delivery frequency was 0.30%, and infection frequency was 0.04%. There were no significant differences in the frequency of extramural deliveries across procedure year (p = .2), estimated gestational age (p = .3), race/ethnicity (p = .2) or maternal age (p = .3). CONCLUSION: Rates of extramural delivery and infection are acceptably low following digoxin use prior to scheduled D&E.

A randomized pilot study on the effectiveness and side-effect profiles of two doses of digoxin as fetocide when administered intraamniotically or intrafetally prior to second-trimester surgical abortion.

BACKGROUND: Digoxin is commonly used to facilitate second-trimester surgical abortion despite limited data regarding its safety and effectiveness for this indication. We conducted a pilot study to determine the incidence of side effects after digoxin administration and whether effectiveness can be improved with variations in dose and technique. STUDY DESIGN: Fifty-two women presenting for elective termination of pregnancy between 18 and 24 weeks' gestation were randomized to one of four digoxin treatment groups: 1.0 mg intraamniotic (1.0 IA), 1.0 mg intrafetal (1.0 IF), 1.5 mg intraamniotic (1.5 IA) or 1.5 mg intrafetal (1.5 IF). Ultrasound was used to assess for the presence of fetal cardiac activity prior to the abortion procedure. Data on the presence and severity of pain, nausea and other potential side effects were collected before digoxin injection, immediately following digoxin injection and on the day after digoxin injection. RESULTS: Digoxin effectively induced fetal death in 87% of women. The failure rate did not vary by route of administration (IA or IF) and was not lowered by increasing the dose from 1.0 to 1.5 mg. IF injections induced fetal death more rapidly than IA injections. Digoxin administration did not result in increased pain or nausea. CONCLUSIONS: IA or IF injection of digoxin is safe and effective for inducing fetal death prior to second-trimester surgical abortion. Doses greater than 1.0 mg may not be necessary.

Serious adverse events associated with the use of misoprostol alone for cervical preparation prior to early second trimester surgical abortion (12-16 weeks).

BACKGROUND: The purpose of this study was to determine the rate of serious adverse events (SAEs) occurring during early second trimester surgical abortion performed following the use of misoprostol alone for cervical preparation. STUDY DESIGN: A retrospective review was undertaken of 6620 elective surgical abortions performed between 12 and 16 weeks estimated gestational age during a 68-month period following cervical preparation with misoprostol alone. Information was obtained from a computer-based practice management system. RESULTS: During the study period, four SAEs occurred: three uterine perforations and one case of hemorrhage secondary to placenta accreta. The perforation rate was 0.45 (95% CI=0.09-1.32) per 1000 abortions. CONCLUSION: This review of our experience with surgical abortion performed from 12 to 16 weeks estimated gestational age following cervical preparation with misoprostol alone shows that the rate of SAEs, specifically uterine perforation, in this group was no greater than that previously reported in the literature.

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.

Women's and providers' attitudes toward menstrual suppression with extended use of oral contraceptives.

The United States Food and Drug Administration approved a dedicated extended regimen of oral contraceptive (OC) pill in the fall of 2003. Few studies have explored how women or providers feel about menstrual suppression. This study describes women's and providers' attitudes toward menstrual suppression. A national sample of 1470 women and 512 providers responded to surveys asking about attitudes toward menstrual suppression. Seventy-eight percent of the women sample had never heard of menstrual suppression with OCs. Fifty-nine percent of women would be interested in not menstruating every month and one third would choose never to have a period. Only 7% of the providers thought it was physically necessary to have a period every month and 44% thought that menstrual suppression is a good idea. While 57% of providers said that their patients do not ask about extended use of OCs, 52% do prescribe them; patient request was the most common reason. Both samples thought that more research should be conducted and that the factors that would influence their decisions included long-term health effects, side effects, future fertility and cost. Results demonstrate that providers need to discuss this option with their patients.

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.